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Congenital athymia is a life-limiting disorder due to rare inborn errors of immunity causing impaired thymus organogenesis or abnormal thymic stromal cell development and function. Athymic infants have a T-lymphocyte-negative, B-lymphocyte-positive, natural killer cell-positive immunophenotype with profound T-lymphocyte deficiency and are susceptible to severe infections and autoimmunity. Patients variably display syndromic features. Expanding access to newborn screening for severe combined immunodeficiency and T lymphocytopenia and broad genetic testing, including next-generation sequencing technologies, increasingly facilitate their timely identification. The recommended first-line treatment is allogeneic thymus transplantation, which is a specialized procedure available in Europe and the United States. Outcomes for athymic patients are best with early diagnosis and thymus transplantation before the development of infectious and inflammatory complications. These guidelines on behalf of the European Society for Immunodeficiencies provide a comprehensive review for clinicians who manage patients with inborn thymic stromal cell defects; they offer clinical practice recommendations focused on the diagnosis, investigation, risk stratification, and management of congenital athymia with the aim of improving patient outcomes., Competing Interests: Disclosure statement A.Y.K. is supported by the Wellcome Trust (222096/Z/20/Z). F.D. is supported by an NIHR Academic Clinical Lectureship and an Academy for Medical Sciences Starter Grant. E.H. and E.G.D. are supported by a grant from the Great Ormond Street Hospital Children’s Charity. O.E.’s laboratory is supported by grants from the Swedish Research Council (2018-02752 and 2022-00781) and the Swedish state under an ALF agreement between the Swedish government and the county councils (ALFGBG-965795). A.V. is supported by a core grant from the Telethon Foundation. F.J.T.’s laboratory is supported in part by EU H2020 grant RECOMB (755170–(b)) and has received funding from the European UnionHorizon 2020 research and innovation program as well as from reNEW, the Novo Nordisk Foundation for Stem Cell Research (NNF21CC0073729). G.A. is supported by an MRC Programme Grant to GA (MR/T029765/a). and G.H. is supported by the Wellcome Trust (211944/Z/18/Z). Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Congenital athymia is a rare T-lymphocytopaenic condition, which requires early corrective treatment with thymus transplantation (TT). Athymic patients are increasingly identified through newborn screening (NBS) for severe combined immunodeficiency (SCID). Lack of relatable information resources contributes to challenging patient and family journeys during the diagnostic period following abnormal NBS results. Patient and Public Involvement and Engagement (PPIE) activities, including parental involvement in paediatrics, are valuable initiatives to improve clinical communication and parental information strategies. Parents of infants with suspected athymia were therefore invited to discuss the information they received during the diagnostic period following NBS with the aim to identify parental information needs and targeted strategies to address these adequately. Parents reported that athymia was not considered with them as a possible differential diagnosis until weeks after initial NBS results. Whilst appropriate clinical information about athymia and TT was available upon referral to specialist immunology services, improved access to easy-to-understand information from reliable sources, including from clinical nurse specialists and peer support systems, remained desirable. A roadmap concept, with written or digital information, addressing parental needs in real time during a potentially complex diagnostic journey, was proposed and is transferrable to other inborn errors of immunity (IEI) and rare diseases. This PPIE activity provides insight into the information needs of parents of infants with suspected athymia who are identified through SCID NBS, and highlights the role for PPIE in promoting patient- and family-centred strategies to improve IEI care., (© 2024. The Author(s).)

Chronic human norovirus (HuNoV) infections in immunocompromised patients result in severe disease, yet approved antivirals are lacking. RNA-dependent RNA polymerase (RdRp) inhibitors inducing viral mutagenesis display broad-spectrum in vitro antiviral activity, but clinical efficacy in HuNoV infections is anecdotal and the potential emergence of drug-resistant variants is concerning. Upon favipiravir (and nitazoxanide) treatment of four immunocompromised patients with life-threatening HuNoV infections, viral whole-genome sequencing showed accumulation of favipiravir-induced mutations which coincided with clinical improvement although treatment failed to clear HuNoV. Infection of zebrafish larvae demonstrated drug-associated loss of viral infectivity and favipiravir treatment showed efficacy despite occurrence of RdRp variants potentially causing favipiravir resistance. This indicates that within-host resistance evolution did not reverse loss of viral fitness caused by genome-wide accumulation of sequence changes. This off-label approach supports the use of mutagenic antivirals for treating prolonged RNA viral infections and further informs the debate surrounding their impact on virus evolution., Competing Interests: Declaration of competing interest Authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom)., Objective: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH., Methods: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation., Results: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation., Conclusion: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Paired box 1 (PAX1) deficiency has been reported in a small number of patients diagnosed with otofaciocervical syndrome type 2 (OFCS2). We described six new patients who demonstrated variable clinical penetrance. Reduced transcriptional activity of pathogenic variants confirmed partial or complete PAX1 deficiency. Thymic aplasia and hypoplasia were associated with impaired T cell immunity. Corrective treatment was required in 4/6 patients. Hematopoietic stem cell transplantation resulted in poor immune reconstitution with absent naïve T cells, contrasting with the superior recovery of T cell immunity after thymus transplantation. Normal ex vivo differentiation of PAX1-deficient CD34 + cells into mature T cells demonstrated the absence of a hematopoietic cell-intrinsic defect. New overlapping features with DiGeorge syndrome included primary hypoparathyroidism (n = 5) and congenital heart defects (n = 2), in line with PAX1 expression during early embryogenesis. Our results highlight new features of PAX1 deficiency, which are relevant to improving early diagnosis and identifying patients requiring corrective treatment., Competing Interests: Declaration of Competing Interest All authors declare no conflict of interest to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

N-methyl-D-aspartate (NMDA) receptor hypofunctionality is a well-studied hypothesis for schizophrenia pathophysiology, and daily dosing of the NMDA receptor co-agonist, D-serine, in clinical trials has shown positive effects in patients. Therefore, inhibition of D-amino acid oxidase (DAAO) has the potential to be a new therapeutic approach for the treatment of schizophrenia. TAK-831 (luvadaxistat), a novel, highly potent inhibitor of DAAO, significantly increases D-serine levels in the rodent brain, plasma, and cerebrospinal fluid. This study shows luvadaxistat to be efficacious in animal tests of cognition and in a translational animal model for cognitive impairment in schizophrenia. This is demonstrated when luvadaxistat is dosed alone and in conjunction with a typical antipsychotic. When dosed chronically, there is a suggestion of change in synaptic plasticity as seen by a leftward shift in the maximum efficacious dose in several studies. This is suggestive of enhanced activation of NMDA receptors in the brain and confirmed by modulation of long-term potentiation after chronic dosing. DAAO is highly expressed in the cerebellum, an area of increasing interest for schizophrenia, and luvadaxistat was shown to be efficacious in a cerebellar-dependent associative learning task. While luvadaxistat ameliorated the deficit seen in sociability in two different negative symptom tests of social interaction, it failed to show an effect in endpoints of negative symptoms in clinical trials. These results suggest that luvadaxistat potentially could be used to improve cognitive impairment in patients with schizophrenia, which is not well addressed with current antipsychotic medications., (© 2023. The Author(s).)

