Physiological Demands of Basic Fire Management Tasks in Members of the Canadian Armed Forces: A Pilot Study.

INTRODUCTION: Members of the Canadian Armed Forces (CAF) are required to meet the minimum standards of the Fitness for Operational Requirements of CAF Employment (FORCE) job-based simulation test (JBST) and must possess the capacity to perform other common essential tasks. One of those tasks is to perform basic fire management tasks during fire emergencies to mitigate damage and reduce the risk of injuries and/or death until professional firefighters arrive at the scene. To date however, the physiological demands of common firefighting tasks have mostly been performed on professional firefighters, thus rendering the transferability of the demands to the general military population unclear. This pilot study aimed to quantify, for the first time, the physiological demands of basic fire management tasks in the military, to determine if they are reflected in the FORCE JBST minimum standard. We hypothesized that the physiological demands of basic fire management tasks within the CAF are below the physiological demands of the FORCE JBST minimum standard, and as such, be lower than the demands of professional firefighting. MATERIALS AND METHODS: To achieve this, 21 CAF members (8 females; 13 males; mean [SD] age: 33 [10] years; height: 174.5 [10.5] cm; weight: 85.4 [22.1] kg, estimated maximal oxygen uptake [$\dot V$O2peak]: 44.4 (7.4) mL kg-1 min-1) participated in a realistic, but physically demanding, JBST developed by CAF professional firefighting subject matter experts. The actions included lifting, carrying, and manipulating a 13-kg powder fire extinguisher and connecting, coupling, and dragging a 38-mm fire hose over 30 m. The rate of oxygen uptake ($\dot V$O2), heart rate, and percentage of heart rate reserve were measured continuously during two task simulation trials, which were interspersed by a recovery period. Rating of perceived exertion (6-no exertion; 20-maximal exertion) was measured upon completion of both task simulations. Peak $\dot V$O2 ($\dot V$O2peak) was estimated based on the results of the FORCE JBST. RESULTS: The mean (SD) duration of both task simulation trials was 3:39 (0:19) min:s, whereas the rest period in between both trials was 62 (19) minutes. The mean O2 was 21.1 (4.7) mL kg-1 min-1 across trials, which represented 52.1 (12.2) %$\dot V$O2peak and ∼81% of the FORCE JBST. This was paralleled by a mean heart rate of 136 (18) beats min-1, mean percentage of heart rate reserve of 61.2 (10.8), and mean rating of perceived exertion of 11 ± 2. Other physical components of the JBST consisted of lifting, carrying, and manipulating a 13-kg load for ∼59 seconds, which represents 65% of the load of the FORCE JBST. The external resistance of the fire hose drag portion increased up to 316 N, translating to a total of 6205 N over 30 m, which represents 96% of the drag force measured during the FORCE JBST. CONCLUSIONS: Our findings demonstrate that the physiological demands of basic fire management tasks in the CAF are of moderate intensity, which are reflected in the CAF physical fitness standard. As such, CAF members who achieve the minimum standard on the FORCE JBST are deemed capable of physically performing basic fire management tasks during fire emergencies.

Development of mAb-based polyglutamine-dependent and polyglutamine length-independent huntingtin quantification assays with cross-site validation.

Huntington's disease (HD) is caused by an expansion of the CAG trinucleotide repeat domain in the huntingtin gene that results in expression of a mutant huntingtin protein (mHTT) containing an expanded polyglutamine tract in the amino terminus. A number of therapeutic approaches that aim to reduce mHTT expression either locally in the CNS or systemically are in clinical development. We have previously described sensitive and selective assays that measure human HTT proteins either in a polyglutamine-independent (detecting both mutant expanded and non-expanded proteins) or in a polyglutamine length-dependent manner (detecting the disease-causing polyglutamine repeats) on the electrochemiluminescence Meso Scale Discovery detection platform. These original assays relied upon polyclonal antibodies. To ensure an accessible and sustainable resource for the HD field, we developed similar assays employing monoclonal antibodies. We demonstrate that these assays have equivalent sensitivity compared to our previous assays through the evaluation of cellular and animal model systems, as well as HD patient biosamples. We also demonstrate cross-site validation of these assays, allowing direct comparison of studies performed in geographically distinct laboratories.

Heat tolerance and the validity of occupational heat exposure limits in women during moderate-intensity work.

