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Richard M Bruce,1,2 Phi Anh Phan,2 Marzia Rigolli,3 Minh C Tran,2 Edmund Pacpaco,4 Najib M Rahman,4 Andrew D Farmery2 1Centre for Human and Applied Physiological Sciences, School of Basic and Medical Biosciences, King’s College London, London, UK; 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 3University of Oxford Centre for Clinical Magnetic Resonance Research, University of Oxford, Oxford, UK; 4Oxford University Hospitals NHS Foundation Trust, Oxford Centre for Respiratory Medicine, Oxford, UKCorrespondence: Richard M BruceKing’s College London, Shepherd’s House, Guy’s Campus, London, SE1 1UL, UKTel +44 20 7848 6324Email Richard.bruce@kcl.ac.ukBackground: There is marked variability in the symptoms and outcomes of patients with chronic obstructive pulmonary disease (COPD) which are poorly predicted by spirometry/FEV1%pred. Furthermore, as spirometry requires the performance of potentially distressing respiratory manoeuvres which are to some extent user-effort dependent, there is need for non-invasive and simple-to-perform techniques to identify subtypes of COPD which are more closely related to clinically relevant outcomes.Materials and Methods: The inspired sinewave test (IST) sinusoidally modulates the inspired concentration of a tracer gas (N2O) over successive tidal breaths. A single-compartment tidal-ventilation lung model processes the amplitude/phase of the expired N2O sinewave and estimates cardiopulmonary variables including: effective lung volume and indices of ventilatory heterogeneity (VH; ELV180/FRCpleth and ELV180/ELVpred). 83 COPD patients and 53 healthy controls performed the IST test, standard pulmonary function tests (Spirometry, body plethysmography and the single breath test of carbon monoxide uptake), and symptom severity questionnaires (COPD assessment test, CAT; mMRC dyspnoea-scale, mMRC-DS; Cough+Mucus score; C+M score).Results: ELV180/FRCpleth and ELV180/ELVpred were significantly lower in patients with COPD vs healthy participants (0.34± 0.11 vs 0.68± 0.14 and 0.7± 0.27 vs 0.98± 0.15, respectively; P< 0.05). Multivariable regression analysis demonstrated that ELV180/FRCpleth was a stronger and independent predictor of CAT, mMRC-DS and C+M score vs FEV1%pred. ELV180/ELVpred was a stronger and independent and better predictor of C+M score vs FEV1%pred. Phenotyping patients, based upon ELV180/ELVpred and FRC%pred, uncovered significant symptomatic differences between groups.Conclusion: The IST indices of VH were superior and independent predictors of symptom severity vs FEV1%pred and has potential as a non-invasive and simple-to-perform method to stratify patients into subgroups related to clinically relevant features of COPD.Keywords: COPD, lung function test, nitrous oxide, medical device, ventilatory heterogeneity

