Topical Cannabidiol Application May Not Attenuate Muscle Soreness or Improve Performance: A Randomized, Double-Blinded, Placebo-Controlled Pilot Study.

Purpose: The purpose of this pilot study was to investigate cannabidiol (CBD) cream's effects on muscle soreness and performance after exercise. Materials and Methods: This double-blinded, placebo-controlled experiment included 15 men and 13 women (n = 28; mean ± standard deviation age: 23.29 ± 2.54 years) untrained in lower-body resistance training. Participants were randomized into control (NG, n = 9), CBD (CG, n = 9), or placebo (PG, n = 10) groups. Participants completed a lower-body fatigue protocol (FP) consisting of unilateral maximal concentric and eccentric isokinetic muscle actions of the quadriceps and hamstrings (5 sets, 10 repetitions, both legs). CG and PG participants applied ∼100 mg CBD or placebo cream, respectively, matched for weight and appearance to the quadriceps on three separate days. NG participants engaged in a sitting rest period matched in duration to cream application processes. Questionnaires, pressure-pain threshold (PPT), peak torque test (PTT), and countermovement jump (CMJ) were assessed. Mixed-model analysis of variance was conducted to assess main effects and interactions (group × muscle × time; group × time). Results: There were no significant interactions or main effects for group for PPT, CMJ, or PTT. There were main effects for time (p < 0.05) for all soreness questions, PPT, CMJ, and PTT. There was one significant interaction (group × time; p = 0.045) for cream/rest effect questions, in which PG participants perceived the effect of cream to be greater than the effect of rest for NG participants. There were main effects for group (p ≤ 0.031) for all soreness questions, in which PG participants perceived enhanced recovery. Conclusions: The present pilot study did not discover any significant impacts of CBD cream use for muscle recovery. For individuals seeking to attenuate muscle soreness and improve performance, the current dose of this topical CBD product may not be an effective treatment.

Posture-related changes in sympathetic baroreflex sensitivity during normal pregnancy.

Normal pregnancy is associated with vast adjustments in cardiovascular autonomic control. Sympathetic baroreflex sensitivity has been reported to be attenuated during pregnancy in animal models, but most studies in humans are cross-sectional and findings from longitudinal case studies are inconclusive. It remains unclear how sympathetic baroreflex sensitivity is altered longitudinally during pregnancy within an individual in different body postures. Therefore, this study examined the impact of posture on sympathetic baroreflex sensitivity in 24 normal-weight normotensive pregnant women. Spontaneous sympathetic baroreflex sensitivity was assessed during early (6-11 weeks) and late (32-36 weeks) pregnancy and 6-10 weeks postpartum in the supine posture and graded head-up tilt (30° and 60°). In addition, data from the postpartum period were compared with (and no different to) 18 age-matched non-pregnant women to confirm that the postpartum period was reflective of a non-pregnant condition (online supplement). When compared with postpartum (-3.8 ± 0.4 bursts/100 heartbeats/mmHg), supine sympathetic baroreflex sensitivity was augmented during early pregnancy (-5.9 ± 0.4 bursts/100 heartbeats/mmHg, P < 0.001). However, sympathetic baroreflex sensitivity at 30° or 60° head-up tilt was not different between any phase of gestation (P > 0.05). When compared to supine, sympathetic baroreflex sensitivity at 60° head-up tilt was significantly blunted during early (Δ2.0 ± 0.7 bursts/100 heartbeats/mmHg, P = 0.024) and late (Δ1.5 ± 0.6 bursts/100 heartbeats/mmHg, P = 0.049) pregnancy but did not change postpartum (Δ0.4 ± 0.6 bursts/100 heartbeats/mmHg, P = 1.0). These data show that time-course changes in sympathetic baroreflex sensitivity are dependent on the posture it is examined in and provides a foundation of normal blood pressure regulation during pregnancy for future studies in women at risk for adverse pregnancy outcomes.

Impact of high-salt versus low-salt intake on the response of sympathetic baroreflex sensitivity to orthostasis in women with a history of normal pregnancy.

