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PubMed2004

High-dose intravenous proton pump inhibition following endoscopic therapy in the acute management of patients with bleeding peptic ulcers in the USA and Canada: a cost-effectiveness analysis.

BACKGROUND: The efficacy of high-dose intravenous proton pump inhibition has recently been shown, yet its cost-effectiveness remains poorly studied. AIM: To assess the cost-effectiveness of this approach separately for American and Canadian health care settings. METHODS: A validated decision model included patients with bleeding ulcers after successful endoscopic haemostasis. Probabilities were determined from the literature, and charges and lengths of stay from national databases. A third-party payer perspective was adopted over a 30-day time horizon. RESULTS: Re-bleeding rates were 5.9% for patients who received high-dose intravenous proton pump inhibition and 22.9% for those who did not. Hospitalization costs for patients with and without re-bleeding were 11,802 US dollars and 7993 US dollars, and 5220 Canadian dollars and 2696 Canadian dollars, respectively. High-dose intravenous proton pump inhibition was more effective and less costly than the alternative of not administering it. The cost-effectiveness ratios for high-dose and no high-dose intravenous proton pump inhibition were 9112 US dollars and 11,819 US dollars (3293 dollars and 4284 dollars for the Canadian case), respectively. Sensitivity and threshold analyses showed that the results were robust across a wide range of clinically relevant assumptions. CONCLUSION: In the USA and Canada, administering high-dose intravenous proton pump inhibition for 3 days is both more effective and less costly than not doing so for patients with bleeding ulcers after successful endoscopic haemostasis.

Anti-Ulcer Agents↗
PubMed2004

Fractionated, stereotactic proton beam treatment of cerebral arteriovenous malformations.

OBJECTIVES: To evaluate the therapeutic efficiency and adverse effects of stereotactic proton beam treatment of cerebral arteriovenous malformations (AVM). MATERIAL AND METHODS: Twenty-six patients treated in Uppsala during 1991-97 were included (men = 14, women = 12; mean age = 39, range = 23-64). The nidus volumes ranged from 0.3 to 102 ml (mean = 24, median = 13). The follow-up included clinical evaluation, magnetic resonance imaging (and/or computed tomography) every 6-12 months for 3 years and final angiography. RESULTS: The volume changes at final follow-up in AVMs >25 ml were -89, -85, -44, -29, -7, 0, 0, +5 and +18 (%); in AVMs 11-24 ml, -100, -100, -97, -92 and 0 (%); and in AVMs <10 ml, -100, -100, -100, -100, -100, -99, -98, -50, -0 and +40 (%). Two patients were lost to follow-up due to cerebral haemorrhage and myocardial infarction. Radiology displayed significant perifocal oedema in one patient and slight oedema in four patients. Of nine patients with epilepsy, seven became seizure-free after therapy while two continued to suffer from seizures. CONCLUSION: Proton beam irradiation is successful in a relatively high proportion of intermediate and large-sized cerebral AVMs. The adverse effects are acceptable. The advantage of proton treatment compared with gamma knife and LINAC stereotactic irradiation is that protons can irradiate even large volumes with a very sharp dose profile against normal surroundings. Thus, proton beam irradiation is a valuable option in the treatment of AVMs larger than 10 ml.

Adult↗
PubMed2001

Pharmacological and pharmacodynamic essentials of H(2)-receptor antagonists and proton pump inhibitors for the practising physician.