To mitigate excessive rises in core temperature (>1 °C) in non-heat acclimatized workers, the American Conference of Governmental Industrial Hygienists (ACGIH) provides heat stress limits (Action Limit Values; ALV), defined by the wet-bulb globe temperature (WBGT) and a worker's metabolic rate. However, since these limits are based on data from men, their suitability for women remains unclear. We therefore assessed core temperature and heart rate in men (n = 19; body surface area-to-mass ratio: 250 (SD 17) cm2/kg) and women (n = 15; body surface area-to-mass ratio: 268 (SD 24) cm2/kg) aged 18-45 years during 180 min of walking at a moderate metabolic rate (200 W/m2) in WBGTs below (16 and 24 °C) and above (28 and 32 °C) ACGIH ALV. Sex did not significantly influence (i) rises in core temperature, irrespective of WBGT, (ii) the proportion of participants with rises in core temperature >1 °C in environments below ACGIH limits, and (iii) work duration before rises in core temperature exceeded 1 °C or volitional termination in environments above ACGIH limits. Although further studies are needed, these findings indicate that for the purpose of mitigating rises in core temperature exceeding recommended limits (>1 °C), ACGIH guidelines have comparable effectiveness in non-heat acclimatized men and women during moderate-intensity work. Novelty: Sex did not appreciably influence thermal strain nor the proportion of participants with core temperatures exceeding recommended limits. Sex did not significantly influence tolerance to uncompensable heat stress. Despite originating from data obtained in only men, current occupational heat stress guidance offered comparable effectiveness in men and women.

Heat Tolerance and Occupational Heat Exposure Limits in Older Men with and without Type 2 Diabetes or Hypertension.

PURPOSE: To mitigate rises in core temperature >1°C, the American Conference of Governmental Industrial Hygienists (ACGIH) recommends upper limits for heat stress (action limit values [ALV]), defined by wet-bulb globe temperature (WBGT) and a worker's metabolic rate. However, these limits are based on data from young men and are assumed to be suitable for all workers, irrespective of age or health status. We therefore explored the effect of aging, type 2 diabetes (T2D), and hypertension (HTN) on tolerance to prolonged, moderate-intensity work above and below these limits. METHODS: Core temperature and heart rate were assessed in healthy, heat unacclimatized young (18-30 yr, n = 13) and older (50-70 yr) men (n = 14) and heat unacclimatized older men with T2D (n = 10) or HTN (n = 13) during moderate-intensity (metabolic rate: 200 W·m-2) walking for 180 min (or until termination) in environments above (28°C and 32°C WBGT) and below (16°C and 24°C WBGT) the ALV for continuous work at this intensity (25°C WBGT). RESULTS: Work tolerance in the 32°C WBGT was shorter in men with T2D (median [IQR]; 109 [91-173] min; P = 0.041) and HTN (120 [65-170] min; P = 0.010) compared with healthy older men (180 [133-180] min). However, aging, T2D, and HTN did not significantly influence (i) core temperature or heart rate reserve, irrespective of WBGT; (ii) the probability that core temperature exceeded recommended limits (>1°C) under the ALV; and (iii) work duration before core temperature exceeded recommended limits (>1°C) above the ALV. CONCLUSION: These findings demonstrate that T2D and HTN attenuate tolerance to uncompensable heat stress (32°C WBGT); however, these chronic diseases do not significantly impact thermal and cardiovascular strain, or the validity of ACIGH recommendations during moderate-intensity work.

Self-reported physical activity level does not alter whole-body total heat loss independently of aerobic fitness in young adults during exercise in the heat.

We evaluated whether self-reported physical activity (PA) level modulates whole-body total heat loss (WB-THL) as assessed using direct calorimetry in 10 young adults (aged 22 ± 3 years) matched for rate of peak oxygen consumption (an index for aerobic fitness), but of low and high self-reported PA, during 3 incremental cycling bouts (∼39%, 52%, and 64% peak oxygen consumption) in the heat (40 °C). We showed that level of self-reported PA does not appear to influence WB-THL independently of peak oxygen consumption.

Increasing age is a major risk factor for susceptibility to heat stress during physical activity.

We evaluated the extent to which age, cardiorespiratory fitness, and body fat can independently determine whole-body heat loss (WBHL) in 87 otherwise healthy adults. We show that increasing age is a major predictor for decreasing WBHL in otherwise healthy adults (aged 20-70 years), accounting for 40% of the variation in the largest study to date. While greater body fat also had a minor detrimental impact on WBHL, there was no significant role for cardiorespiratory fitness.