Previous studies have identified that Geobacter sulfurreducens has three different electron transfer pathways for respiration, and it switches between these pathways to adapt to the redox potential of its electron acceptor. However, only a small fraction of the electron carriers from each pathway have been identified. In this study, we combined electrochemical and gene expression data to identify electron carriers in the inner membrane, periplasm, outer membrane, and exterior of the cell that may be induced by the use of the three different electron transfer pathways. Cyclic voltammetry was performed on thin biofilms grown on anodes poised at different redox potentials, providing a quantitative assessment of the relative use of three electron-transfer pathways in each condition (catalytic midpoint potentials (E KA s) of -0.227 V [Low], -0.15 V [Medium], -0.1 V [High] vs. SHE). Transcriptomic analyses as a function of electrochemical signals or fumarate utilization showed differential induction in inner membrane (Medium: cbcL), periplasmic (Low: ppcB/ppcE, Medium: ppcA), outer membrane (Low: extA/extC, Medium: extJ/extK, Fumarate: extF/extG), and extracellular (Medium: omcZ, High/Fumarate: omcS/omcT) cytochromes, suggesting the pathway signals are associated with complex transcriptomic responses in genes across the electron transfer pathway. Our method combining electrochemical modeling and transcriptomics could be adapted to better understand electron transport in other electroactive organisms with complex metabolisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Proteins are essential components of all living cells and so the study of their in situ expression, proteomics, has wide reaching applications. Peptide identification in proteomics typically relies on matching high resolution tandem mass spectra to a protein database but can also be performed de novo . While artificial spectra have been successfully incorporated into database search pipelines to increase peptide identification rates, little work has been done to investigate the utility of artificial spectra in the context of de novo peptide identification. Here, we perform a critical analysis of the use of artificial data for the training and evaluation of de novo peptide identification algorithms. First, we classify the different fragment ion types present in real spectra and then estimate the number of spurious matches using random peptides. We then categorise the different types of noise present in real spectra. Finally, we transfer this knowledge to artificial data and test the performance of a state-of-the-art de novo peptide identification algorithm trained using artificial spectra with and without relevant noise addition. Noise supplementation increased artificial training data performance from 30% to 77% of real training data peptide recall. While real data performance was not fully replicated, this work provides the first steps towards an artificial spectrum framework for the training and evaluation of de novo peptide identification algorithms. Further enhanced artificial spectra may allow for more in depth analysis of de novo algorithms as well as alleviating the reliance on database searches for training data., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Geobacter sulfurreducens is an electroactive bacterium capable of reducing metal oxides in the environment and electrodes in engineered systems 1,2 . Geobacter sp. are the keystone organisms in electrogenic biofilms, as their respiration consumes fermentation products produced by other organisms and reduces a terminal electron acceptor e.g. iron oxide or an electrode. To respire extracellular electron acceptors with a wide range of redox potentials, G. sulfurreducens has a complex network of respiratory proteins, many of which are membrane-bound 3-5 . We have identified intracytoplasmic membrane (ICM) structures in G. sulfurreducens. This ICM is an invagination of the inner membrane that has folded and organized by an unknown mechanism, often but not always located near the tip of a cell. Using confocal microscopy, we can identify that at least half of the cells contain an ICM when grown on low potential anode surfaces, whereas cells grown at higher potential anode surfaces or using fumarate as electron acceptor had significantly lower ICM frequency. 3D models developed from cryo-electron tomograms show the ICM to be a continuous extension of the inner membrane in contact with the cytoplasmic and periplasmic space. The differential abundance of ICM in cells grown under different thermodynamic conditions supports the hypothesis that it is an adaptation to limited energy availability, as an increase in membrane-bound respiratory proteins could increase electron flux. Thus, the ICM provides extra inner-membrane surface to increase the abundance of these proteins. G. sulfurreducens is the first Thermodesulfobacterium or metal-oxide reducer found to produce ICMs., (© 2023. The Author(s).)

Inborn errors of thymic stromal cell development and function which are associated with congenital athymia result in life-threatening immunodeficiency with susceptibility to infections and autoimmunity. Athymic patients can be treated by thymus transplantation using cultured donor thymus tissue. Outcomes in patients treated at Duke University Medical Center and Great Ormond Street Hospital (GOSH) over the past three decades have shown that sufficient T-cell immunity can be recovered to clear and prevent infections, but post-treatment autoimmune manifestations are relatively common. Whilst thymus transplantation offers the chance of long-term survival, significant challenges remain to optimise the outcomes for the patients. In this review, we will discuss unmet needs and offer practical guidance based on the experience of the European Thymus Transplantation programme at GOSH. Newborn screening (NBS) for severe combined immunodeficiency (SCID) and routine use of next-generation sequencing (NGS) platforms have improved early recognition of congenital athymia and increasing numbers of patients are being referred for thymus transplantation. Nevertheless, there remain delays in diagnosis, in particular when the cause is genetically undefined, and treatment accessibility needs to be improved. The majority of athymic patients have syndromic features with acute and chronic complex health issues, requiring life-long multidisciplinary and multicentre collaboration to optimise their medical and social care. Comprehensive follow up after thymus transplantation including monitoring of immunological results, management of co-morbidities and patient and family quality-of-life experience, is vital to understanding long-term outcomes for this rare cohort of patients. Alongside translational research into improving strategies for thymus replacement therapy, patient-focused clinical research will facilitate the design of strategies to improve the overall care for athymic patients., Competing Interests: Dr E Graham Davies reports personal fees from Videregen Limited, Leeds, UK, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Howley et al.)

Almost all state-of-the-art de novo peptide sequencing algorithms now use machine learning models to encode fragment peaks and hence identify amino acids in mass spectrometry (MS) spectra. Previous work has highlighted how the inherent MS challenges of noise and missing peptide peaks detrimentally affect the performance of these models. In the present research we extracted and evaluated the encoding modules from 3 state-of-the-art de novo peptide sequencing algorithms. We also propose a convolutional neural network-graph neural network machine learning model for encoding peptide ions in tandem MS spectra. We compared the proposed encoding module to those used in the state-of-the-art de novo peptide sequencing algorithms by assessing their ability to identify b-ions and y-ions in MS spectra. This included a comprehensive evaluation in both real and artificial data across various levels of noise and missing peptide peaks. The proposed model performed best across all data sets using two different metrics (area under the receiver operating characteristic curve (AUC) and average precision). The work also highlighted the effect of including additional features such as intensity rank in these encoding modules as well as issues with using the AUC as a metric. This work is of significance to those designing future de novo peptide identification algorithms as it is the first step toward a new approach.

Geobacter sulfurreducens is a ubiquitous iron-reducing bacterium in soils, and in engineered systems, it can respire an electrode to produce measurable electric current. Its unique metabolism, heavily dependent on an extensive network of cytochromes, requires a unique cell composition. In this work, we used metallomics, cell fraction and elemental analyses, and transcriptomics to study and analyze the cell composition of G. sulfurreducens. Elemental composition studies (C, H, O, N, and ash content) showed high C:O and H:O ratios of approximately 1.7:1 and 0.25:1, indicative of more reduced cell composition that is consistent with high lipid content. Our study shows that G. sulfurreducens cells have a large amount of iron (2 ± 0.2 μg/g dry weight) and lipids (32 ± 0.5% dry weight/dry weight) and that this composition does not change whether the cells are grown with a soluble or an insoluble electron acceptor. The high iron concentration, higher than similar microorganisms, is attributed to the production of cytochromes that are abundant in transcriptomic analyses in both solid and soluble electron acceptor growth. The unique cell composition of G. sulfurreducens must be considered when growing this microorganism for lab studies and commercial applications. IMPORTANCE Geobacter sulfurreducens is an electroactive microorganism. In nature, it grows on metallic minerals by transferring electrons to them, effectively "breathing" metals. In a manmade system, it respires an electrode to produce an electric current. It has become a model organism for the study of electroactive organisms. There are potential biotechnological applications of an organism that can bridge the gap between biology and electrical signal and, as a ubiquitous iron reducer in soils around the world, G. sulfurreducens has an impact on the global iron cycle. We measured the concentrations of metals, macromolecules, and basic elements in G. sulfurreducens to define this organism's composition. We also used gene expression data to discuss which proteins those metals could be associated with. We found that G. sulfurreducens has a large amount of lipid and iron compared to other bacteria-these observations are important for future microbiologists and biotechnologists working with the organism.