Previous studies have demonstrated that sympathetic baroreflex sensitivity (BRS) increases during orthostatic stress in humans. We recently showed that dietary salt intake affects sympathetic neural control in healthy premenopausal women. This study aimed to determine whether salt loading versus salt reduction would impact sympathetic BRS during orthostasis in premenopausal women with a history of normal pregnancy. Nine healthy women [42 ± 3 (SD) yr] were given a standardized isocaloric high-salt (250 mEq sodium/day) or low-salt (50 mEq sodium/day) diet for 1 wk each (∼2 mo apart with the order randomized), whereas water intake was ad libitum. Laboratory testing was performed following each high- and low-salt period in the midluteal phase of the menstrual cycle. Hemodynamics and muscle sympathetic nerve activity (MSNA) were measured at baseline (supine; 2 min) and during a graded head-up tilt (30° for 5 min and 60° for 20 min). Sympathetic BRS was assessed during baseline and head-up tilt. Hemodynamics were not different between salt conditions during baseline or tilt. Both supine and upright MSNA indices were lower in high salt than low salt (all P < 0.05), however, there was no interaction effect (P = 0.507-0.996). On moving from supine to upright, sympathetic BRS remained unchanged in high salt but increased in low salt (P = 0.028 for interaction). Thus, salt loading diminishes the responsiveness of sympathetic BRS during orthostasis compared with salt reduction in healthy premenopausal women with prior normal pregnancy. Whether this is one underlying mechanism for salt-induced development of hypertension during ambulation remains to be determined.

Predictors of Work Efficiency in Structural Firefighters.

OBJECTIVE: Develop a novel work efficiency (WE) metric to quantify firefighter physical ability and identify correlates of WE. METHODS: Physical fitness and anthropometric measurements were taken on 19 male firefighters. Firefighters performed a timed maximal effort simulated fireground test (SFGT). WE was quantified as: (1/[Air depletion × SFGT completion time]) × 10,000. Regression analyses were used to identify predictors of WE. RESULTS: WE was significantly correlated to age, relative body fat, fat mass, occupational experience, jump height, inverted row repetitions, relative bench press and squat strength, treadmill time to exhaustion, relative ventilatory threshold, and relative peak oxygen consumption. Treadmill time to exhaustion and relative lower body strength accounted for the greatest variance in WE (R2 = 0.72, root mean square error = 0.07). CONCLUSION: Aerobic endurance and relative lower body strength were related to an occupationally-specific assessment of firefighter physical ability.

Effects of salt intake on sympathetic neural and pressor responses to cold pressor test in premenopausal women with a history of normal pregnancy.

Excessive salt intake is considered a risk factor for the development of hypertension. Additionally, aberrant neurocirculatory responses to a cold stimulus are associated with an increased risk of hypertension. This study aimed to determine whether salt loading versus salt reduction would impact hemodynamic and sympathetic neural responses during the cold pressor test (CPT) in premenopausal women with a history of normal pregnancy. Nine healthy premenopausal women [42 ± 3 (SD) yr] were given a standardized isocaloric high-salt (HS; 250 mEq sodium/day) or low-salt (LS; 50 mEq sodium/day) diet for 1-wk each (∼2 mo apart with the order randomized), while water intake was ad libitum. Laboratory testing was performed following each HS and LS period in the mid-luteal phase of the menstrual cycle. Subjects were in the supine position and beat-by-beat blood pressure (BP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were continuously measured during 1-min baseline followed by 2-min CPT, and 3-min recovery. BP and HR increased during the CPT (both P < 0.001); the responses were similar between HS and LS. MSNA increased during the CPT, but the increment (Δ) was greater during HS than LS (29 ± 6 vs. 15 ± 4 bursts/min; P < 0.001). The transduction of MSNA for vasoconstriction during the CPT was lower in HS (P < 0.05). Thus, salt loading augments sympathetic neural reactivity to the cold stimulus with similar pressor responses compared with salt reduction, which may be attributed to the blunted neurovascular transduction-a compensatory mechanism for hemodynamic homeostasis in premenopausal women with a history of normal pregnancy.

Salt intake impacts sympathetic neural control but not morning blood pressure surge in premenopausal women with a history of normal pregnancy.

