Rapid Detection of Cleanliness on Direct Bonded Copper Substrate by Using UV Hyperspectral Imaging.

In the manufacturing process of electrical devices, ensuring the cleanliness of technical surfaces, such as direct bonded copper substrates, is crucial. An in-line monitoring system for quality checking must provide sufficiently resolved lateral data in a short time. UV hyperspectral imaging is a promising in-line method for rapid, contactless, and large-scale detection of contamination; thus, UV hyperspectral imaging (225-400 nm) was utilized to characterize the cleanliness of direct bonded copper in a non-destructive way. In total, 11 levels of cleanliness were prepared, and a total of 44 samples were measured to develop multivariate models for characterizing and predicting the cleanliness levels. The setup included a pushbroom imager, a deuterium lamp, and a conveyor belt for laterally resolved measurements of copper surfaces. A principal component analysis (PCA) model effectively differentiated among the sample types based on the first two principal components with approximately 100.0% explained variance. A partial least squares regression (PLS-R) model to determine the optimal sonication time showed reliable performance, with R2cv = 0.928 and RMSECV = 0.849. This model was able to predict the cleanliness of each pixel in a testing sample set, exemplifying a step in the manufacturing process of direct bonded copper substrates. Combined with multivariate data modeling, the in-line UV prototype system demonstrates a significant potential for further advancement towards its application in real-world, large-scale processes.

Time course of changes in V̇o2peak and O2 extraction during ramp cycle exercise following HIIT versus moderate-intensity continuous training in type 2 diabetes.

In the present study, we assessed the time course of adaptations in peak oxygen uptake (V̇o2peak) and muscle fractional oxygen (O2) extraction (using near-infrared spectroscopy) following 12 wk of low-volume high-intensity interval training (HIIT) versus moderate-intensity continuous endurance training (MICT) in adults with uncomplicated type 2 diabetes (T2D). Participants with T2D were randomly assigned to MICT (n = 12, 50 min of moderate-intensity cycling) or HIIT (n = 9, 10 × 1 min at ∼90% maximal heart rate) or to a nonexercising control group (n = 9). Exercising groups trained three times per week and measurements were taken every 3 wk. The rate of muscle deoxygenation (i.e., deoxygenated hemoglobin and myoglobin concentration, Δ[HHb + Mb]) profiles of the vastus lateralis muscle were normalized to 100% of the response, plotted against % power output (PO), and fitted with a double linear regression model. V̇o2peak increased (P < 0.05) by week 3 of MICT (+17%) and HIIT (+8%), with no further significant changes thereafter. Total increases in V̇o2peak posttraining (P < 0.05) were 27% and 14%, respectively. The %Δ[HHb + Mb] versus %PO slope of the first linear segment (slope1) was reduced (P < 0.05) beyond 3 wk of HIIT and MICT, with no further significant changes thereafter. No changes in V̇o2peak or slope1 were observed in the control group. Low-volume HIIT and MICT induced improvements in V̇o2peak following a similar time course, and these improvements were likely, at least in part, due to an improved microvascular O2 delivery.

Priming exercise accelerates pulmonary oxygen uptake kinetics during "work-to-work" cycle exercise in middle-aged individuals with type 2 diabetes.