Computational models can shape our understanding of cell and tissue remodelling, from cell spreading, to active force generation, adhesion, and growth. In this mini-review, we discuss recent progress in modelling of chemo-mechanical cell behaviour and the evolution of multicellular systems. In particular, we highlight recent advances in (i) free-energy based single cell models that can provide new fundamental insight into cell spreading, cancer cell invasion, stem cell differentiation, and remodelling in disease, and (ii) mechanical agent-based models to simulate large numbers of discrete interacting cells in proliferative tumours. We describe how new biological understanding has emerged from such theoretical models, and the trade-offs and constraints associated with current approaches. Ultimately, we aim to make a case for why theory should be integrated with an experimental workflow to optimise new in-vitro studies, to predict feedback between cells and their microenvironment, and to deepen understanding of active cell behaviour., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Proteomics aims to characterise system-wide protein expression and typically relies on mass-spectrometry and peptide fragmentation, followed by a database search for protein identification. It has wide ranging applications from clinical to environmental settings and virtually impacts on every area of biology. In that context, de novo peptide sequencing is becoming increasingly popular. Historically its performance lagged behind database search methods but with the integration of machine learning, this field of research is gaining momentum. To enable de novo peptide sequencing to realise its full potential, it is critical to explore the mass spectrometry data underpinning peptide identification. In this research we investigate the characteristics of tandem mass spectra using 8 published datasets. We then evaluate two state of the art de novo peptide sequencing algorithms, Novor and DeepNovo, with a particular focus on their performance with regard to missing fragmentation cleavage sites and noise. DeepNovo was found to perform better than Novor overall. However, Novor recalled more correct amino acids when 6 or more cleavage sites were missing. Furthermore, less than 11% of each algorithms' correct peptide predictions emanate from data with more than one missing cleavage site, highlighting the issues missing cleavages pose. We further investigate how the algorithms manage to correctly identify peptides with many of these missing fragmentation cleavages. We show how noise negatively impacts the performance of both algorithms, when high intensity peaks are considered. Finally, we provide recommendations regarding further algorithms' improvements and offer potential avenues to overcome current inherent data limitations., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.)

HPC or super-computing clusters are designed for executing computationally intensive operations that typically involve large scale I/O operations. This most commonly involves using a standard MPI library implemented in C/C++. The MPI-I/O performance in HPC clusters tends to vary significantly over a range of configuration parameters that are generally not taken into account by the algorithm. It is commonly left to individual practitioners to optimise I/O on a case by case basis at code level. This can often lead to a range of unforeseen outcomes. The ExSeisDat utility is built on top of the native MPI-I/O library comprising of Parallel I/O and Workflow Libraries to process seismic data encapsulated in SEG-Y file format. The SEG-Y File data structure is complex in nature, due to the alternative arrangement of trace header and trace data. Its size scales to petabytes and the chances of I/O performance degradation are further increased by ExSeisDat. This research paper presents a novel study of the changing I/O performance in terms of bandwidth, with the use of parallel plots against various MPI-I/O, Lustre (Parallel) File System and SEG-Y File parameters. Another novel aspect of this research is the predictive modelling of MPI-I/O behaviour over SEG-Y File benchmarks using Artificial Neural Networks (ANNs). The accuracy ranges from 62.5% to 96.5% over the set of trained ANN models. The computed Mean Square Error (MSE), Mean Absolute Error (MAE) and Mean Absolute Percentage Error (MAPE) values further support the generalisation of the prediction models. This paper demonstrates that by using our ANNs prediction technique, the configurations can be tuned beforehand to avoid poor I/O performance., Competing Interests: Conflicts of interestThere is no conflict of interest among the authors of this paper., (© The Author(s) 2021.)

Purpose: TAK-831 is a highly selective and potent inhibitor of D-amino acid oxidase (DAAO) currently under clinical development for schizophrenia. In this study, a mechanistic multilayer quantitative model that parsimoniously connects pharmacokinetics (PK), target occupancy (TO) and D-serine concentrations as a pharmacodynamic (PD) readout was established in mice., Methods: PK, TO and PD time-profiles were obtained in mice and analyzed by mechanistic binding kinetics model connected with an indirect response model in a step wise fashion. Brain distribution was investigated to elucidate a possible mechanism driving the hysteresis between PK and TO., Results: The observed nonlinear PK/TO/PD relationship was well captured by mechanistic modeling framework within a wide dose range of TAK-831 in mice. Remarkably different brain distribution was observed between target and reference regions, suggesting that the target-mediated slow binding kinetics rather than slow penetration through the blood brain barrier caused the observed distinct kinetics between PK and TO., Conclusion: A quantitative mechanistic model for concentration- and time-dependent nonlinear PK/TO/PD relationship was established for TAK-831 in mice with accounting for possible rate-determining process. The established mechanistic modeling framework will provide a quantitative means for multilayer biomarker-assisted clinical development in multiple central nervous system indications.

Summary: The overarching aim of microbiome analysis is to uncover the links between microbial phylogeny and function in order to access ecosystem functioning. This can be done using several experimental strategies targeting different biomolecules, including DNA (metagenomics), RNA (metatranscriptomics) and proteins (metaproteomics). Despite the importance of linking microbial function to phylogeny there are currently no visualization tools that effectively integrate this information. Chordomics is a Shiny-based application for linked -omics data analysis, allowing users to visualize microbial function and phylogeny on a single plot and compare datasets across time and environments., Availability and Implementation: Chordomics is available on GitHub: https://github.com/kevinmcdonnell6/chordomics; software is coded in R and JavaScript and a demonstration version is available at https://kmcd.shinyapps.io/ChordomicsDemo/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Irregular N-methyl-D-aspartate receptor (NMDAR) function is one of the main hypotheses employed to facilitate understanding of the underlying disease state of schizophrenia. Although direct agonism of the NMDAR has not yielded promising therapeutics, advances have been made by modulating the NMDAR co-agonist site which is activated by glycine and D-serine. One approach to activate the co-agonist site is to increase synaptic D-serine levels through inhibition of D-amino acid oxidase (DAO), the major catabolic clearance pathway for this and other D-amino acids. A number of DAO inhibitors have been developed but most have not entered clinical trials. One exception to this is sodium benzoate which has demonstrated efficacy in small trials of schizophrenia and Alzheimer's disease. Herein we provide data on the effect of sodium benzoate and an optimised Takeda compound, PGM030756 on ex vivo DAO enzyme occupancy and cerebellar D-serine levels in mice. Both compounds achieve high levels of enzyme occupancy; although lower doses of PGM030756 (1, 3 and 10 mg/kg) were required to achieve this compared to sodium benzoate (300, 1000 mg/kg). Cerebellar D-serine levels were increased by both agents with a delay of approximately 6 h after dosing before the peak effect was achieved. Our data and methods may be useful in understanding the effects of sodium benzoate that have been seen in clinical trials of schizophrenia and Alzheimer's disease and to support the potential clinical assessment of other DAO inhibitors, such as PGM030756, which demonstrate good enzyme occupancy and D-serine increases following administration of low oral doses.

Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Serotonin-1A receptors may play a role in the pathophysiology of depression and suicide. In postmortem brain tissue, agonist binding to serotonin-1A receptors is reportedly increased or unchanged in depression or suicide, while neuroimaging studies report a decrease in antagonist binding to these receptors in subjects with depression. In this study, both agonist and antagonist radioligand binding to serotonin-1A receptors were examined in postmortem orbitofrontal cortex from subjects with major depressive disorder (MDD). Brain tissue was collected at autopsy from 11 subjects with MDD and 11 age- and gender-matched normal control subjects. Two depressed subjects had a recent psychoactive substance use disorder. Six subjects with MDD had a prescription for an antidepressant drug in the last month of life, and, of these six, postmortem bloods from only two subjects tested positive for an antidepressant drug. There was no significant difference between cohorts for age, postmortem interval or tissue pH. The receptor agonist [3H]8-OH-DPAT or the antagonist [3H]MPPF were used to autoradiographically label serotonin-1A receptors in frozen sections from cytoarchitectonically-defined left rostral orbitofrontal cortex (area 47). There was no significant difference between depressed and control subjects in agonist binding to serotonin-1A receptors. However, antagonist binding was significantly decreased in outer layers of orbitofrontal cortex in MDD. This observation in postmortem tissue confirms reports using an antagonist radioligand in living subjects with depression. Decreased antagonist binding to serotonin-1A receptors in outer layers of orbitofrontal cortex suggests diminished receptor signaling and may be linked to corresponding neuronal changes detected previously in these depressed subjects.

Purpose: The American College of Sports Medicine and the Centers for Disease Control and Prevention (ACSM-CDC) recommend 30 min of daily moderate-intensity physical activity for health; however, the effectiveness of this recommendation in lowering blood pressure (BP) in hypertensives is unclear. The present study tested the hypothesis that walking activity following the ACSM-CDC physical activity recommendation would lower BP in postmenopausal women with high BP., Methods: Resting BP was measured in 24 postmenopausal women with borderline to stage 1 hypertension at baseline, 12 wk, and 24 wk. Fifteen women in the exercise (EX) group walked 3 km.d-1 above their daily lifestyle walking, whereas 9 women in the control (CON) group did not change their activity. Walking activity was self-measured with a pedometer in both groups., Results: Resting systolic BP was reduced in the EX group after 12 wk by 6 mm Hg (P < 0.005) and was further reduced by 5 mm Hg at the end of 24 wk (P < 0.005). There was no change in diastolic BP with walking. The CON group experienced no change in BP at either 12 or 24 wk. Body mass was modestly reduced by 1.3 kg in the EX group after 24 wk (P < 0.05); however, it was not correlated with the change in BP. There were no changes in selected variables known to impact BP including percent body fat, fasting plasma insulin, or dietary intake., Conclusion: In conclusion, a 24-wk walking program meeting the ACSM-CDC physical activity recommendation is effective in lowering systolic BP in postmenopausal women with borderline to stage 1 hypertension.

The accuracy of a computerized metabolic system, using inspiratory and expiratory methods of measuring ventilation, was assessed in eight male subjects. Gas exchange was measured at rest and during five stages on a cycle ergometer. Pneumotachometers were placed on the inspired and expired side to measure inspired (VI) and expired ventilation (VE). The devices were connected to two systems sampling expired O(2) and CO(2) from a single mixing chamber. Simultaneously, the criterion (Douglas bag, or DB) method assessed VE and fractions of O(2) and CO(2) in expired gas (FE(O(2)) and FE(CO(2))) for subsequent calculation of O(2) uptake (VO(2)), CO(2) production (VCO(2)), and respiratory exchange ratio. Both systems accurately measured metabolic variables over a wide range of intensities. Though differences were found between the DB and computerized systems for FE(O(2)) (both inspired and expired systems), FE(CO(2)) (expired system only), and VO(2) (inspired system only), the differences were extremely small (FE(O(2)) = 0.0004, FE(CO(2)) = -0.0003, VO(2) = -0.018 l/min). Thus a computerized system, using inspiratory or expiratory configurations, permits extremely precise measurements to be made in a less time-consuming manner than the DB technique.

Purpose: To define and describe the essential terminology associated with dose-response issues in physical activity and health., Methods: Recent consensus documents, position stands, and reports were used to provide reference definitions and methods of classifying physical activity and exercise., Results: The two principal categories of physical activity are occupational physical activity (OPA) and leisure-time physical activity (LTPA). OPA is usually referenced to an 8-h d, whereas the duration of LTPA is quite variable. LTPA includes all forms of aerobic activities, structured endurance exercise programs, resistance-training programs, and sports. Energy expenditure associated with aerobic activity can be expressed in absolute terms (kJ x min(-1)), referenced to body mass (METs), or relative to some maximal physiological response (i.e., maximal heart rate (HR) or aerobic power (VO(2max))). The net cost of physical activity should be used to express energy expenditure relative to dose-response issues. The intensity of resistance training is presented in terms relative to the greatest weight that can be lifted one time in good form (1RM). The intensity of OPA followed the guidance of a previous consensus conference. The intensity of most LTPA can be categorized using the standard aerobic exercise classifications; however, for long-duration (2+ hours) LTPA, the classifications for OPA may be more appropriate., Conclusion: Physical activities should be classified in a consistent and standardized manner in terms of both energy expenditure and the relative effort required.

Objective: The purpose of this study was to determine if the food exchange system allows subjects' nutrient intake to remain at recommended levels during a weight-loss program., Design: Subjects in an intervention were prescribed an energy-restriction diet and exercise program lasting 32 weeks, and nutrient intake was measured prestudy and after 12, 16, and 32 weeks., Subjects/setting: Healthy but overweight and obese premenopausal women (n = 219) were recruited at 6 university sites into community-based weight loss programs. One hundred fifteen women completed all aspects of the study., Intervention: Energy intake was set at 0.8 x resting metabolic rate (RMR) for weeks 1 through 12, 1.0 x RMR for weeks 13 through 20, and 1.2 x RMR for weeks 21 through 32. Energy intake was based on food exchange tables, with the number of food exchanges adjusted to encourage a distribution of 55% carbohydrate, 30% fat, and 15% protein. Subjects increased their daily walking distance to 3.2 km above prestudy levels., Main Outcome Measures: Nutrient intake was measured from four 3-day food records., Statistical Analyses Performed: Repeated measures analysis of variance, with specific time point changes assessed from paired t tests adjusted for multiple comparisons., Results: Body mass decreased by a mean +/- SD of 6.7 +/- 3.2 kg at week 12 and 7.8 +/- 6.2 kg by week 32. Walking distance increased by an average of 17.2 +/- 10.0 km/week during the first 12 weeks, and 12.4 +/- 12.4 km/week during the last 20 weeks. Despite a 23% to 36% reduction in energy intake during the study, intake of most nutrients was maintained. Intake of vitamin E, calcium, iron, and zinc decreased significantly from prestudy levels during the first 16 weeks of the intervention, but not at week 32., Applications/conclusions: Intake of most nutrients can remain at recommended levels when overweight and obese women follow the American Diabetes Association/American Dietetic Association food exchange system during a community-based weight-loss program.