Salt intake may alter blood pressure (BP) regulation, but no study has investigated the impact of salt reduction versus salt loading on morning blood pressure surge (MBPS) and sympathetic neural control in premenopausal women with a history of normal pregnancy. Nine healthy women (42 ± 3 yr; mean ± SD) were given a low-salt diet (LS; 50 mEq sodium/day) and high-salt diet (HS; 250 mEq sodium/day) for 1 wk each (~2 mo apart with the order randomized), while water intake was ad libitum. Ambulatory BP at 24 h was measured, and the percent change in blood volume (BV) was calculated following LS and HS. MBPS was defined as the morning systolic BP (averaged for 2 h after wake-up) minus the lowest nocturnal systolic BP. Beat-by-beat BP, heart rate, and muscle sympathetic nerve activity (MSNA) were measured during supine rest. Signal averaging was used to characterize changes in beat-by-beat mean arterial pressure and total vascular conductance following spontaneous MSNA bursts to assess sympathetic vascular transduction. Ambulatory BP and MBPS (32 ± 7 vs. 26 ± 12 mmHg, P = 0.208) did not differ between LS and HS. From LS to HS, BV increased by 4.3 ± 3.7% (P = 0.008). MSNA (30 ± 20 vs. 18 ± 13 bursts/100 heartbeats, P = 0.005) was higher, whereas sympathetic vascular transduction was lower in LS than HS (both, P < 0.01). Changes in MSNA from LS to HS were correlated to percent changes in BV (r = -0.673; P = 0.047). Thus, salt intake affects sympathetic neural control but not MBPS in premenopausal women with a history of normal pregnancy. The underlying mechanisms remain unknown; however, alterations in sympathetic vascular transduction may, in part, contribute.NEW & NOTEWORTHY This is the first study to demonstrate that MBPS and ambulatory BP were not affected by salt intake despite a significant change in sympathetic outflow in healthy premenopausal women with a history of normal pregnancy. This may be due to compensatory adaptations in MSNA and sympathetic vascular transduction during salt reduction versus salt loading.

Arterial stiffness during whole-body passive heat stress in healthy older adults.

We tested the hypothesis that whole-body passive heat stress reduces arterial stiffness in older adults. At preheat stress (baseline) and when core temperature was elevated by 0.6 ± 0.2°C (mild) and 1.2 ± 0.3°C (moderate), arterial stiffness was measured in eight healthy younger (26 ± 5 years) and eight healthy older (70 ± 4 years) adults in the supine position. Arterial stiffness was estimated from carotid-to-femoral pulse wave velocity (cfPWV, applanation tonometry). cfPWV was higher at baseline in older adults (8.8 ± 2.3 m/sec vs. 5.6 ± 0.9 m/sec, P < 0.01) and this difference was maintained throughout passive heat stress (P < 0.01). cfPWV did not change (P ≥ 0.49) with passive heat stress in either younger (at moderate heat stress: 6.0 ± 1.0 m/sec) or older (at moderate heat stress: 8.5 ± 1.6 m/sec) adults. However, the influence of baseline cfPWV on the change in cfPWV during mild (r = -0.66, P = 0.04) and moderate (r = -0.87, P < 0.01) heat stress were inversely related in older adults, and the strength of these relations was not statistically different (P = 0.08). In younger adults, the influence of baseline cfPWV on the change in cfPWV during mild heat stress was also inversely related (r = -0.79, P = 0.01), while the strength of this relation was attenuated at moderate heat stress (r = -0.24, P = 0.30). Changes in arterial stiffness during passive heat stress in adults aged ≥65 year are likely dependent on the magnitude of baseline arterial stiffness and not necessarily age.

Role of Corin in Blood Pressure Regulation in Normotensive and Hypertensive Pregnancy.