PURPOSE: The time constant of phase II pulmonary oxygen uptake kinetics ([Formula: see text]) is increased when high-intensity exercise is initiated from an elevated baseline (work-to-work). A high-intensity priming exercise (PE), which enhances muscle oxygen supply, does not reduce this prolonged [Formula: see text] in healthy active individuals, likely because [Formula: see text] is limited by metabolic inertia (rather than oxygen delivery) in these individuals. Since [Formula: see text] is more influenced by oxygen delivery in type 2 diabetes (T2D), this study tested the hypothesis that PE would reduce [Formula: see text] in T2D during work-to-work cycle exercise. METHODS: Nine middle-aged individuals with T2D and nine controls (ND) performed four bouts of constant-load, high-intensity work-to-work transitions, each commencing from a baseline of moderate-intensity. Two bouts were completed without PE and two were preceded by PE. The rate of muscle deoxygenation ([HHb + Mb]) and surface integrated electromyography (iEMG) were measured at the right and left vastus lateralis, respectively. RESULTS: Subsequent to PE, [Formula: see text] was reduced (P = 0.001) in T2D (from 59 ± 17 to 37 ± 20 s) but not (P = 0.24) in ND (44 ± 10 to 38 ± 7 s). The amplitude of the [Formula: see text] slow component ([Formula: see text]2 As) was reduced (P = 0.001) in both groups (T2D: 0.16 ± 0.09 to 0.11 ± 0.04 l/min; ND: 0.21 ± 0.13 to 0.13 ± 0.09 l/min). This was accompanied by a reduction in ΔiEMG from the onset of [Formula: see text] slow component to end-exercise in both groups (P < 0.001), while [HHb + Mb] kinetics remained unchanged. CONCLUSIONS: PE accelerates [Formula: see text] in T2D, likely by negating the O2 delivery limitation extant in the unprimed condition, and reduces the [Formula: see text]As possibly due to changes in muscle fibre activation.

Randomised controlled trial comparing immobilisation in above-knee plaster of Paris to controlled ankle motion boots in undisplaced paediatric spiral tibial fractures.

BACKGROUND: Management of common childhood spiral tibial fractures, known as toddler's fractures, has not significantly changed in recent times despite the availability of immobilisation devices known as controlled ankle motion (CAM) boots. We compared standard therapy with these devices on quality-of-life measures. METHODS: A prospective randomised controlled trial, comparing immobilisation with an above-knee plaster of Paris cast (AK-POP) with a CAM boot in children aged 1-5 years with proven or suspected toddler's fractures presenting to a tertiary paediatric ED in Perth, Western Australia, between March 2018 and February 2020. The primary outcome measure was ease of personal care, as assessed by a Care and Comfort Questionnaire (eight questions scored from 0, very easy, to 8, impossible) completed by the caregiver and assessed during three treatment time-points and preintervention and postintervention. Secondary outcome measures included weight-bearing status as well as complications of fracture healing and number of pressure injuries. RESULTS: 87 patients were randomised (44 CAM boot, median age 2 (IQR 1.5-2.3), 71% male; 43 AK-POP, median age 2 (IQR 1.7-2.8), 80% male), a significant difference in the care and comfort score was demonstrated at all treatment time-points; with the AK-POP group reporting greater personal care needs on assessment on day 2, day 7-10 and 4-week review (all p≤0.001). Weight-bearing status was significantly different at day 7-10 (77.5% CAM vs 53.8% AK-POP, p=0.027). There was no difference in fracture healing or pressure areas between the two treatment groups. CONCLUSIONS: Immobilisation of toddler's fractures in a CAM boot allows faster return to activities of daily living and weight-bearing without any effect on fracture healing. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12618001311246).

Use of Hyperspectral Imaging for the Quantification of Organic Contaminants on Copper Surfaces for Electronic Applications.

To correctly assess the cleanliness of technical surfaces in a production process, corresponding online monitoring systems must provide sufficient data. A promising method for fast, large-area, and non-contact monitoring is hyperspectral imaging (HSI), which was used in this paper for the detection and quantification of organic surface contaminations. Depending on the cleaning parameter constellation, different levels of organic residues remained on the surface. Afterwards, the cleanliness was determined by the carbon content in the atom percent on the sample surfaces, characterized by XPS and AES. The HSI data and the XPS measurements were correlated, using machine learning methods, to generate a predictive model for the carbon content of the surface. The regression algorithms elastic net, random forest regression, and support vector machine regression were used. Overall, the developed method was able to quantify organic contaminations on technical surfaces. The best regression model found was a random forest model, which achieved an R2 of 0.7 and an RMSE of 7.65 At.-% C. Due to the easy-to-use measurement and the fast evaluation by machine learning, the method seems suitable for an online monitoring system. However, the results also show that further experiments are necessary to improve the quality of the prediction models.