The purpose of this investigation was to assess the accuracy of the COSMED K4 b2 portable metabolic measurement system against the criterion Douglas bag (DB) method. During cycle ergometry on consecutive days, oxygen consumption (VO2), carbon dioxide production (VCO2), minute ventilation (VE), and respiratory exchange ratio (R) were measured at rest and during power outputs of 50, 100, 150, 200, and 250W. No significant differences (P > 0.05) were observed in VO2 between the K4 b2 and DB at rest and at 250W. Though the K4 b2 values were significantly higher (P<0.05) than DB values at 50, 100, 150, and 200 W, the magnitude of these differences was small (0.088, 0.092, 0.096, and 0.088 L x min(-1), respectively). VCO2 and VE values from the K4 b2 were significantly lower than the DB at 200 and 250 W, while no significant differences were observed from rest through 150W. The slight overestimation of VO2 (50-200 W) combined with the underestimation of VCO2 (200 and 250W) by the K4 b2 resulted in significantly lower R values at every stage. These findings suggest the COSMED K4 b2 portable metabolic measurement system is acceptable for measuring oxygen uptake over a fairly wide range of exercise intensities.

Objective: The purpose of this study was to validate the use of the leg-to-leg bioelectrical impedance analysis (BIA) system in assessing change in body composition over 32 weeks in overweight and obese women participating in a community weight management program., Design: Intervention, with subjects prescribed an energy-restriction diet and exercise program for 32 weeks and body composition measured pre-study and after 12 and 32 weeks., Subjects and Setting: Overweight and obese premenopausal women (n=201) with no overt disease were recruited at six sites into community-based weight loss programs. One hundred and twenty-four women completed all aspects of the study., Intervention: Energy intake was set at 0.8 x resting metabolic rate (RMR) for weeks 1 through 12, 1.0 x RMR for weeks 13 through 20 and 1.2 x RMR for weeks 21 through 32. Energy intake was based on a food exchange table, with the number of food exchanges adjusted to encourage a percent distribution of 55% carbohydrate, 30% fat and 15% protein. Subjects increased their daily walking distance by 3.2 km above pre-study levels., Measures of Outcome: Underwater weighing, seven skinfolds, and leg-to-leg BIA tests were used to assess body composition., Results: A 3 x 3 repeated measures ANOVA revealed no significant difference in detecting change in FFM at 12 and 32 weeks among underwater weighing, BIA and skinfold, (F(4,492)=1.73, p=0.141) (decrease in FFM of 1.0+/-3.3 kg, 1.7+/-2.2 kg, and 1.4+/-3.3 kg respectively, 32 weeks)., Conclusions: The leg-to-leg BIA system provides a valid measure of body composition change in overweight premenopausal women during a 32-week community-based weight loss program.

In the exercising human, maximal oxygen uptake (VO2max) is limited by the ability of the cardiorespiratory system to deliver oxygen to the exercising muscles. This is shown by three major lines of evidence: 1) when oxygen delivery is altered (by blood doping, hypoxia, or beta-blockade), VO2max changes accordingly; 2) the increase in VO2max with training results primarily from an increase in maximal cardiac output (not an increase in the a-v O2 difference); and 3) when a small muscle mass is overperfused during exercise, it has an extremely high capacity for consuming oxygen. Thus, O2 delivery, not skeletal muscle O2 extraction, is viewed as the primary limiting factor for VO2max in exercising humans. Metabolic adaptations in skeletal muscle are, however, critical for improving submaximal endurance performance. Endurance training causes an increase in mitochondrial enzyme activities, which improves performance by enhancing fat oxidation and decreasing lactic acid accumulation at a given VO2. VO2max is an important variable that sets the upper limit for endurance performance (an athlete cannot operate above 100% VO2max, for extended periods). Running economy and fractional utilization of VO2max also affect endurance performance. The speed at lactate threshold (LT) integrates all three of these variables and is the best physiological predictor of distance running performance.

The purpose of this study was to test the validity of the Aerosport KB1-C portable metabolic measurement system against the criterion Douglas bag method. During cycle ergometry, simultaneous measurements of minute ventilation (VE), oxygen consumption (VO2), and carbon dioxide production (VCO2) were made at rest and at power outputs of 50, 100, 150, 200, and 250 W. No significant differences (P > 0.05) were observed for VE, VO2, and VCO2 between the KB1-C and Douglas bag at 100, 150, and 250 W, while the KB1-C was significantly different (P < 0.05) from Douglas bag values at rest, 50, and 200 W. R values were found to be significantly different (P < 0.05) at 100, 150, and 200 W, while no significant differences were observed at rest, 50, and 250 W. The fractional concentrations of oxygen (FEO2) and carbon dioxide (FECO2) were not significantly different at 50, 100, 200, and 250 W while values at rest and 150 W were significantly different (P < 0.05). These findings show that the Aerosport KB1-C portable metabolic system is acceptable for measuring oxygen uptake in the range of 1.5 and 3.5 L x min(-1), using the medium flow pneumotach setting. At lower intensities, the low-flow pneumotach setting provides acceptable results.

We examined the effect of acute exercise and reduced cortisol on pituitary and adrenal responsiveness and the impact of reduced plasma cortisol on maximal oxygen consumption (VO2max) in eight trained (T) and eight untrained (UT) males. Subjects completed two graded maximal exercise tests (GXT), each preceded by either overnight metyrapone (MET) or placebo (PLA) administration. Blood samples were collected before and after GXT. With PLA, resting corticotropin (ACTH) levels were higher in T versus UT men; however, cortisol and 11-deoxycortisol were similar between groups. Following GXT on PLA, cortisol was unchanged but 11-deoxycortisol increased in both groups; however, ACTH increased only in UT men. For both groups, cortisol, 11-deoxycortisol, and ACTH were different post-GXT with MET versus PLA. Furthermore, following GXT with MET, the ACTH response was greater in T versus UT subjects. VO2max was not altered by MET in either group. We conclude that (1) at rest, only ACTH levels differed between T and UT men; (2) individually, the GXT and MET provide a similar ACTH response in UT but not in T subjects; (3) when GXT and MET are superimposed, they provide a stronger stimulus to pituitary and adrenal reserve than either test alone; (4) the combination of MET and GXT elicits a greater ACTH response in T compared with UT men; and (5) an acute reduction in plasma cortisol does not alter VO2max.