In this study we have used a highly immersive virtual reality (VR) cycling environment where incongruence between virtual hill gradient (created by visual gradient and bike tilt angle) and actual workload (pedalling resistance) can experimentally manipulate perception of exercise effort. This therefore may provide a method to examine the role of effort perception in cardiorespiratory control during exercise. Twelve healthy untrained participants (7 men, age 26 ± 5 years) were studied during five visits. On visit 1 participants underwent cardiopulmonary exercise testing, and during subsequent visits (2-4) participants performed repeated hill climbs at different gradients (of 3%, 6% and 9% in counterbalanced order) with the actual workload 'congruent' with virtual hill gradient. On visit 5 participants completed three incongruent trials with virtual hill gradients of 3%, 6% and 9% but a fixed workload equal to that for the 6% climb (iVR3%, iVR6% and iVR9% trials). Despite no difference in power output, there was a significantly elevated rating of perceived exertion (RPE) and mean arterial blood pressure in iVR9% compared to iVR3% and iVR6%, although this effect decayed over time. There was no effect on any respiratory variable, and no significant reduction in RPE or cardiovascular responses was observed during the iVR3% trial. These data suggest that perception of effort and cardiovascular responses to exercise can be manipulated experimentally via virtual hill gradient (using visual and/or vestibular cues) in a VR environment. This work supports those previously showing the existence of a control mechanism which integrates perception of effort and the cardiovascular response to exercise in humans. KEY POINTS: We aimed to assess whether using a highly immersive virtual reality (VR) cycling environment to create incongruence between perceived effort (virtual hill gradient) and actual effort (pedal resistance) can manipulate cardiorespiratory responses to exercise. At an equivalent power output cycling up a steeper virtual hill produced greater ratings of perceived exertion (RPEs) and blood pressure responses compared to a virtual hill congruent to power output. This work suggests the existence of a control mechanism which integrates perception of exercise effort and the cardiovascular response to exercise, which can be experimentally manipulated by VR., (© 2025 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Exercise is a powerful tool for disease prevention and rehabilitation. Commercially available virtual reality (VR) devices and apps offer an immersive platform to gamify exercise and potentially enhance physiological and psychological benefits. However, no work has compared immersive exercise to closely matched 2D screen-based equivalents with the same visual and auditory stimuli. This study aims to compare the acute effects of an exercise session using a commercial immersive VR workout to the same stimuli and workout presented on a screen. 17 healthy participants (male = 7, female = 10; aged 24.18±4.56 years), completed a 12-minute guided VR boxing exercise session in FitXR™ and a screen-based equivalent. Physiological responses were recorded continuously using a heart rate monitor and telemetricmetabolic cart system. Psychological and perceptual responses were measured using their ratings of perceived exertion, the physical activity enjoyment scale, and the physical activity affect scale. In the immersive VR participants chose to engage in more intense exercise (%VO2max; p = 0.044), showed higher levels of all enjoyment subscales (p<0.05) and reported higher positive affect (p = 0.003) and lower negative affect (p = 0.045) following exercise compared to the screen-based equivalent. However, the design here could not determine which elements of immersive VR contributed to the positive effects. Immersive VR may offer a more efficient alternative to other forms of screen based and exergaming workouts and could be offered as a gateway into exercise., Competing Interests: OR received contract research fuding from FitXR, (Copyright: © 2024 Barbour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The muscle metaboreflex effect on pulmonary ventilation (V̇ E ) regulation is more apparent during rhythmic exercise than rest, possibly because this reflex interacts with other mechanisms regulating V̇ E during voluntary contractions, such as central command. Therefore, we tested whether one part of central command, the descending component of motor execution (i.e., descending motor drive), and the muscle metaboreflex interact synergistically to regulate V̇ E . Thirteen healthy adults (9 men) completed four experiments in random order under isocapnia. The muscle metaboreflex was activated by rhythmic handgrip exercise at 60% maximal voluntary contraction (MVC) force with the dominant hand. Then, the muscle metaboreflex remained active during a 4-min recovery period via postexercise circulatory occlusion (PECO), or it was inactivated, maintaining free blood flow to the dominant upper limb. During the last 2 min of the handgrip exercise recovery, participants either performed rhythmic voluntary plantar flexion with the dominant leg at 30% MVC torque to generate descending motor drive or the dominant leg's calf muscles were involuntarily activated by electrical stimulation at a similar torque level (i.e., without descending motor drive). V̇ E increased to a similar level during handgrip exercise in all conditions (≈22 L/min, P = 0.364). PECO maintained V̇ E elevated above recovery with free blood flow (≈17 L/min vs. ≈13 L/min, P = 0.009). However, voluntary and involuntary plantar flexion with or without PECO evoked similar V̇ E responses (Δ ≈ 4 L/min, P = 0.311). Therefore, an interaction between descending motor drive and muscle metaboreflex is not ubiquitous for V̇ E regulation during rhythmic exercise. NEW & NOTEWORTHY Voluntary (i.e., with descending motor drive) and involuntary (i.e., no descending motor drive) plantar flexion elicited similar ventilatory responses when postexercise circulatory occlusion was or was not used in an upper limb. These results indicate that the descending motor drive component of the central command and the muscle metaboreflex do not interact to regulate pulmonary ventilation during rhythmic exercise, which suggests that a supposed interaction between central command-muscle metaboreflex is more complex than previously thought.