Corin (an atrial natriuretic peptide-converting enzyme) represents a potential biomarker for gestational hypertensive disorders; yet, its role in blood pressure (BP) regulation throughout pregnancy remains unclear. We investigated the time course of change in blood corin content in relation to BP and sympathetic nerve activity throughout pregnancy. Forty-four women (29±0.9 years) participated. Following-term, 23 had low-risk (no personal history of gestational hypertensive disorders) normal pregnancies, 13 had high-risk (personal history of gestational hypertensive disorders) normal pregnancies, and 8 developed gestational hypertension. BP, heart rate, muscle sympathetic nerve activity, and serum corin were measured before pregnancy, during early (4-8 weeks) and late pregnancy (32-36 weeks), and postpartum (6-10 weeks). Overall, compared with prepregnancy, corin remained unchanged during early pregnancy, increased markedly during late pregnancy ( P<0.001), and returned to prepregnancy levels postpartum. In women who developed gestational hypertension, the change in corin from early to late pregnancy was greater than those with low-risk normal pregnancies (Δ971±134 versus Δ486±79 pg/mL; P<0.05). Throughout pregnancy, BP and muscle sympathetic nerve activity were augmented in women with gestational hypertension (all P<0.05). Finally, changes in corin from early to late pregnancy were related to all indices of BP ( R=0.454-0.551; all P<0.01) in late pregnancy, whereas burst frequency, burst incidence, and total muscle sympathetic nerve activity ( R=0.576-0.614; all P<0.001) in early pregnancy were related to changes in corin from early to late pregnancy. Corin plays a unique role in BP regulation throughout normotensive and, especially, hypertensive pregnancy and may represent a promising biomarker for determining women at high risk of adverse pregnancy outcome.

A method for developing organisation-wide manual handling based physical employment standards in a military context.

The benefit of job-related employment standards in physically demanding occupations are well known. A number of methodological frameworks have been established to guide the development of physical employment standards for single job functions. In the case of an organisation comprised of multiple and diverse employment specialisations, such as the Australian Army, it is impractical to develop unique employment standards for each occupation. OBJECTIVES: To present an approach to organisational level physical employment standards development that seeks to retain occupationally specific task characteristics by applying a movement cluster approach. DESIGN: Structured methodological overview. METHODS: An outline of the research process used in performing job tasks analysis are presented, including the identification, quantification and characterisation, and verification of physically demanding manual handling tasks. The methodology used to filter task information collected from this job analyses to group manual handling tasks with similar characteristics (termed clusters), across a range of employment specialisations is given. Finally, we provide examples of test development based on these key manual handling clusters to develop a limited suite of tests with high content, criterion and face validity that may be implementable across a large organisation. RESULTS: Job task analysis was performed on 57 employment specialisations, identifying 458 tasks that were grouped into 10 movement based clusters. The rationalisation of criterion tasks through clustering informed the development of a limited suite of tests with high content, criterion and face validity that may be implementable across a large organisation. CONCLUSION: This approach could be applied when developing physical employment standards across other multi-occupation organisations.

Left ventricular remodeling and arterial afterload in older women with uncontrolled and controlled hypertension.

OBJECTIVE: The prevalence of hypertension increases with advancing age in women. Blood pressure control is more difficult to achieve in older women, and despite well-controlled blood pressure, the cardiovascular mortality remains high. However, the underlying mechanisms are not understood. METHODS: Nineteen women with uncontrolled hypertension on drug treatment (70 ±â€Š2 [SE] years, ambulatory awake blood pressure; 152 ±â€Š2/84 ±â€Š2 mm Hg), 19 with controlled hypertension (68 ±â€Š1 years, 128 ±â€Š2/71 ±â€Š2 mm Hg), and 31 healthy normotensive women (68 ±â€Š1 years, 127 ±â€Š1/73 ±â€Š1 mm Hg) were recruited. Participants were weaned from antihypertensive drugs and underwent 3 weeks of run-in before cardiac-vascular assessments. Left ventricular morphology was evaluated with cardiac magnetic resonance imaging. Arterial load and vascular stiffness were measured via ultrasound and applanation tonometry. RESULTS: Left ventricular mass normalized by body surface area was not different between hypertension groups (uncontrolled vs controlled: 50.0 ±â€Š1.7 vs 51.8 ±â€Š2.3 g/m), but it was lower in the normotensive group (41.7 ±â€Š0.9 g/m; one-way analysis of variance [ANOVA] P = 0.004). Likewise, central pulse wave velocity was not different between hypertension groups (11.5 ±â€Š0.6 vs 11.1 ±â€Š0.5 m/s) and lower in the normotensive group (9.1 ±â€Š0.3 m/s; 1-way ANOVA P = 0.0001). Total peripheral resistance was greater in uncontrolled hypertension (HTN) compared with normotensive group (2051 ±â€Š323 vs 1719 ±â€Š380 dyns/cm), whereas controlled HTN group (1925 ±â€Š527 dyns/cm) was not different to either groups. CONCLUSION: Regardless of current blood pressure control, hypertensive older women exhibited increased cardiac mass and arterial stiffness compared with normotensives. Future large-scale longitudinal studies are warranted to directly investigate the mechanisms for the high cardiovascular mortality among older hypertensive women with well-controlled blood pressure.