The suppression of gastric acid secretion with anti-secretory agents has been the mainstay of medical treatment for patients with acid-related disorders. Although the majority of Helicobacter pylori -related peptic ulcers can be healed with antibiotics, ulcer healing and symptom control can be significantly improved when antibiotics are given with anti-secretory agents, especially with a proton pump inhibitor. There is a dynamic relationship between the suppression of intragastric acidity and the healing of peptic ulcer and erosive oesophagitis and control of acid-related symptoms. The suppression of gastric acid secretion achieved with H(2)-receptor antagonists has, however, proved to be suboptimal for effectively controlling acid-related disorders, especially for healing erosive oesophagitis and for the relief of reflux symptoms. H(2)-receptor antagonists are also not effective in inhibiting meal-stimulated acid secretion, which is required for managing patients with erosive oesophagitis. Furthermore, the rapid development of tolerance to H(2)-receptor antagonists and the rebound acid hypersecretion after the withdrawal of an H(2)-receptor antagonist further limit their clinical use. Although low-dose H(2)-receptor antagonists are currently available as over-the-counter medications for self-controlling acid-related symptoms, their pharmacology and pharmacodynamics have not been well studied, especially in the self-medicating population. Proton pump inhibitors have been proved to be very effective for suppressing intragastric acidity to all known stimuli, although variations exist in the rapidity of onset of action and the potency of acid inhibition after oral administration at the approved therapeutic doses, which may have important clinical implications for the treatment of gastro-oesophageal reflux disease and perhaps for eradicating H. pylori infection when a proton pump inhibitor is given with antibiotics. Once-daily dosing in the morning is more effective than dosing in the evening for all proton pump inhibitors with respect to the suppression of intragastric acidity and daytime gastric acid secretion in particular, which may result from a better bio-availability being achieved with the morning dose. When higher doses are needed, these drugs must be given twice daily to achieve the optimal suppression of 24 hour intragastric acidity. Preliminary results have shown that esomeprazole, the optical isomer of omeprazole, given at 40 mg, is significantly more effective than omeprazole 40 mg, lansoprazole 30 mg or pantoprazole 40 mg for suppressing gastric acid secretion. However, more studies in different patient populations are needed to compare esomeprazole with the existing proton pump inhibitors with regard to their efficacy, cost-effectiveness and long-term safety for the management of acid-related disorders.

Anti-Ulcer Agents↗
PubMed2001

Histamine receptor antagonists, proton pump inhibitors and their combination in the treatment of gastro-oesophageal reflux disease.

The medical treatment of gastro-oesophageal reflux disease is accomplished with the appropriate use of anti-secretory therapy, principally H(2)-receptor antagonists and proton pump inhibitors. In fact, there is a direct correlation between the length of time, in terms of the number of hours per day that the intragastric pH is above 4, and the healing of the oesophagitis. Nowadays, H(2)-receptor antagonists are of limited use as primary treatment, being inferior to proton pump inhibitors in both healing and symptom relief. Although the majority of patients can be effectively managed with carefully titrated doses of proton pump inhibitors, a small number will continue to show difficulty in the management of their disease, principally because of inadequate nocturnal acid control. These patients may benefit from a combination of proton pump inhibitors twice daily with an H(2)-receptor antagonist at bedtime. This article reviews the use of H(2)-antagonists, proton pump inhibitors and their combination in the management of the patient with gastro-oesophageal reflux disease.

Anti-Ulcer Agents↗
PubMed2005

ATP-dependent rotation of mutant ATP synthases defective in proton transport.

During ATP hydrolysis, the gammaepsilon c10 complex (gamma and epsilon subunits and a c subunit ring formed from 10 monomers) of F0F1 ATPase (ATP synthase) rotates relative to the alpha3beta3delta ab2 complex, leading to proton transport through the interface between the a subunit and the c subunit ring. In this study, we replaced the two pertinent residues for proton transport, cAsp-61 and aArg-210 of the c and a subunits, respectively. The mutant enzymes exhibited lower ATPase activities than that of the wild type but exhibited ATP-dependent rotation in planar membranes, in which their original assemblies are maintained. The mutant enzymes were defective in proton transport, as shown previously. These results suggest that proton transport can be separated from rotation in ATP hydrolysis, although rotation ensures continuous proton transport by bringing the cAsp-61 and aArg-210 residues into the correct interacting positions.

Adenosine Triphosphate↗
PubMed2004

The clinical potential of intensity modulated proton therapy.

Intensity Modulated Proton Therapy (IMPT) differs from conventional proton therapy in its ability to deliver depth-shifted, arbitrarily complex proton fluence maps from each incident field direction. As the individual Bragg peaks delivered from any field can be distributed in three-dimensions throughout the target volume, IMPT provides many more degrees of freedom for designing dose distributions than IMRT or conventional proton therapy techniques. So how can the flexibility of IMPT best be exploited? Here we argue that IMPT has two main advantages over photon IMRT and conventional proton therapy: the ability to better 'sculpt' the dose to the target and around neighbouring critical structures, and the ability to find clinically acceptable solutions whilst simultaneously reducing the sensitivity of the treatments to potential delivery errors. The concept of IMPT as a tool for generating 'safer' plans opens an interesting new avenue of research from the point of view of plan optimisation, the potential of which is only just beginning to be explored.