Establishing whether speech and language therapy after stroke has beneficial effects on speaking ability is challenging because of the need to control for multiple non-therapy factors known to influence recovery. We investigated how speaking ability at three time points post-stroke differed in patients who received varying amounts of clinical therapy in the first month post-stroke. In contrast to prior studies, we factored out variance from: initial severity of speaking impairment, amount of later therapy, and left and right hemisphere lesion size and site. We found that speaking ability at one month post-stroke was significantly better in patients who received early therapy ( n  = 79), versus those who did not ( n  = 64), and the number of hours of early therapy was positively related to recovery at one year post-stroke. We offer two non-mutually exclusive interpretations of these data: (1) patients may benefit from the early provision of self-management strategies; (2) therapy is more likely to be provided to patients who have a better chance of recovery (e.g., poor physical and/or mental health may impact suitability for therapy and chance of recovery). Both interpretations have implications for future studies aiming to predict individual patients' speech outcomes after stroke, and their response to therapy.

New Findings: What is the topic of this review? In this review, we examine the evidence for control mechanisms underlying exercise hyperpnoea, giving attention to the feedback from thin-fibre skeletal muscle afferents, and highlight the frequently conflicting findings and difficulties encountered by researchers using a variety of experimental models. What advances does it highlight? There has been a recent resurgence of interest in the role of skeletal muscle afferent involvement, not only as a mechanism of healthy exercise hyperpnoea but also in the manifestation of breathlessness and exercise intolerance in chronic disease., Abstract: The ventilatory response to dynamic submaximal exercise is immediate and proportional to metabolic rate, which maintains isocapnia. How these respiratory responses are controlled remains poorly understood, given that the most tightly controlled variable (arterial partial pressure of CO 2 /H + ) provides no error signal for arterial chemoreceptors to trigger reflex increases in ventilation. This review discusses evidence for different postulated control mechanisms, with a focus on the feedback from group III/IV skeletal muscle mechanosensitive and metabosensitive afferents. This concept is attractive, because the stimulation of muscle mechanoreceptors might account for the immediate increase in ventilation at the onset of exercise, and signals from metaboreceptors might be proportional to metabolic rate. A variety of experimental models have been used to establish the contribution of thin-fibre muscle afferents in ventilatory control during exercise, with equivocal results. The inhibition of afferent feedback via the application of lumbar intrathecal fentanyl during exercise suppresses ventilation, which provides the most compelling supportive evidence to date. However, stimulation of afferent feedback at rest has no consistent effect on respiratory output. However, evidence is emerging for synergistic interactions between muscle afferent feedback and other stimulatory inputs to the central respiratory neuronal pool. These seemingly hyperadditive effects might explain the conflicting findings encountered when using different experimental models. We also discuss the increasing evidence that patients with certain chronic diseases exhibit exaggerated muscle afferent activation during exercise, resulting in enhanced cardiorespiratory responses. This might provide a neural link between the well-established limb muscle dysfunction and the associated exercise intolerance and exertional dyspnoea, which might offer therapeutic targets for these patients., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

New Findings: What is the central question of this study? Classically, the stimulation of thin-fibre skeletal muscle afferents, via the application of postexercise circulatory occlusion (PECO) at rest, fails to generate ventilatory responses. We used a new experimental protocol to examine whether the involvement of these metabosensitive afferents in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. What is the main finding and its importance? We found that PECO of one leg augmented the ventilatory and heart rate responses to single-legged exercise of the contralateral leg, suggesting that metaboreceptive muscle afferents contribute to the control of the exercise hyperpnoea., Abstract: Inhibition of thin-fibre skeletal muscle afferent neurotransmission attenuates ventilatory and cardiovascular responses to exercise. However, stimulation of muscle metaboreceptive afferents at rest, via postexercise circulatory occlusion (PECO), classically fails to generate increases in ventilation or heart rate. It is possible that the involvement of muscle afferent feedback in ventilatory control can only be revealed during exercise, when other potentially synergistic inputs that increase central respiratory drive are activated. Therefore, we assessed the cardiorespiratory responses to single-legged cycling exercise with or without PECO of the contralateral leg. Thirteen healthy participants performed left-legged cycling exercise (40 or 60 W) followed by either: (i) no PECO (Con trial); or (ii) PECO (PECO trial) of the left leg for 3 min. During this 3 min period, right-legged cycling exercise was performed at the same workload as the preceding left-legged exercise (40 or 60 W). During 60 W right-legged cycling, ventilation relative to baseline was significantly higher in the PECO versus Con trial (22.9 ± 2 versus 18.7 ± 1.8 l min -1 ; P < 0.05), but there was no difference between the trials performed at 40 W. The change in heart rate was significantly greater during right-legged cycling in the PECO versus Con trial in the 40 (41.2 ± 4 versus 34.1 ± 3.1 beats min -1 ; P < 0.05) and 60 W trials (49.7 ± 2.7 versus 43.4 ± 3.7 beats min -1 ; P < 0.05). There were no differences in oxygen uptake, carbon dioxide production and ratings of perceived exertion between trials. These findings suggest that stimulation of muscle metaboreceptive afferents can drive increases in ventilation and heart rate during dynamic exercise., (© 2019 The Authors. Experimental Physiology © 2019 The Physiological Society.)