Long-term effects of a renin inhibitor versus a thiazide diuretic on arterial stiffness and left ventricular diastolic function in elderly hypertensive patients.

Arterial stiffness and cardiac function are important predictors of cardiovascular events in patients with hypertension, even with adequate blood pressure (BP) control. We evaluated whether a direct renin inhibitor, aliskiren, reduces arterial stiffness and modulates left ventricular function compared with a diuretic, hydrochlorothiazide, in elderly hypertensive patients. Twenty-one hypertensive patients [67 ± 14 (SD) yr] were randomly assigned to receive 6-mo aliskiren (n = 11) or hydrochlorothiazide (n = 10)-based therapy. We assessed ß-stiffness of the local arteries, arterial elastance (Ea), and echocardiographic variables, including early (E) and late (A) mitral inflow velocity, deceleration time of E, early (E') and late (A') diastolic mitral annular velocity, and left ventricular end-systolic elastance (Ees) before and after treatment. BP decreased similarly (P < 0.001) after both therapies. ß-Stiffness of the carotid artery decreased after aliskiren but increased after hydrochlorothiazide treatment (aliskiren: 6.42 ± 2.34 pre vs. 5.07 ± 1.29 post; hydrochlorothiazide: 5.05 ± 1.78 vs. 7.25 ± 2.68, P = 0.001 for interaction). ß-Stiffness of the femoral and radial arteries were not different after either treatment. Different from aliskiren, E decreased (73 ± 16 vs. 67 ± 14 cm/s, P = 0.026), and the deceleration time was prolonged (218 ± 40 vs. 236 ± 35 ms, P = 0.032) after hydrochlorothiazide therapy, whereas the E/A, and E' remained unchanged after both treatments. Ea and Ees decreased after aliskiren therapy (both P < 0.05), whereas the Ea/Ees (ventricular-arterial coupling) was maintained after both treatments. Thus, aliskiren decreased the stiffness of carotid artery and left ventricular end-systolic elastance with maintenance of ventricular-arterial coupling without any effects on diastolic filling, while hydrochlorothiazide increased carotid arterial stiffness and slowed early diastolic filling in elderly hypertensive patients.

Novel Bacterial Topoisomerase Inhibitors with Potent Broad-Spectrum Activity against Drug-Resistant Bacteria.

The novel bacterial topoisomerase inhibitor class is an investigational type of antibacterial inhibitor of DNA gyrase and topoisomerase IV that does not have cross-resistance with the quinolones. Here, we report the evaluation of the in vitro properties of a new series of this type of small molecule. Exemplar compounds selectively and potently inhibited the catalytic activities of Escherichia coli DNA gyrase and topoisomerase IV but did not block the DNA breakage-reunion step. Compounds showed broad-spectrum inhibitory activity against a wide range of Gram-positive and Gram-negative pathogens, including biodefence microorganisms and Mycobacterium tuberculosis No cross-resistance with fluoroquinolone-resistant Staphylococcus aureus and E. coli isolates was observed. Measured MIC90 values were 4 and 8 µg/ml against a panel of contemporary multidrug-resistant isolates of Acinetobacter baumannii and E. coli, respectively. In addition, representative compounds exhibited greater antibacterial potency than the quinolones against obligate anaerobic species. Spontaneous mutation rates were low, with frequencies of resistance typically <10-8 against E. coli and A. baumannii at concentrations equivalent to 4-fold the MIC. Compound-resistant E. coli mutants that were isolated following serial passage were characterized by whole-genome sequencing and carried a single Arg38Leu amino acid substitution in the GyrA subunit of DNA gyrase. Preliminary in vitro safety data indicate that the series shows a promising therapeutic index and potential for low human ether-a-go-go-related gene (hERG) inhibition (50% inhibitory concentration [IC50], >100 µM). In summary, the compounds' distinct mechanism of action relative to the fluoroquinolones, whole-cell potency, low potential for resistance development, and favorable in vitro safety profile warrant their continued investigation as potential broad-spectrum antibacterial agents.

Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a history of hypertensive pregnancy.

PURPOSE: Women with a history of hypertensive pregnancy are at greater risk for future cardiovascular events; however, the mechanisms for this increased risk are unknown. Evidence suggests that an exercise stimulus unmasks latent hypertensive tendencies, identifying individuals at the greatest risk for developing cardiovascular disease. The current study examined the hypothesis that women with a hypertensive pregnancy history exhibit an augmented exercise pressor response. METHODS: Normotensive women with a history of healthy pregnancy (CON; n = 9) and hypertensive pregnancy (HP+; n = 12) were studied during the mid-luteal phase of the menstrual cycle. Heart rate (HR), systolic and diastolic blood pressure (SBP, DBP), and muscle sympathetic nerve activity (MSNA) were measured during a cold pressor test (CPT), and, following a sufficient period of recovery, during static handgrip to fatigue (SHG) and post-exercise circulatory arrest (PECA). RESULTS: The BP, HR, and MSNA responses to the CPT were similar between groups. The SBP response to SHG and PECA was similar between groups, but DBP and HR were significantly greater in HP+ women (both p < 0.05). MSNA burst frequency, but not burst incidence or total activity, tended to be elevated in HP+ women during the stressor (peak Δ from baseline 31 ± 13 vs. 23 ± 13 bursts/min; p for group = 0.06). CONCLUSION: Despite no clinical signs of cardiovascular disease or hypertension, women with a history of hypertensive pregnancy display an enhanced cardiovascular reactivity to an exercise stimulus compared to women with a healthy pregnancy history. This response may be indicative of impaired cardiovascular control that precedes the clinical manifestation of hypertension or cardiovascular events.

Predicting Endurance Time in a Repetitive Lift and Carry Task Using Linear Mixed Models.

OBJECTIVES: Repetitive manual handling tasks account for a substantial portion of work-related injuries. However, few studies report endurance time in repetitive manual handling tasks. Consequently, there is little guidance to inform expected work time for repetitive manual handling tasks. We aimed to investigate endurance time and oxygen consumption of a repetitive lift and carry task using linear mixed models. METHODS: Fourteen male soldiers (age 22.4 ± 4.5 yrs, height 1.78 ± 0.04 m, body mass 76.3 ± 10.1 kg) conducted four assessment sessions that consisted of one maximal box lifting session and three lift and carry sessions. The relationships between carry mass (range 17.5-37.5 kg) and the duration of carry, and carry mass and oxygen consumption, were assessed using linear mixed models with random effects to account for between-subject variation. RESULTS: Results demonstrated that endurance time was inversely associated with carry mass (R2 = 0.24), with significant individual-level variation (R2 = 0.85). Normalising carry mass to performance in a maximal box lifting test improved the prediction of endurance time (R2 = 0.40). Oxygen consumption presented relative to total mass (body mass, external load and carried mass) was not significantly related to lift and carry mass (ß1 = 0.16, SE = 0.10, 95%CI: -0.04, 0.36, p = 0.12), indicating that there was no change in oxygen consumption relative to total mass with increasing lift and carry mass. CONCLUSION: Practically, these data can be used to guide work-rest schedules and provide insight into methods assessing the physical capacity of workers conducting repetitive manual handling tasks.

Efficacy of a Novel Tricyclic Topoisomerase Inhibitor in a Murine Model of Neisseria gonorrhoeae Infection.

There is an urgent need for new antibiotics to treat multidrug-resistant Neisseria gonorrhoeae In this report, the microbiology, in vivo pharmacokinetics, and efficacy of REDX05931, a representative novel tricyclic topoisomerase inhibitor, were evaluated. REDX05931 demonstrated high oral bioavailability in mice and reduced N. gonorrhoeae infection after a single dose in a mouse model of gonorrhea. These data support the potential of this series of small molecules as a new treatment for drug-resistant gonorrheal infections.