UV Hyperspectral Imaging as Process Analytical Tool for the Characterization of Oxide Layers and Copper States on Direct Bonded Copper.

Hyperspectral imaging and reflectance spectroscopy in the range from 200-380 nm were used to rapidly detect and characterize copper oxidation states and their layer thicknesses on direct bonded copper in a non-destructive way. Single-point UV reflectance spectroscopy, as a well-established method, was utilized to compare the quality of the hyperspectral imaging results. For the laterally resolved measurements of the copper surfaces an UV hyperspectral imaging setup based on a pushbroom imager was used. Six different types of direct bonded copper were studied. Each type had a different oxide layer thickness and was analyzed by depth profiling using X-ray photoelectron spectroscopy. In total, 28 samples were measured to develop multivariate models to characterize and predict the oxide layer thicknesses. The principal component analysis models (PCA) enabled a general differentiation between the sample types on the first two PCs with 100.0% and 96% explained variance for UV spectroscopy and hyperspectral imaging, respectively. Partial least squares regression (PLS-R) models showed reliable performance with R2c = 0.94 and 0.94 and RMSEC = 1.64 nm and 1.76 nm, respectively. The developed in-line prototype system combined with multivariate data modeling shows high potential for further development of this technique towards real large-scale processes.

Inhibition of CorA-Dependent Magnesium Homeostasis Is Cidal in Mycobacterium tuberculosis.

Mechanisms of magnesium homeostasis in Mycobacterium tuberculosis are poorly understood. Here, we describe the characterization of a pyrimidinetrione amide scaffold that disrupts magnesium homeostasis in the pathogen by direct binding to the CorA Mg2+/Co2+ transporter. Mutations in domains of CorA that are predicted to regulate the pore opening in response to Mg2+ ions conferred resistance to this scaffold. The pyrimidinetrione amides were cidal against the pathogen under both actively replicating and nonreplicating conditions in vitro and were efficacious against the organism during macrophage infection. However, the compound lacked efficacy in infected mice, possibly due to limited exposure. Our results indicate that inhibition of Mg2+ homeostasis by CorA is an attractive target for tuberculosis drug discovery and encourage identification of improved CorA inhibitors.

The metaboreflex does not contribute to the increase in muscle sympathetic nerve activity to contracting muscle during static exercise in humans.

KEY POINTS: It is not clear how sympathetic activity to contracting muscle is controlled. We recorded muscle sympathetic nerve activity (MSNA) to the ipsilateral tibialis anterior muscle during 4 min of isometric dorsiflexion of the ankle and 6 min of post-exercise ischaemia, which was repeated contralaterally. MSNA to the contracting muscle increased within 1 min of static exercise and returned to pre-contraction levels at the end. Unlike the increase in MSNA seen in the non-contracting muscle, post-exercise ischaemia had no effect on MSNA to the contracted muscle. We conclude that central command is the primary mechanism responsible for increasing MSNA to contracting muscle and also that the metaboreflex is not expressed in contracting muscle. ABSTRACT: Both central command and metaboreflex inputs from contracting muscles increase muscle sympathetic nerve activity (MSNA) to non-contracting muscle during sustained isometric exercise. We recently showed that MSNA to contracting muscle also increases in an intensity-dependent manner, although whether this can be sustained by the metaboreflex is unknown. MSNA was recorded from the left common peroneal nerve and individual spikes of MSNA extracted from the nerve signal. Eleven subjects performed a series of 4 min dorsiflexions of the left ankle at 10% of maximum voluntary contraction under three conditions: without ischaemia, with 6 min of post-exercise ischaemia, and with ischaemia during and after exercise; these were repeated in the right leg. Compared with pre-contraction values, MSNA to the contracting muscles increased and plateaued in the first minute of contraction (50 ± 18 vs. 34 ± 10 spikes min-1 , P = 0.01), returned to pre-contraction levels within 1 min of the contraction ending and was not influenced by ischaemia during or after contraction. Conversely, MSNA to the non-contracting muscles was not different from pre-contraction levels in the first minute of contraction (34 ± 9 vs. 32 ± 5 spikes min-1 , P = 0.48), whereas it increased each minute and was significantly greater by the second minute (44 ± 8 spikes min-1 , P = 0.01). Ischaemia augmented the MSNA response to contraction (63 ± 25 spikes min-1 after 4 min, P < 0.05) and post-exercise ischaemia (63 ± 27 spikes min-1 after 6 min, P < 0.01) for the non-contracting muscles only. These findings support our conclusion that the metaboreflex is not expressed in the contracting muscle during sustained static exercise.