Background: Cardiac output (Q˙) monitoring can support the management of high-risk surgical patients, but the pulmonary artery catheterisation required by the current 'gold standard'-bolus thermodilution (Q˙ T )-has the potential to cause life-threatening complications. We present a novel noninvasive and fully automated method that uses the inspired sinewave technique to continuously monitor cardiac output (Q˙ IST )., Methods: Over successive breaths the inspired nitrous oxide (N 2 O) concentration was forced to oscillate sinusoidally with a fixed mean (4%), amplitude (3%), and period (60 s). Q˙ IST was determined in a single-compartment tidal ventilation lung model that used the resulting amplitude/phase of the expired N 2 O sinewave. The agreement and trending ability of Q˙ IST were compared with Q˙ T during pharmacologically induced haemodynamic changes, before and after repeated lung lavages, in eight anaesthetised pigs., Results: Before lung lavage, changes in Q˙ IST and Q˙ T from baseline had a mean bias of -0.52 L min -1 (95% confidence interval [CI], -0.41 to -0.63). The concordance between Q˙ IST and Q˙ T was 92.5% as assessed by four-quadrant analysis, and polar plot analysis revealed a mean angular bias of 5.98° (95% CI, -24.4°-36.3°). After lung lavage, concordance was slightly reduced (89.4%), and the mean angular bias widened to 21.8° (-4.2°, 47.6°). Impaired trending ability correlated with shunt fraction (r=0.79, P<0.05)., Conclusions: The inspired sinewave technique provides continuous and noninvasive monitoring of cardiac output, with a 'marginal-good' trending ability compared with cardiac output based on thermodilution. However, the trending ability can be reduced with increasing shunt fraction, such as in acute lung injury., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

New Findings: What is the central question of this study? We present a new non-invasive medical technology, the inspired sine-wave technique, which involves inhalation of sinusoidally fluctuating concentrations of a tracer gas. The technique requires only passive patient cooperation and can monitor different cardiorespiratory variables, such as end-expired lung volume, ventilatory heterogeneity and pulmonary blood flow. What is the main finding and its importance? In this article, we demonstrate that the measurements of end-expired lung volume are repeatable and accurate, in comparison to whole-body plethysmography, and the technique is sensitive to the changes in ventilatory heterogeneity associated with advancing age. As such, it has the potential to provide clinically valuable information., Abstract: The inspired sine-wave technique (IST) is a new method that can provide simple, non-invasive cardiopulmonary measurements. Over successive tidal breaths, the concentration of a tracer gas (i.e. nitrous oxide, N 2 O) is sinusoidally modulated in inspired air. Using a single-compartment tidal-ventilation lung model, the resulting amplitude/phase of the expired sine wave allows estimation of end-expired lung volume (ELV), pulmonary blood flow and three indices for ventilatory heterogeneity (VH; ELV 180 /FRC pleth , ELV 180 /FRC pred and ELV 60 /ELV 180 ). This investigation aimed to determine the repeatability and agreement of ELV with FRC pleth and, as normal ageing results in well-established changes in pulmonary structure and function, whether the IST estimates of ELV and VH are age dependent. Forty-eight healthy never-smoker participants (20-86 years) underwent traditional pulmonary function testing (e.g. spirometry, body plethysmography) and the IST test, which consisted of 4 min of quiet breathing through a face mask while inspired N 2 O concentrations were oscillated in a sine-wave pattern with a fixed mean (4%) and amplitude (3%) and a period of either 180 or 60 s. The ELV 180 /FRC pleth and ELV 180 /FRC pred were age dependent (average decreases of 0.58 and 0.48% year -1 ), suggesting an increase in VH with advancing age. The ELV showed a mean bias of -1.09 litres versus FRC pleth , but when normalized for the effects of age this bias reduced to -0.35 litres. The IST test has potential to provide clinically useful information necessitating further study (e.g. for mechanically ventilated or obstructive lung disease patients), but these findings suggest that the increases in VH with healthy ageing must be taken into account in clinical investigations., (© 2018 The Authors. Experimental Physiology © 2018 The Physiological Society.)