Biological profiling of novel tricyclic inhibitors of bacterial DNA gyrase and topoisomerase IV.

OBJECTIVES: The objective of this study was to characterize the in vitro and in vivo biological properties of a novel series of small-molecule bacterial type IIA topoisomerase inhibitors. METHODS: Bacterial susceptibility testing was performed by broth microdilution. Resistance frequencies were determined by plating bacteria onto agar containing test compound and enumerating mutants. Bacteria were passaged using subinhibitory concentrations of antibacterials to generate resistance. Target enzyme inhibition was determined by exposure to antibacterials and DNA; topoisomers were visualized by gel electrophoresis. Oral and intravenous pharmacokinetic profiles were determined in mice. In vivo efficacy was determined using a mouse model of septicaemia and thigh infection with MSSA and MRSA, respectively. RESULTS: Representative compounds REDX04139, REDX05604 and REDX05931 demonstrated in vitro potency against a range of Gram-positive and fastidious Gram-negative pathogens. Clinical isolate testing revealed REDX04139 and REDX05931 had MIC90 values of 0.25 and 0.5 mg/L, respectively, for MRSA and MIC90 values of 2 mg/L for streptococci. REDX04139 was bactericidal in vitro against Staphylococcus aureus at 8× MIC over 6 h. Pharmacokinetic profiling of REDX04139 and REDX05604 in mice revealed low clearance and excellent bioavailability (≥71%). REDX04139 provided 100% survival against S. aureus in a mouse septicaemia model, while REDX05604 reduced bacterial load by up to 3.7 log units in the MRSA mouse thigh infection model. CONCLUSIONS: Redx Pharma has discovered a novel series of topoisomerase inhibitors that are being further developed for drug-resistant bacteria.

Sympathetic Neural and Hemodynamic Responses During Cold Pressor Test in Elderly Blacks and Whites.

The sympathetic response during the cold pressor test (CPT) has been reported to be greater in young blacks than whites, especially in those with a family history of hypertension. Because blood pressure (BP) increases with age, we evaluated whether elderly blacks have greater sympathetic activation during CPT than age-matched whites. BP, heart rate, cardiac output, and muscle sympathetic nerve activity were measured during supine baseline, 2-minute CPT, and 3-minute recovery in 47 elderly (68 ± 7 [SD] years) volunteers (12 blacks and 35 whites). Baseline BP, heart rate, cardiac output, or muscle sympathetic nerve activity did not differ between races. Systolic and diastolic BP and heart rate increased during CPT (all P<0.001) with no racial differences (all P > 0.05). Cardiac output increased during CPT and ≤ 30 s of recovery in both groups, but was lower in blacks than whites. Muscle sympathetic nerve activity increased during CPT in both groups (both P<0.001); the increase in burst frequency was similar between groups, whereas the increase in total activity was smaller in blacks (P=0.030 for interaction). Peak change (Δ) in diastolic BP was correlated with Δ total activity at 1 minute into CPT in both blacks (r=0.78,P=0.003) and whites (r=0.43,P=0.009), whereas the slope was significantly greater in blacks (P=0.007). Thus, elderly blacks have smaller sympathetic and central hemodynamic (eg, cardiac output) responses, but a greater pressor response for a given sympathetic activation during CPT than elderly whites. This response may stem from augmented sympathetic vascular transduction, greater sympathetic activation to other vascular bed(s), or enhanced nonadrenergically mediated vasoconstriction in elderly blacks.

A Box Lift and Place Assessment is Related to Performance of Several Military Manual Handling Tasks.

Soldiers undergo regular physical testing to assess their functional capacity. However, current physical tests, such as push-ups, sit-ups, and pull-ups, do not necessarily assess job-specific physical capability. This article assesses the utility of generic predictive tests and a task-related predictive test in predicting performance against four job-critical military manual handling tasks. The box lift and place test was found to be the superior predictor in performance of four job tasks; a pack lift and place (R(2) = 0.76), artillery gunner loading simulation (R(2) = 0.36), bombing up an M1 tank simulation, (R(2) = 0.47) and a bridge building simulation (R(2) = 0.63). Pull-ups and push-ups were poor predictors of performance in the majority of job tasks. Although the box lift and place had a larger correlation with the artillery gunner loading task than the generic assessment, it only accounted for 36% of the variance, indicating that a task simulation may be more appropriate to assess soldiers' capacity to perform this job task. These results support the use of a box lift and place rather than generic fitness tests for the evaluation of military manual handling tasks.