Humans↗
PubMed2001

Biophysical modelling of proton radiation effects based on amorphous track models.

PURPOSE: To define a photon-equivalent dose in charged particle therapy one needs to know the RBE (Relative Biological Effectiveness) in the target region as well as in the surrounding tissue. RBE estimates are difficult since both the physical input parameters, i.e. LET distributions, and, even more so, the biological input parameters, i.e. cell nucleus size and local response, are not known in general. Track structure theory provides a basis for predicting dose-response curves for particle irradiation. There are (at least) two somewhat different algorithms: the Amorphous Track Partition model (ATP) and the Amorphous Track Local effect model (ATL). Both have been reported to give good agreement with observed radiobiological data. We were interested in a general comparison and in the predictive power of these models for protons. MATERIALS AND METHODS: We compared the principles of the two track structure approaches. The general dependencies of the model predictions on the input parameters are investigated. The model predictions for protons with respect to cell survival of V79 cells are compared with measurements. RESULTS: Although based on similar assumptions, the application of track structure theory in terms of the computational procedure is different for the two models. The ATP model provides a set of equations to predict inter- and intratrack radiation response whereas the ATL model is based on Monte Carlo simulations. One conceptual difference is the use of average doses in subtargets in the ATP model compared with the use of local doses in infinitesimal compartments in the ATL model. The ATP concept introduces an empirical scaling of the cross-section from subcellular to cellular response. The ATL concept inherently requires a critical adjustment of parameters handling the high local dose region near the track centre. The models predict proton survival curves reasonably well but neither shows good agreement with experimental data over the entire range of proton energy and absorbed dose considered. CONCLUSION: Designed for heavy ion applications, the models show weaknesses in the prediction of proton radiation effects. Amorphous track models are based on assumptions about the properties of the biological target and the radiation field that can be questioned. In particular, the assumption of subtargets and the multitarget/single-hit response function on one hand and the parameterization of radial dose and high dose cellular response on the other hand leave question marks.

Animals↗
PubMed1997

Monte Carlo and analytical calculation of proton pencil beams for computerized treatment plan optimization.

Proton pencil beams in water, in a format suitable for treatment planning algorithms and covering the radiotherapy energy range (50-250 MeV), have been calculated using a modified version of the Monte Carlo code PTRAN. A simple analytical model has also been developed for calculating proton broad-beam dose distributions which is in excellent agreement with the Monte Carlo calculations. Radial dose distributions are also calculated analytically and narrow proton pencil-beam dose distributions derived. The physical approximations in the Monte Carlo code and in the analytical model together with their limitations are discussed. Examples showing the use of the calculated set of proton pencil beams as input to an existing photon treatment planning algorithm based on biological optimization are given for fully 3D scanned proton pencil beams; these include intensity modulated beams with range shift and scanning in the transversal plane.

Algorithms↗
PubMed1999

Intensity modulation methods for proton radiotherapy.

The characteristic Bragg peak of protons or heavy ions provides a good localization of dose in three dimensions. Through their ability to deliver laterally and distally shaped homogenous fields, protons have been shown to be a precise and practical method for delivering highly conformal radiotherapy. However, in an analogous manner to intensity modulation for photons, protons can be used to construct dose distributions through the application of many individually inhomogeneous fields, but with the localization of dose in the Bragg peak providing the possibility of modulating intensity within each field in two or three dimensions. We describe four different methods of intensity modulation for protons and describe how these have been implemented in an existing proton planning system. As a preliminary evaluation of the efficacy of these methods, each has been applied to an example case using a variety of field combinations. Dose-volume histogram analysis of the resulting dose distributions shows that when large numbers of fields are used, all techniques exhibit both good target homogeneity and sparing of neighbouring critical structures, with little difference between the four techniques being discerned. As the number of fields is decreased, however, only a full 3D modulation of individual Bragg peaks can preserve both target coverage and sparing of normal tissues. We conclude that the 3D method provides the greatest flexibility for constructing conformal doses in challenging situations, but that when large numbers of beam ports are available, little advantage may be gained from the additional modulation of intensity in depth.

Computing Methodologies↗
PubMed2005

Biological weighted effective dose in 205 MeV clinical proton beam.