Learning the basic competencies of critical thinking are very important in the education of any young scientist, and teachers must be prepared to help students develop a valuable set of analytic tools. In my experience, this is best achieved by encouraging students to study areas with little scientific consensus, such as the control mechanisms of the exercise ventilatory response, as it can allow greater objectivity when evaluating evidence, while also giving students the freedom to think independently and problem solve. In this article, I discuss teaching strategies by which physiology, biomedical science, and sport science students can simultaneously develop their understanding of respiratory control mechanisms and learn to critically analyze evidence thoroughly. This can be best achieved by utilizing both teacher-led and student-led learning environments, the latter of which encourages the development of learner autonomy and independent problem solving. In this article, I also aim to demonstrate a systematic approach of critical assessment that students can be taught, adapt, and apply independently. Among other things, this strategy involves: 1 ) defining the precise phenomenon in question; 2 ) understanding what investigations must demonstrate to explain the phenomenon and its underlying mechanisms; 3 ) evaluating the explanations/mechanisms of the phenomenon and the evidence for them; and 4 ) forming strategies to produce strong evidence, if none exists., (Copyright © 2017 the American Physiological Society.)

Key Points: Recent evidence indicates a role for group III/IV muscle afferents in reflex control of the human ventilatory response to exercise. Dyspnoea in chronic obstructive pulmonary disease (COPD) may be linked to this reflex response. This study shows that activation of the muscle metaboreflex causes a ventilatory response in COPD patients but not in healthy controls. This indicates abnormal involvement of muscle afferents in the control of ventilation in COPD which may be a contributing factor to exercise dyspnoea., Abstract: Blockade of thin fibre muscle afferent feedback during dynamic exercise reduces exercise hyperpnoea in health and chronic obstructive pulmonary disease (COPD). Therefore, we hypothesised that activation of the muscle metaboreflex at rest would cause hyperpnoea. We evaluated the effect of muscle metaboreflex activation on ventilation, in resting COPD patients and healthy participants. Following a bout of rhythmic hand grip exercise, post exercise circulatory occlusion (PECO) was applied to the resting forearm to sustain activation of the muscle metaboreflex, in 18 COPD patients (FEV 1 /FVC ratio < 70%), 9 also classified as chronically hypercapnic, and 9 age- and gender-matched controls. The cardiovascular response to exercise and the sustained blood pressure elevation during PECO was similar in patients and controls. During exercise ventilation increased by 6.64 ± 0.84 in controls and significantly (P < 0.05) more, 8.38 ± 0.81 l min -1 , in patients. During PECO it fell to baseline levels in controls but remained significantly (P < 0.05) elevated by 2.78 ± 0.51 l min -1 in patients until release of circulatory occlusion, with no significant difference in responses between patient groups. Muscle metaboreflex activation causes increased ventilation in COPD patients but not in healthy participants. Chronic hypercapnia in COPD patients does not exaggerate this response. The muscle metaboreflex appears to be abnormally involved in the control of ventilation in COPD and may be a contributing factor to exercise dyspnoea., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