Asian women have attenuated sympathetic activation but enhanced renal-adrenal responses during pregnancy compared to Caucasian women.

Asians have a lower prevalence of hypertensive disorders of pregnancy than Caucasians. Since sympathetic overactivity and dysregulation of the renal-adrenal system (e.g. low aldosterone levels) have been found in preeclamptic women, we hypothesized that Asians have lower muscle sympathetic nerve activity (MSNA) and greater aldosterone concentrations during normal pregnancy than Caucasians. In a prospective study, blood pressure (BP), heart rate (HR), and MSNA were measured during supine and upright tilt (30 deg and 60 deg for 5 min each) in 9 Asians (32 ± 1 years (mean ± SEM)) and 12 Caucasians (29 ± 1 years) during pre-, early (≤8 weeks of gestation) and late (32-36 weeks) pregnancy, and post-partum (6-10 weeks after delivery). Supine MSNA increased with pregnancy in both groups (P < 0.001); it was significantly lower in Asians than Caucasians (14 ± 3 vs. 23 ± 3 bursts min(-1) and 16 ± 5 vs. 30 ± 3 bursts min(-1) in early and late pregnancy, respectively; P = 0.023). BP decreased during early pregnancy (P < 0.001), but was restored during late pregnancy. HR increased during pregnancy (P < 0.001) with no racial difference (P = 0.758). MSNA increased during tilting and it was markedly lower in Asians than Caucasians in late pregnancy (31 ± 6 vs. 49 ± 3 bursts min(-1) at 60 deg tilt; P = 0.003). Upright BP was lower in Asians, even in pre-pregnancy (P = 0.006), and this racial difference persisted during pregnancy. Direct renin and aldosterone increased during pregnancy (both P < 0.001); these hormones were greater in Asians (P = 0.086 and P = 0.014). Thus, Asians have less sympathetic activation but more upregulated renal-adrenal responses than Caucasians during pregnancy. These results may explain, at least in part, why Asian women are at low risk of hypertensive disorders in pregnancy.

Heart rate recovery after maximal exercise is blunted in hypertensive seniors.

Abnormal heart rate recovery (HRR) after maximal exercise may indicate autonomic dysfunction and is a predictor for cardiovascular mortality. HRR is attenuated with aging and in middle-age hypertensive patients, but it is unknown whether HRR is attenuated in older-age adults with hypertension. This study compared HRR among 16 unmedicated stage 1 hypertensive (HTN) participants [nine men/seven women; 68 ± 5 (SD) yr; awake ambulatory blood pressure (BP) 149 ± 10/87 ± 7 mmHg] and 16 normotensive [control (CON)] participants (nine men/seven women; 67 ± 5 yr; 122 ± 4/72 ± 5 mmHg). HR, BP, oxygen uptake (V̇o2), cardiac output (Qc), and stroke volume (SV) were measured at rest, at two steady-state work rates, and graded exercise to peak during maximal treadmill exercise. During 6 min of seated recovery, the change in HR (ΔHR) was obtained every minute and BP every 2 min. In addition, HRR and R-R interval (RRI) recovery kinetics were analyzed using a monoexponential function, and the indexes (HRRI and RRII) were calculated. Maximum V̇o2, HR, Qc, and SV responses during exercise were not different between groups. ΔHR was significantly different (P < 0.001) between the HTN group (26 ± 8) and the CON group (36 ± 12 beats/min) after 1 min of recovery but less convincing at 2 min (P = 0.055). BP recovery was similar between groups. HRRI was significantly lower (P = 0.016), and there was a trend of lower RRII (P = 0.066) in the HTN group compared with the CON group. These results show that in older-age adults, HRR is attenuated further with the presence of hypertension, which may be attributable to an impairment of autonomic function.