The contribution of high linear energy transfer (L) charged particles to dosimetric and microdosimetric characteristics in a clinical proton beam was experimentally studied using an ionization chamber and track etched detectors. The particles mentioned are produced by proton nuclear interactions; at the Bragg peak region slowed down protons also contribute in the L region above several keV microm(-1). Due to these particles the biological weighted effective dose (BWED) of the beam changes with depth. The spectra of particles with L above 7 keV microm(-1) were established by means of track etched detectors, which permitted us to determine their contribution to dosimetric and microdosimetric characteristics of clinical proton beams. The studies were realized in the clinical proton beam of the JINR Dubna Phasotron, with a primary energy of 205 MeV. The relative contribution to the absorbed dose of the particles with L above 7 keV microm(-1) increases from several per cent at the beam entrance to several tens of per cent at the Bragg peak region. The relative biological weighted efficiency (RBWE) for radiotherapy has been calculated using a biological weighting function. It increases with depth from 1.02 at the beam entrance to about 1.25 at the Bragg peak region.

Animals↗
PubMed2006

Proton therapy.

Proton therapy has become a subject of considerable interest in the radiation oncology community and it is expected that there will be a substantial growth in proton treatment facilities during the next decade. I was asked to write a historical review of proton therapy based on my personal experiences, which have all occurred in the United States, so therefore I have a somewhat parochial point of view. Space requirements did not permit me to mention all of the existing proton therapy facilities or the names of all of those who have contributed to proton therapy.

Health Physics↗
PubMed2006

Ion recombination correction in the Clatterbridge Centre of Oncology clinical proton beam.

Most codes of practice for dosimetry of proton beams do not give a clear recommendation on the determination of recombination correction factors for ionization chambers. In this work, recombination corrections were measured in the low-energy clinical proton beam of the Clatterbridge Centre of Oncology (CCO) using data collected at different dose rates and different polarizing voltages. This approach allows the separation of contributions from initial and volume recombination and was compared with results from extrapolation and two-voltage methods. A modified formulation of the method is presented for a modulated beam in which the ionization current is time dependent. Using a set-up with two identical chambers placed face-to-face yielded highly accurate data for plane-parallel ionization chambers. This method may also be used for high-energy photon and electron beam dosimetry. At typical dose rates of 26 Gy min(-1) used clinically at the CCO, the recombination correction is 0.8% and thus is of importance for reference dosimetry. The proton beam should be treated as purely continuous given the high pulse repetition frequency of the cyclotron beam. The results show that the volume recombination parameter for protons is consistent with values measured for photon beams. Initial recombination was found to be independent of beam quality, except for a tendency to increase at the distal edge of the Bragg peak; this is only relevant for depth dose measurements. Using a general equation for recombination and generic values for the initial and volume recombination parameters (A = 0.25 V and m2 = 3.97 x 10(3) s cm(-1) nC(-1) V2), the experimental results are reproduced within 0.1% for all conditions met in this work. For the CCO beam and similar proton beams used for treating optical targets operating at high dose rates, the recombination correction factor can be overestimated by up to 2%, resulting in an overestimation of dose to water by the same amount, if the recommendation from IAEA TRS-398, which is only valid for pulsed beams, is followed without consideration.

Algorithms↗
PubMed2001

Proton transfer dynamics of GART: the pH-dependent catalytic mechanism examined by electrostatic calculations.