Normotensive individuals who exhibit an exaggerated blood pressure (BP) response to exercise have an increased risk of future hypertension. However, previous studies failed to control for resting BP despite the fact that an elevated resting BP in the normotensive range is also a strong predictor of future hypertension. Therefore, we determined whether maximal systolic BP is associated with resting BP. Resting BP was measured in 68 healthy normotensive men on three separate days. The subjects then performed a graded, maximal exercise test on a Monark cycle ergometer. Maximal systolic BP was strongly correlated with resting systolic BP (r = 0.64, P < 0.0001). Subjects with elevations in systolic BP during maximal exercise (> 220 mmHg) also had higher (P < 0.005) resting BP than those without (< 220 mmHg). When stepwise regression analyses were performed, systolic BP at rest was a significant independent predictor of maximal systolic BP, explaining over 40% of the variability. These results suggest that exaggerated BP response as a predictor of future hypertension reported in previous studies may be little more than a simple reflection of elevated resting BP. Specifically, these studies should not be interpreted as demonstrating that exercise BP is a better predictor of future hypertension than resting BP alone. In the future, defining the BP 'response' to exercise as a change score (i.e. maximal BP minus resting BP) may be advantageous as it permits the effects of exercise to be examined independently of the level of resting BP.

This study examined the physiological effect of reduced plasma cortisol (C) during prolonged exercise in humans. The effects of normal C (NC) were compared with metyrapone-induced low C (LC) on plasma substrate availability and the respiratory exchange ratio during 2 h of exercise at approximately 60% peak O2 consumption in nine subjects. The C responses were compared with preexercise (Pre) levels and with a rest day (Con). At rest, C was attenuated by approximately 70% for LC compared with NC. At rest, plasma glucose, lactate, glycerol, beta-hydroxybutyrate, alanine, branched-chain amino acids, insulin, glucagon, growth hormone, epinephrine, and norepinephrine were similar under LC and NC (P > 0.05). During exercise under NC, plasma C increased compared with Pre, whereas it remained unchanged during LC. During NC, plasma C was elevated at 90 min (compared with Con) and at 120 min (compared with Con and Pre). During exercise, plasma glucose decreased to the same extent and lactate was similar under both conditions, whereas plasma glycerol, beta-hydroxybutyrate, alanine, and branched-chain amino acids were higher (P < 0.01) under NC. Plasma insulin declined (P = 0.01) to a greater extent under LC, whereas growth hormone, epinephrine, and norepinephrine tended to be higher (0.05

In calculating the physical activity index (PAI) on the college alumnus questionnaire, it is assumed that 8 kcal are expended for every 20 steps climbed. This value is equal to an energy cost of 0.40 kcal.step-1. Since it is assumed that subjects climb and descend an equal number of stairs, the total value reflects the energy cost of stepping up (estimated at 0.30 kcal.step-1) and stepping down (estimated at 0.10 kcal.step-1). However, these values appear to be based on theoretical calculations rather than empirical observation. The purpose of this study was to quantify the energy cost of stair climbing and stair descending by measuring oxygen uptake. Twenty subjects performed continuous stair-climbing and stair-descending on an escalator at a stepping rate of 70 step.min-1. Heart rate was monitored by telemetry, and oxygen uptake was measured by the Douglas bag technique from 5 to 7 min. Results showed that the gross energy cost of stair climbing is 8.6 METs, and that of stair descending is 2.9 METs. Thus, for a 70-kg person the gross caloric costs of ascending stairs (0.15 kcal.step-1) and descending stairs (0.05 kcal.step-1) are one-half of the values previously assumed. In conclusion, the algorithm for calculating PAI on the college alumnus questionnaire should be modified to reflect a total cost of 0.20 kcal for going up and down one step. Even more precise estimates can be obtained by adjusting for body weight (going up and down one flight of stairs requires 1.63 MET.min).

The beneficial effects of regular exercise are primarily based on data using land-based exercise. Currently, no data exist that demonstrate the efficacy of swimming exercise for the treatment of obesity and cardiovascular risk factors, despite the fact that swimming is a widely recommended exercise mode. Eighteen previously sedentary obese individuals were divided into a swim-training group and a non-exercising control group. The training group swam at 60% of maximal heart rate reserve for 45 min per day for 3 days per week for 10 weeks, whereas the control group remained sedentary. The swim-training programme produced significant cardiovascular training effects, as evidenced by reductions (P < 0.05) in resting and submaximal heart rate values in the training group. Significant reductions (P < 0.05) were also observed in the rating of perceived exertion and blood lactate concentrations during fixed submaximal exercise on an arm cycle ergometer. Caloric and macronutrient intake estimated from the dietary records stayed constant before and after training. Body mass, body fat percentage (36 +/- 2% vs. 35 +/- 2%) and body mass index, as well as regional adiposity, showed no statistically significant changes. Neither the training nor the control groups experienced significant changes in fasting serum glucose and insulin concentrations and glucose-insulin ratio during the study. Total, high-density lipoprotein (HDL)- and low-density lipoprotein (LDL)-cholesterol did not change significantly in either group. It was concluded that swim training of the duration, frequency and intensity used in the present study failed to elicit favourable modifications in these traditional cardiovascular risk factors.

The purpose of this study was to compare muscle fibre type proportions and capillary density in untrained, college-aged blacks (n = 14) and whites (n = 14). Both groups were similar in terms of peak oxygen uptake (VO2peak), measured during cycle ergometry (blacks: 42.6 +/- 4, whites: 44.3 +/- 4 ml.kg-1 min-1, mean +/- SD). Muscle samples were obtained from the quadriceps femoris (vastus lateralis) by the needle biopsy technique. Fibre type was determined by myosin ATPase stain (pH = 4.54) and capillaries were identified by amylase-periodic acid Schiff (PAS) stain. The percentage of type I, IIa, and IIb fibres in the blacks was 39.5 +/- 11.5, 40.0 +/- 8.4, and 22.8 +/- 9.8, respectively. In whites the percentage of type I, IIa, and IIb fibres was 44.9 +/- 8.5, 36.6 +/- 6.9, and 18.3 +/- 9.6, respectively. No significant differences were noted between the two racial groups for type I, IIa, or IIb fibres. Capillary density was 277 +/- 39/mm2 in the blacks compared to 289 +/- 32/mm2 in the whites. Capillary density was positively correlated to percentage of type I fibres (r = 0.497) and negatively correlated to percentage of type IIa fibres (r = -0.389), in the overall study population. These data suggest that if racial differences in fibre type do exist, such differences are small compared to the variability in this measure.

Background: Despite the fact that swimming is often recommended for the prevention and treatment of hypertension, no study has examined the potential efficacy of regular swimming exercise for lowering the blood pressure in hypertensive humans., Objective: To test the hypothesis that regular swimming exercise lowers the resting blood pressure., Design: A 10-week closely supervised swimming training program compared with a non-exercising control group., Patients: Eighteen previously sedentary men and women [aged 48 +/- 2 years (mean +/- SEM)] with stage 1 or 2 essential hypertension., Results: The resting heart rated, an index of cardiovascular adaptation, decreased in the swimming training group from 81 +/- 4 to 71 +/- 3 beats/min (P < 0.01). The body mass and body fat percentage did not show statistically significant changes. The systolic blood pressure of patients in the seated position fell significantly (P < 0.05) from 150 +/- 5 to 144 +/- 4 mmHg. The seated diastolic blood pressure did not change significantly. A similar magnitude of reductions in systolic blood pressure (P < 0.05) was also found in patients in the supine position. No significant changes in plasma catecholamine concentrations, casual forearm vascular resistance, plasma volume and blood volume were observed. There were no significant changes in any of these variables in the control group., Conclusion: Swimming training elicits significant reductions in arterial blood pressure at rest in individuals with hypertension. This is a clinically important finding since swimming can be a highly useful alternative to land-based exercises for hypertensive patients with obesity, exercise-induced asthma, or orthopedic injuries.