New Findings: What is the central question of this study? During hypercapnia but not normocapnia, activation of muscle afferents by postexercise circulatory occlusion increases ventilation, possibly due to additional activation of metabolite-stimulated muscle afferents. Alternatively, chemoreflex activation caused by hypercapnia may have a synergistic interaction with muscle afferent feedback, so stimulating breathing. What is the main finding and its importance? Muscle afferent activation during muscle hypercapnia with concurrent systemic normocapnia did not increase breathing. With systemic hypercapnia, there was a response that did not change with hyperoxic hypercapnia. A synergistic interaction between central chemoreception and muscle afferent feedback is therefore indicated. During hypercapnia, activation of thin-fibre muscle afferents using postexercise circulatory occlusion (PECO) provokes a ventilatory response not seen in normocapnia. We investigated the ventilatory responses to PECO when hypercapnia was restricted to the active muscle ('Local' trial) or during systemic hypercapnia ('Systemic' trial). In the Local trial, a hypercapnic gas mixture (5% CO2 in air) was inhaled for 5 min when circulation to the active calf muscle was open, then rapidly closed by thigh-cuff inflation (200 mmHg), immediately before a return to breathing room air and performance of isometric exercise and PECO. In the Systemic trial, circulation through the muscle was closed throughout the exercise and PECO phases, performed during the hypercapnic gas inhalation. In a third trial, in Systemic conditions a hyperoxic hypercapnic gas mixture (95% O2 and 5% CO2 ) was breathed for 1 min during PECO ('Hyperoxia' trial). The increase in ventilation during calf muscle exercise was not different between trials. In the Local trial, ventilation fell to pre-exercise levels during PECO, but in the Systemic trial it remained at end-exercise levels (4.9 ± 0.8 l min(-1) ) and was equally well maintained throughout the Hyperoxia trial (4.3 ± 1 l min(-1) ). Cardiovascular responses during PECO were not different in the three trials, indicating similar activation of muscle afferents. Sustained elevation of ventilation during PECO in the Systemic but not the Local trial suggests that ventilation is stimulated via an interaction between muscle afferent feedback and hypercapnia-induced chemoreceptor activation. The similar ventilatory responses in Systemic and Hyperoxia conditions further suggest that in this respect, central rather than peripheral chemoreceptors play the major role., (© 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.)

Respiratory and cardiovascular responses to muscle mechanoreflex (passive calf stretch) and metaboreflex activation (local circulatory occlusion) were examined during inhalation of a hypercapnic gas mixture in four trials. These controlled for the effects of central command, metabolite sensitization of muscle afferents and hypercapnia-induced elevation of central respiratory drive. In an isokinetic dynamometer, with circulation through the right leg occluded by inflation of a thigh cuff, 13 participants either rested (control trial; CON) or plantarflexed their ankle at 50% maximal force for 1.5 min (voluntary exercise trial; EX). Thereafter, circulatory occlusion was maintained and the calf passively stretched before return to the resting position. Both trials were performed while breathing air, as well as while breathing a normoxic, hypercapnic (5% CO(2)) gas mixture (CO(2) trial and CO(2)+EX trial). Hypercapnic gas inhalation increased baseline minute ventilation (V), heart rate and mean arterial pressure (+27.67 ± 1.74 l min(-1), +7 ± 0.85 beats min(-1) and +13 ± 3.41 mmHg, respectively; means ± SEM) above control values (9.78 ± 0.86 l min(-1), 62 ± 2.3 beats min(-1) and 88 ± 2.6 mmHg, respectively). Voluntary exercise further increased these variables from baseline during both trials (P < 0.05). During the continued circulatory occlusion after voluntary exercise, mean arterial pressure remained significantly elevated (P < 0.05). Minute ventilation returned to baseline during circulatory occlusion following exercise in the EX trial, but in the CO(2)+EX trial the V remained elevated at end-exercise levels during this period (+7.12 ± 1.13 l min(-1)). Passive stretch caused further increases in V during CO(2)+EX and CO(2) trials but not in CON and EX. These results indicate that in the absence of central command, either muscle metaboreflex and/or mechanoreflex activation stimulates ventilation during concurrent hypercapnia.