The enzyme glycinamide ribonucleotide transformylase (GART) catalyzes the transfer of a formyl group from formyl tetrahydrofolate (fTHF) to glycinamide ribonucleotide (GAR), a process that is pH-dependent with pK(a) of approximately 8. Experimental studies of pH-rate profiles of wild-type and site-directed mutants of GART have led to the proposal that His108, Asp144, and GAR are involved in catalysis, with His108 being an acid catalyst, while forming a salt bridge with Asp144, and GAR being a nucleophile to attack the formyl group of fTHF. This model implied a protonated histidine with pK(a) of 9.7 and a neutral GAR with pK(a) of 6.8. These proposed unusual pK(a)s have led us to investigate the electrostatic environment of the active site of GART. We have used Poisson-Boltzmann-based electrostatic methods to calculate the pK(a)s of all ionizable groups, using the crystallographic structure of a ternary complex of GART involving the pseudosubstrate 5-deaza-5,6,7,8-THF (5dTHF) and substrate GAR. Theoretical mutation and deletion analogs have been constructed to elucidate pairwise electrostatic interactions between key ionizable sites within the catalytic site. Also, a construct of a more realistic catalytic site including a reconstructed pseudocofactor with an attached formyl group, in an environment with optimal local van der Waals interactions (locally minimized) that imitates closely the catalytic reactants, has been used for pK(a) calculations. Strong electrostatic coupling among catalytic residues His108, Asp144, and substrate GAR was observed, which is extremely sensitive to the initial protonation and imidazole ring flip state of His108 and small structural changes. We show that a proton can be exchanged between GAR and His108, depending on their relative geometry and their distance to Asp144, and when the proton is attached on His108, catalysis could be possible. Using the formylated locally minimized construct of GART, a high pK(a) for His108 was calculated, indicating a protonated histidine, and a low pK(a) for GAR(NH(2)) was calculated, indicating that GAR is in neutral form. Our results are in qualitative agreement with the current mechanistic picture of the catalytic process of GART deduced from the experimental data, but they do not reproduce the absolute magnitude of the pK(a)s extracted from fits of k(cat)-pH profiles, possibly because the static time-averaged crystallographic structure does not describe adequately the dynamic nature of the catalytic site during binding and catalysis. In addition, a strong effect on the pK(a) of GAR(NH(2)) is produced by the theoretical mutations of His108Ala and Asp144Ala, which is not in agreement with the observed insensitivity of the pK(a) of GAR(NH(2)) modeled from the experimental data using similar mutations. Finally, we show that important three-way electrostatic interactions between highly conserved His137, with His108 and Asp144, are responsible for stabilizing the electrostatic microenvironment of the catalytic site. In conclusion, our data suggest that further detailed computational and experimental work is necessary.

Binding Sites↗
PubMed2006

Diagnostic value of the proton pump inhibitor test for gastro-oesophageal reflux disease in primary care.

AIM: To assess the diagnostic accuracy of the proton pump inhibitor test in a primary care population as well as its additional value over reflux history, using the symptom association probability outcome during 24-h oesophageal pH recording as reference test for gastro-oesophageal reflux disease. METHODS: Subjects with symptoms suggestive of gastro-oesophageal reflux disease were recruited from primary care. After a 24-h pH recording with calculation of the symptom association probability, subjects started using 40 mg esomeprazole once daily for 13 days. The proton pump inhibitor test was considered positive when the subjects reported adequate symptom suppression. Data are presented as means with 95% confidence intervals. RESULTS: Successful 24-h pH recording was accomplished in 84 of the 90 subjects, while the symptom association probability was calculable in 74. The symptom association probability was positive in 70% of the subjects. The sensitivity of the proton pump inhibitor test was 0.91 (CI 0.78-0.96) and the specificity was 0.26 (CI 0.10-0.49). The mean likelihood ratio was 1.2 (CI 0.9-1.6) with little variation over the 13 consecutive proton pump inhibitor test days. The likelihood ratios of gastro-oesophageal reflux disease symptoms were comparable, ranging around 1. CONCLUSIONS: In primary care patients with reflux symptoms gastro-oesophageal reflux disease is highly prevalent. Under these conditions the additional value of short-term treatment with a proton pump inhibitor for diagnosing gastro-oesophageal reflux disease is limited.

Adult↗
PubMed1995

A review of proton beam radiation therapy.

Beams of protons have been used for radiation treatment for approximately 40 years. This paper provides a short summary of activities from institutions that have contributed to the field over this period. The paper reviews some of the basic interactions of protons with matter that are relevant to radiation treatment and summarizes current knowledge pertaining to the response of biological systems to proton beam radiation. The technical means of producing and delivering proton treatment beams are discussed along with examples of the implementation of these methods at treatment facilities around the world. Finally, the clinical dosimetry of proton beams is summarized and sample data are presented.

Biophysics↗
PubMed1999

Treatment of macular degeneration with proton beams.