Development and Validation of a Quasi-Quantitative Bioassay for Neutralizing Antibodies Against CP-870,893.

The human monoclonal antibody CP-870,893 is a CD40 receptor agonist currently being developed for the treatment of cancer. A bioassay to measure neutralizing antibodies (Nab) to CP-870,893 in 5% human serum matrix was developed and validated utilizing the Daudi cell line and flow cytometric detection. Additionally, samples from CP-870,893 treated cynomolgus monkeys were analyzed in the bioassay and compared to results obtained using a competitive receptor-binding (CRB) Nab immunoassay to determine if the CRB assay may be used in place of the bioassay. Treatment of Daudi cells for 2 d with CP-870,893 leads to a concentration-dependent increase in CD54 cell surface expression. The presence of antidrug Nab attenuates CP-870,893 binding to CD40 and the induction of CD54. An anti-idiotype monoclonal antibody (Mab) and a monkey sera pool were identified as positive controls for neutralization of CP-870,893. During development, it was observed that the assay robustness was altered by culture media and FBS substitutions. For validation the following parameters were established: cutpoint factors in the presence (0.779) and absence (1.282) of 50 ng/ml CP-870,893, linear region of the concentration-response (1-100 ng/ml CP-870,893), intra- and inter-assay precision (CV

Potent inhibitors of the hepatitis C virus NS3 protease: design and synthesis of macrocyclic substrate-based beta-strand mimics.

The virally encoded NS3 protease is essential to the life cycle of the hepatitis C virus (HCV), an important human pathogen causing chronic hepatitis, cirrhosis of the liver, and hepatocellular carcinoma. The design and synthesis of 15-membered ring beta-strand mimics which are capable of inhibiting the interactions between the HCV NS3 protease enzyme and its polyprotein substrate will be described. The binding interactions between a macrocyclic ligand and the enzyme were explored by NMR and molecular dynamics, and a model of the ligand/enzyme complex was developed.

Peptide-based inhibitors of the hepatitis C virus NS3 protease: structure-activity relationship at the C-terminal position.

The structure-activity relationship at the C-terminal position of peptide-based inhibitors of the hepatitis C virus NS3 protease is presented. The observation that the N-terminal cleavage product (DDIVPC-OH) of a substrate derived from the NS5A/5B cleavage site was a competitive inhibitor of the NS3 protease was previously described. The chemically unstable cysteine residue found at the P1 position of these peptide-based inhibitors could be replaced with a norvaline residue, at the expense of a substantial drop in the enzymatic activity. The fact that an aminocyclopropane carboxylic acid (ACCA) residue at the P1 position of a tetrapeptide such as 1 led to a significant gain in the inhibitory enzymatic activity, as compared to the corresponding norvaline derivative 2, prompted a systematic study of substituent effects on the three-membered ring. We report herein that the incorporation of a vinyl group with the proper configuration onto this small cycle produced inhibitors of the protease with much improved in vitro potency. The vinyl-ACCA is the first reported carboxylic acid containing a P1 residue that produced NS3 protease inhibitors that are significantly more active than inhibitors containing a cysteine at the same position.

Effects of volatile aromatics, aldehydes, and phenols in tobacco smoke on viability and proliferation of mouse lymphocytes.

Thirteen chemicals present in tobacco smoke were assessed for their effect on viability and proliferation of mouse lymphocytes in vitro. Acetaldehyde, benzene, butyraldehyde, isoprene, styrene, and toluene produced no effect on either viability or proliferation after 3 h of exposure. Formaldehyde, catechol, acrylonitrile, propionaldehyde, and hydroquinone significantly inhibited T-lymphocyte and B-lymphocyte proliferation with IC50 values ranging from 1.19 x 10(-5) M to 8.20 x 10(-4) M after 3 h of exposure. Acrolein and crotonaldehyde not only inhibited T-cell and B-cell proliferation, but also acted on viability with IC50 values ranging from 2.06 x 10(5) M to 4.26 x 10(-5) M. Mixtures of acrolein, formaldehyde, and propionaldehyde or crotonaldehyde were tested and interactive effects at 0.5 and 1 x IC50 were observed. Two mixtures significantly inhibited T-cell proliferation when compared to the control at 0.1 x IC50 concentration. The present study shows that some chemicals known to be present in tobacco smoke exert an effect on lymphocyte viability and proliferation in vitro.