The overall risk associated with exposure to a chemical is determined by combining quantitative estimates of exposure to the chemical with their known health effects. For chemicals that cause carcinogenicity, oral slope factors (OSFs) and inhalation unit risks are used to quantitatively estimate the carcinogenic potency or the risk associated with exposure to the chemical by oral or inhalation route, respectively. Frequently, there is a lack of animal or human studies in the literature to determine OSFs. This study aims to circumvent this problem by developing quantitative structure-activity relationship (QSAR) models to predict the OSFs of chemicals. The OSFs of 70 chemicals based on male/female human, rat, and mouse bioassay data were obtained from the United States Environmental Protection Agency's Integrated Risk Information System (IRIS) database. A global QSAR model that considered all 70 chemicals as well as species and/or sex-specific QSARs were developed in this study. Study results indicate that the species and sex-specific QSARs (r(2)>0.8, q(2)>0.7) had a better predictive abilities than the global QSAR developed using data from all species and sexes (r(2)=0.77, q(2)=0.73). The QSARs developed in this study were externally validated, and demonstrated reasonable predictive abilities., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Determining the carcinogenicity and carcinogenic potency of new chemicals is both a labor-intensive and time-consuming process. In order to expedite the screening process, there is a need to identify alternative toxicity measures that may be used as surrogates for carcinogenic potency. Alternative toxicity measures for carcinogenic potency currently being used in the literature include lethal dose (dose that kills 50% of a study population [LD(50)]), lowest-observed-adverse-effect-level (LOAEL) and maximum tolerated dose (MTD). The purpose of this study was to investigate the correlation between tumor dose (TD(50)) and three alternative toxicity measures as an estimator of carcinogenic potency. A second aim of this study was to develop a Classification and Regression Tree (CART) between TD(50) and estimated/experimental predictor variables to predict the carcinogenic potency of new chemicals. Rat TD(50)s of 590 structurally diverse chemicals were obtained from the Cancer Potency Database, and the three alternative toxicity measures considered in this study were estimated using TOPKAT, a toxicity estimation software. Though poor correlations were obtained between carcinogenic potency and the three alternative toxicity (both experimental and TOPKAT) measures for the CPDB chemicals, a CART developed using experimental data with no missing values as predictor variables provided reasonable estimates of TD(50) for nine chemicals that were part of an external validation set. However, if experimental values for the three alternative measures, mutagenicity and logP are not available in the literature, then either the CART developed using missing experimental values or estimated values may be used for making a prediction.

A test program was conducted to evaluate the mutagenicity of toxaphene residuals extracted from aged soils and from fish collected in creeks near a toxaphene-contaminated site. The ultimate objective was to determine if the residual toxaphene congeners were more or less mutagenic than those in technical-grade toxaphene. The study showed that the mutagenicity of the bioaccumulated toxaphene congeners in fish, expressed as colony revertants per microg of residual toxaphene, was no greater than that of technical-grade toxaphene. The mutagenic impact of the toxaphene residuals in aged soil statistically was less than that for technical-grade toxaphene. Two specific congeners, a hexachlorobornane (labeled Hx-Sd) and a heptachlorobornane (labeled Hp-Sd), were found to accumulate over time in both soil and fish extracts, but did not show increased mutagenic impacts relative to that produced by technical-grade toxaphene.

The performance of the rat chronic lowest observed adverse effect level (LOAEL, the lowest exposure level at which there are biologically significant increases in the severity of adverse effects) model in Toxicity Prediction by Komputer Assisted Technology (TOPKAT), a commercial quantitative structure-activity relationship software package, was tested on a database of chemicals that are of interest to the U.S. EPA's Office of Pesticide Programs. The testing was repeated on a database of chemicals from three U.S. EPA sources that report peer-reviewed LOAELs. The results of this study were also contrasted with the results of the testing performed during TOPKAT's model-building process., (Copyright 2004 American Chemical Society)