Subfoveal neovascular membranes (SNVMs) are a leading cause of severe visual loss in the elderly in the United States. Previously, the only treatment that could halt progression of this disease was laser photocoagulation, which was, however, accompanied by immediate reduction in visual acuity. A single narrow proton beam was used to irradiate 45 patients to either 8 or 14 Cobalt Gray Equivalent. The alignment technique and dosimetry of these treatments are described. The proton beam direction, range, and modulation were planned with the assistance of an eye-specific planning program. A single anterior beam was used, with patients looking nasally toward a blinking fixation light at an angle of 30 degrees. Patients were aligned using a light field projected through a slit collimator. Patients' positions were monitored during treatment with a short-focal-length camera. Depth dose in a flat phantom was measured with a small-diameter parallel plate ionization chamber. Lateral profiles were measured at several depths with silver halide film. Each treatment session lasted 15 min, of which 1 min consisted of beam delivery. The proton beam stopped in the orbital cavity, delivering no primary proton dose to the brain. Dose to the center of the lens of the involved eye was less than 0.5% of the dose delivered to the macula. Treatments of SNVMs with proton beams require only a short visit to the hospital, little immobilization effort, and a minimal amount of treatment room and beam time. Compared to previous treatment trials using x-ray beams, the dose to nonocular tissues is reduced significantly.

Dose-Response Relationship, Radiation↗
PubMed1990

Expression of Na(+)-H+ exchange and ATP-dependent proton extrusion in growing rat IMCD cells.

As the last step of urinary acidification, the inner medullary collecting duct (IMCD) is thought to secrete protons into the tubular lumens by means of a H(+)-translocating adenosinetriphosphatase (H(+)-ATPase). However, recent studies have also shown the existence of Na(+)-H+ exchange activity in IMCD cells. Although the physiological function of the antiporter in IMCD cells is unknown, activation of Na(+)-H+ exchange in other cell-culture systems has been suggested to be closely associated with the process of cell growth. Thus presence of Na(+)-H+ exchange may relate to the growth phase of these cells. To examine intracellular pH (pHi) regulation in growing IMCD cells, we studied proton transport by Na(+)-dependent and Na(+)-independent mechanisms by microfluorimetry using the pHi-sensitive dye 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein acetoxymethyl ester (BCECF/AM). Actively growing cells, defined by [3H]thymidine incorporations, demonstrated an amiloride-sensitive Na(+)-dependent pHi recovery after an acid load. No pHi recovery was evident in the absence of Na+, indicating the importance of Na(+)-H+ exchange for pHi recovery. However, when evaluated in quiescent cells, Na(+)-dependent pHi recovery appeared to be diminished. Instead, a Na(+)-independent pHi recovery which was inhibitable by ATP depletion and by 1 mM N-ethylmaleimide was present, suggesting function of a H(+)-ATPase. These findings indicate that Na(+)-dependent proton extrusion activity (Na(+)-H+ exchange) but not Na(+)-independent proton extrusion activity is expressed during the rapid growth phase of IMCD cells, whereas the more quiescent cells express Na(+)-independent ATP-dependent proton extrusion activity and a possibly less active Na(+)-H+ exchanger.

Adenosine Triphosphate↗
PubMed2004

Effects of short- and medium-term calorie restriction on muscle mitochondrial proton leak and reactive oxygen species production.

Reductions in cellular oxygen consumption (Vo2) and reactive oxygen species (ROS) production have been proposed as mechanisms underlying the anti-aging effects of calorie restriction (CR). Mitochondria are a cell's greatest "sink" for oxygen and also its primary source of ROS. The mitochondrial proton leak pathway is responsible for 20-30% of Vo2 in resting cells. We hypothesized that CR leads to decreased proton leak with consequential decreases in Vo2, ROS production, and cellular damage. Here, we report the effects of short-term (2-wk, 2-mo) and medium-term (6-mo) CR (40%) on rat muscle mitochondrial proton leak, ROS production, and whole animal Vo2. Whole body Vo2 decreased with CR at all time points, whereas mass-adjusted Vo2 was normal until the 6-mo time point, when it was 40% lower in CR compared with control rats. At all time points, maximal leak-dependent Vo2 was lower in CR rats compared with controls. Proton leak kinetics indicated that mechanisms of adaptation to CR were different between short- and medium-term treatments, with the former leading to decreases in protonmotive force (Deltap) and state 4 Vo2 and the latter to increases in Deltap and decreases in state 4 Vo2. Results from metabolic control analyses of oxidative phosphorylation are consistent with the idea that short- and medium-term responses are distinct. Mitochondrial H2O2 production was lower in all three CR groups compared with controls. Overall, this study details the rapid effects of short- and medium-term CR on proton leak, ROS production, and metabolic control of oxidative phosphorylation. Results indicate that a reduction in mitochondrial Vo2 and ROS production may be a mechanism for the actions of CR.

Analysis of Variance↗