The traditional view of VO2max owes a great deal to the work of A. V. Hill, who conducted experiments on exercising man in Manchester, England, in the 1920's. Hill and colleagues proposed that there is an upper limit to oxygen uptake (VO2max), that there are inter-individual differences in this variable, and that VO2max is limited by the circulatory and/or respiratory systems. They demonstrated that oxygen uptake increases linearly with running speed, but in some subjects it eventually "reaches a maximum beyond which no effort can drive it," a phenomenon now referred to as the VO2 plateau. In recent years, Timothy Noakes has strongly criticized Hill's concept of VO2max. He maintains that the absence of a VO2 plateau in some subjects is proof that oxygen delivery is not a limiting factor for VO2max. This view fails to recognize that the plateau is not the principal evidence for a cardiorespiratory limitation. Noakes rejects the VO2max paradigm of A. V. Hill in its entirety. The alternative paradigm he proposes is that endurance performance is limited by "muscle factors." Noakes suggests that the best distance runners have muscle characteristics that allow them to achieve higher running speeds, and since running speed is linearly related to oxygen uptake, an indirect consequence of this is that they will have higher VO2max values. This is exactly the opposite of how the relationship between VO2max and running speed at the end of a maximal exercise test should be viewed. Noakes offers little evidence to support his views, and they conflict with a vast body of scientific evidence showing that oxygen transport is a major determinant of endurance performance. After carefully reviewing the evidence on both sides of the issue, we conclude that the older "classical" VO2max paradigm of A. V. Hill is the correct one.

Objectives: The objectives of the present study were (1) to evaluate the pressor response to an isometric handgrip exercise in normotensive black and white males; (2) to measure plasma catecholamine levels pre- and post-exercise, as an index of sympathetic nervous system activity; and (3) to quantify the pressor response to bolus intravenous injections of phenylephrine (an alpha-specific agonist)., Methods: Cardiovascular and catecholamine responses to an isometric handgrip exercise (3 minutes at 30% MVC) were measured in 15 normotensive blacks and whites. In another phase of the study, pressor responses to bolus injections of phenylephrine were assessed to evaluate alpha-adrenergic sensitivity., Results: The blood pressure in the blacks increased from 119/69 to 160/120 mm HG during isometric exercise, while in the whites it increased from 118/67 to 153/110 mm HG. The blacks exhibited a greater diastolic blood pressure reactivity, as evidenced by a significant race x time interaction (p < 0.05). The heart rate responses were not significantly different between the two groups. The plasma levels of norepinephrine were similar at rest, but were 25% lower in the blacks than in the whites following isometric exercise (p < 0.01). Black subjects also demonstrated an increased pressor response to intravenous injections of phenylephrine at rest (p < 0.05)., Conclusions: The enhanced vascular sensitivity to norepinephrine may have contributed to the greater exercise pressor response in the blacks.

This study compared the classic discontinuous Taylor et al. (1955) protocol to a continuous version of the same protocol to evaluate maximal physiological responses, and the quantitative values and incidence of achievement of the various maximal oxygen uptake (VO2max) criteria in 10 males (24.1 +/- 2.5 yr). Criteria were a plateau in VO2 (change < 2.1 ml.kg-1.min-1), HR = age adjusted maximal, PER > or = 1.15, and lactate > 8 mmol.l-1. Values for VO2max (56.8 +/- 4.7 vs 55.8 +/- 4.2 ml.kg-1.min-1), ventilation (150.7 +/- 16 vs 149.5 +/- 17.5 l.min-1 BTPS), and HR (186.3 +/- 7.7 beats.min-1 vs 191.7 +/- 6.7 beats.min-1) were similar (P < 0.05) between the discontinuous protocol (DT) and the continuous protocol (CT), respectively. Values for RER (1.28 +/- 0.05 vs 1.22 +/- 0.05) and lactate (14.3 +/- 2.7 vs 11.9 +/- 2.7 mmol.l-1) were greater (P < 0.05) on the DT than the CT. Criteria achievement were the following: 40% (CT) and 10% (DT) for HR; 50% (CT) and 60% (DT) for a VO2 plateau; and, 90% (CT) and 100% (DT) for RER and lactate. It is concluded that a VO2 plateau is not a prerequisite for defining VO2max and is of limited use as the primary objective criterion for evaluating the quality of a graded exercise test. Therefore, the achievement of secondary objective criteria, specifically RER and lactate in combination, increases the likelihood that the highest VO2 value achieved is VO2max.

In an attempt to determine whether the lactate threshold (LT) is the result of a sudden increase in plasma epinephrine (Epi), eight healthy college-aged males (22.4 +/- 0.4 yr) were recruited to perform three cycle ergometer exercise tests. Each subject performed a graded exercise test (GXT) to determine LT, Epi threshold, and norepinephrine threshold (64.6 +/- 2.4, 62.5 +/- 2.4, and 60.8 +/- 4.3% peak oxygen uptake, respectively). Each subject also completed, in random order, two 30-min submaximal (20% peak oxygen uptake below LT) exercise tests. During one test, graded Epi infusions were carried out at rates of 0.02-0.12 micrograms.kg-1.min-1; the other served as a control test. Infusion resulted in plasma Epi concentrations similar to those observed during GXT. The increase in blood lactate with Epi infusion was significantly greater than that during the control test (3.0 +/- 0.3 vs. 1.4 +/- 0.1 mmol/l at minute 30) but did not approach levels exhibited during GXT. We suggest an interaction of the increasing plasma Epi with other factors may be responsible for the sudden increase in blood lactate during graded exercise.

Historically, the achievement of maximal oxygen uptake (VO2max) has been based on objective criteria such as a leveling off of oxygen uptake with an increase in work rate, high levels of lactic acid in the blood in the minutes following the exercise test, elevated respiratory exchange ratio, and achievement of some percentage of an age-adjusted estimate of maximal heart rate. These criteria are reviewed relative to their history, the degree to which they have been achieved in published research, and how investigators and reviewers follow them in current practice. The majority of the criteria were based on discontinuous protocols, often carried out over several days. Questions are raised about the applicability of these criteria to modern continuous graded exercise test protocols, and our lack of consistency in the terminology we use relative to the measurement of maximal oxygen uptake.