Disinfection by-products (DBPs) are produced as a result of disinfecting water using various treatment methods. Over the years, chlorine has remained the most popular disinfecting agent due to its ability to kill pathogens. However, in 1974, it was discovered that the superchlorination of drinking water resulted in the production of chloroform and other trihalomethanes. Since then hundreds of additional DBPs have been identified, including haloacetic acids and haloacetonitriles with very little or no toxicological data available, thus necessitating the use of additional methods for hazard estimation. Quantitative Structure Toxicity Relationship (QSTR) is one such method and utilizes a computer-based technology to predict the toxicity of a chemical solely from its molecular attributes. The current research was conducted utilizing the TOPKAT/QSTR software package which is comprised of robust, cross-validated QSTR models for assessing mutagenicity, rodent carcinogenicity (female/male; rat/mouse), developmental toxicity, skin sensitization, lowest-observed-adverse-effect level (LOAEL), fathead minnow LC(50), rat oral LD(50) and Daphia magna EC(50). A total of 252 DBPs were analyzed for the likelihood that they would produce tumors and developmental effects using the carcinogenicity and developmental toxicity submodels of TOPKAT. The model predictions were evaluated to identify generalizations between the functional groups (e.g. alcohols, acids, etc.) and specific toxic endpoints. Developmental toxicity was identified as an endpoint common to the majority of aliphatic mono- and dicarboxylic acids, aliphatic halogenated and non-halogenated ketones, and aliphatic haloacetonitriles. In the case of the carcinogenicity submodels, most aliphatic aldehydes were identified as carcinogens only in the female mouse submodel. The majority of the aliphatic and aromatic dicarboxylic acids were identified as carcinogens in the female rat submodel. All other functional groups examined were largely predicted as non-carcinogens in all the cancer submodels (i.e. male/female rats and mice). The QSTR results should aid in the prioritization for evaluation of toxic endpoints in the absence of in vivo bioassays.

One hundred patients who underwent jejunoileal bypass for obesity were followed for a mean period of 2 1/2 years. Four patients developed a clinical illness that resembled a systemic form of tuberculosis during the first postoperative year. This incidence exceeds that found in the general population by sixtyfold. Any patient with jejunoileal bypass who develops an illness with accelerated weight loss, enlarged lymph nodes, and unexplained fever with chills should be suspected of having tuberculosis. Aggressive diagnostic measures are required. Treatment with isoniazid and ethambutol at usual doses can be successful, but blood levels should be measured to confirm adequacy until additional information becomes available.

A total of 161 patients with chronic obstructive pulmonary disease (COPD) plus 100 control subjects (identified during a study of heart disease in 6,860 Japanese-American men aged 52 to 75 years who were residing in Hawaii) were analyzed for phenotype in search of the antitrypsin gene Z, which has been shown to be associated with pulmonary emphysema in other racial groups. No carriers of the Z gene were found, and the question of whether the rarity or absence of this gene relates to a low frequency of COPD among Japanese-Americans is reviewed.

Phenol, a monohydroxy derivative of benzene, occurs naturally in animal waste and by decomposition of organic wastes. It is also produced by man, originally by fractional distillation of coal tar, but more recently by cumene hydroperoxidation and toluene oxidation. As a result of large production volume and natural sources, occupational and environmental exposure to phenol is likely. Phenol poisoning can occur by skin absorption, vapor inhalation, or ingestion, and, regardless of route of exposure, can result in detrimental health effects. Acute toxicity has been observed in man and experimental animals, resulting in muscle weakness, convulsions, and coma. In addition, studies have shown that although teratogenic effects have not been associated with exposure to phenol by either inhalation or oral route, high doses of phenol are fetotoxic. This paper addresses these studies and others in an attempt to determine if human health is at risk to those levels of phenol present in the environment and workplace. However, because data are limited, further research is necessary to analyze the mutagenic and carcinogenic potential of this chemical.

We studied 143 Pi MZ heterozygous (MZ) subjects from random populations that had been examined previously for alpha 1-antitrypsin phenotype. Each Pi MZ subject was closely matched with a Pi M control subject from the same population at each of 6 centers. An expanded National Heart, Lung and Blood Institute (NHLBI) respiratory symptom questionnaire was completed by each subject. Pulmonary function tests designed to detect established as well as early obstructive airway abnormalities were administered. Multivariate analysis of the variance of data from the questionnaire and pulmonary function tests corrected for age, race, sex, and smoking history showed no significant difference (p less than 0.05) between subjects of Pi MZ and Pi M phenotype. The size of the populations studied and number of observations made for each variable were sufficient to assure that small differences could be detected with 95% power. We conclude that MZ phenotype alone carries no greater risk of developing lung disease than M phenotype.