The purpose of this study was to examine the cardiovascular responses of sprinters and distance runners to isometric (IE) and dynamic exercise (DE). Normotensive males were selected and grouped according to prior running performance: sprinter (N = 6) or distance runner (N = 6). Each subject completed an incremental DE (cycle ergometry) test (6-min stages) at 20%, 40%, and 60% of VO2peak, and 3 min of isometric handgrip at 30% of MVC. Blood pressure (BP), heart rate (HR), cardiac output (Q), oxygen uptake, and blood lactate were measured, while mean arterial blood pressure (MABP), cardiac index (CI), and systemic vascular resistance (SVR) were calculated during each stage of DE. BP and HR were measured during each minute of IE. Muscle biopsies of the vastus lateralis revealed a significant difference in capillary density (capillaries per mm2 and capillaries per fiber) between the sprinters and distance runners (323 +/- 23 vs 409 +/- 27 and 2.2 +/- 0.2 vs 3.2 +/- 0.3, P < 0.05) and for the percentage of Type I fibers (46.4 +/- 4% vs 64.8 +/- 7%, P < 0.05). The IE challenge elicited a greater BP response at minute 3 in the sprinters, which was associated with a greater HR response. During DE, there were no significant differences in BP or HR between the groups. However, at 60% of VO2peak, the distance runners had a significantly higher cardiac index and a lower systemic vascular resistance than the sprinters (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Variation in the aerobic demand (VO2) of submaximal running was quantified among trained and untrained subjects stratified by performance capability. Based on a retrospective analysis of seven published studies, maximal aerobic power (VO2max), and submaximal VO2 values were analyzed in three groups of trained distance runners (Category 1 (C1) (elite runners; N = 22), Category 2 (C2) (sub-elite runners; N = 41), and Category 3 (C3) (good runners; N = 16), and one group (N = 10) of untrained subjects (Category 4; C4). Results indicated that VO2max differed significantly (P < 0.05) across groups, such that C1 > C2 > C3 > C4. Analysis of submaximal VO2 data also revealed that C4 was more uneconomical than C1, C2, and C3 and that C2 and C3 were less economical than C1. Average within-group variability in submaximal VO2 was similar across categories and a marked overlap of minimum, mean and maximal economy values existed across categories. These data suggest that 1) trained subjects are more economical than untrained subjects, 2) elite runners display better economy compared to less-talented counterparts, and 3) economical and uneconomical runners can be found in all performance categories.

Polylactate (PL), a semi-soluble amino acid/lactate salt, is a newly developed carbohydrate supplement purported to increase endurance. Our purpose was to determine if the addition of PL to a glucose polymer solution (GP) extends exercise time relative to a pure GP solution. In a double blind and random crossover design, 5 subjects exercised twice to exhaustion at 70% of VO2max. During the trials, they consumed GP or a GP/PL mixture at the rate of 0.3 g carbohydrate per kg of body wt in a 7% solution every 20 min until exhaustion. The GP/PL mixture contained 6.25 g GP to 0.75 g PL per 100 ml of water. Mixture composition was critical because PL, as supplied by the manufacturer and under our experimental conditions, produced severe gastro-intestinal efflux in concentrations > or = 2.5%; PL was tolerable in concentrations < or = 0.75%. At 20 min intervals, we measured VO2, respiratory exchange ratio, heart rate, and perceived exertion. At 30 min intervals, we measured serum glucose, insulin, free fatty acids, and glycerol as well as whole blood lactate and pH. We found that the addition of PL to a GP solution had no measurable physiological or performance effects.

The present investigation compared the pattern of substrate utilization during prolonged walking in obese women with upper (UB) and lower (LB) body fat patterns and the effect of beta-adrenergic receptor blockade on that response. Twenty healthy, premenopausal, obese volunteers (% fat > or = 30%) were characterized by waist-to-hip (WHR) circumference ratios into two distinct groups (UB: WHR > or = 0.85, LB: WHR < or = 0.75). The groups (n = 10 each) were similar for BMI, age, % fat, and maximal aerobic power (VO2max). Subjects participated in two 60-min walk bouts at 55-60% VO2max. The trials (placebo (C) and 80 mg propranolol (PR)) were performed in random order, 110 min after ingestion, with 2-4 days between tests. Open-circuit spirometry was employed to calculate the VO2, VCO2 and respiratory exchange ratio (RER) at 10 min intervals. A significant (P < 0.0001) decline in RER with time was evident in both trials. However, no group differences existed in RER values during either the C trial (RER range = 0.81-0.88) or the PR trial (RER range = 0.86-0.91). The PR trial induced a 23% reduction in the amount of calories utilized as fat compared to C in both WHR groups. Both groups of women showed equal capabilities for performing prolonged exercise with typical and appropriate metabolic shift in fuel mobilization from carbohydrate to fat. Despite the well-defined differences in metabolic activity of adipose cells shown in vitro, this study indicates that women with significantly different regions of adipose tissue stores have similar physiological potentials for substrate use during exercise.

The application of automated blood pressure measurement during exercise has been limited by inaccuracies introduced by the effects of accompanying motion and noise. We evaluated a newly developed automated blood pressure monitor for measuring exercise blood pressure (Colin STBP-680; Colin, San Antonio, Texas, USA). The STBP-680 uses acoustic transduction with the assistance of the electrocardiogram R-wave to trigger the sampling period for blood pressure measurement. The automated monitor readings were compared with simultaneous technician mercury sphygmomanometric readings in the same arm. Blood pressure was measured in 18 men at rest and during exercise at 40% VO2 peak, (low intensity), 70% VO2 peak (moderate intensity) and VO2 peak (high intensity) on the cycle ergometer. Mean(s.d.) systolic blood pressure difference between the automated monitor and mercury manometer readings at rest and during exercise at low, moderate and high work intensities were 3(0) mmHg, 3(2) mmHg, 1(1) mmHg, and 0(11) mmHg respectively (analysis of variance; P > 0.05). Resting diastolic blood pressure obtained with the STBP-680 was similar to the mercury manometer readings (78(10) versus 81(7) mmHg (P > 0.05). Exercise diastolic pressure at the low level of work intensity was almost identical between the automated monitor and mercury manometer readings (64(8) versus 65(10) mmHg (not significant)). Diastolic blood pressure readings between the STBP-680 and mercury manometer showed a greater difference at the moderate and high workloads (11 mmHg and 9 mmHg, respectively), but this difference was not significant (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to examine the effect of one- and two-leg training on arm and two-leg maximum aerobic power. Seven subjects cycle-trained both legs simultaneously for 30 min.day-1, 4 days.week-1 for 4 weeks. Nine subjects cycle-trained each leg 15 min.day-1, 4 days.week-1 for 4 weeks. Both groups trained at a heart rate equal to that measured at 75% of their two-leg maximum aerobic power. Thus, during each training session the groups performed 30 min of work at the same heart rate intensity. Five subjects served as a non-training control group. Arm and leg maximum oxygen uptake tests were conducted before and after training. Only two-leg training induced significant gains in arm aerobic power (P < 0.0003), whereas both modes of training resulted in significant increases in two-leg aerobic power (P < 0.0008). The data demonstrate that improvements in arm aerobic power were dependent on the quantity of leg muscle mass involved in the training, whereas gains in two-leg aerobic power occurred regardless of whether the legs were trained separately or simultaneously.

The purpose of this study was to examine the effect of moderate resistance weight training (MRWT) on peak arm aerobic power as measured by arm cranking ergometry. Fourteen sedentary college age males, divided equally into two groups, served as subjects. The seven subjects in the MRWT group completed 12, 1-hr bouts of weight lifting over a 4 week period, exercising on Monday, Wednesday and Friday of each week. Exercise sessions included 3 sets of 10 repetitions of the following lifts: bench press, overhead dumbbell press, dumbbell arm curl, and behind the neck pull down. The remaining seven subjects served as a non-training control group, whose purpose was to account for possible learning effects on the arm ergometer test that could distort the statistical relevance of the aerobic power data. These subjects did not serve as a control for the weight training exercises, as the procedures used to determine muscular strength may produce a modest training effect. Peak arm aerobic power and muscular strength, as measured by the one-repetition maximum for each lift, were determined before and after the training program. The average increase in strength for all lifts combined for the trained group was 20.0%. They also experienced a 13.4% (p < .005) increase in peak arm aerobic power, whereas there was no significant change in this variable for the control group. It is concluded that peak arm aerobic power is enhanced by the changes in muscular strength produced by 4 wks of MRWT.