Effect of intradialytic resistance training on pulse wave velocity and associated cardiovascular disease biomarkers in end stage renal disease.

AIMS: Cardiovascular disease (CVD) is the leading cause of mortality in patients with end-stage renal disease (ESRD) receiving maintenance haemodialysis treatment. This study investigated the effect of a 12-week intradialytic progressive resistance training (PRT) intervention on pulse wave velocity (PWV) and associated haemodynamic, anthropometric, and hematologic outcomes in patients with ESRD. METHODS: Twenty-two patients with ESRD (59% men, 71.3 ± 11.0 years) were recruited. Supervised PRT (three sets of 11 exercises) was prescribed three times per week during routine dialysis. The primary outcome was brachial-ankle PWV via applanation tonometry. Secondary outcomes included augmentation index, brachial and aortic blood pressures, endothelial progenitor cells, C-reactive protein, blood lipids and anthropometrics. RESULTS: The intradialytic PRT regimen resulted in no significant change in PWV between control and intervention periods [mean difference = 0 (95% CI = -0.1 to 0.1); P = 0.58]. Similarly, no significant change was noted in any secondary outcome measures between the control and intervention periods. Post-hoc analyses limited to high adherers (≥75% attendance; n = 11) did not differ from the primary analysis, indicating no dose-response effect of our intervention. CONCLUSION: Our 12-week PRT intervention did not change PWV or any secondary outcomes. Future studies should determine if higher dosages of intradialytic PRT (i.e. longer duration and/or higher intensity) can be applied as a method to improve arterial stiffness to potentially reduce cardiovascular disease and associated mortality this cohort.

Venous occlusion plethysmography vs. Doppler ultrasound in the assessment of leg blood flow kinetics during different intensities of calf exercise.

PURPOSE: It has recently been shown that venous occlusion plethysmography (VOP) can successfully assess the rate of increase in leg blood flow (LBF) (LBF kinetics) responses during calf exercise, but there is lack of data supporting its validity. METHODS: Using Doppler ultrasound (DU) as a criterion standard technique, we tested the hypothesis that VOP would provide similar estimates of LBF kinetics responses as DU during calf plantar-flexion exercise at a range of different intensities. Ten healthy men performed repeated intermittent calf plantar-flexion contractions (3 s duty cycles, 1 s contraction/2 s relaxation) at 30, 50 and 70% maximum voluntary contraction (MVC) on different days. RESULTS: Resting LBF values were significantly (P < 0.05) larger for DU than VOP but the overall mean LBF responses during exercise were not different (P > 0.05) between DU and VOP (30% MVC: 330 ± 78 vs. 313 ± 92 ml/min; 50% MVC: 515 ± 145 vs. 483 ± 164 ml/min; 70% MVC: 733 ± 218 vs. 616 ± 229 ml/min). LBF kinetics analyses revealed that the end-amplitude at the highest intensity (70% MVC) was significantly higher when measured by DU compared with VOP, but all other kinetics parameters were not different between VOP and DU. CONCLUSIONS: Given that these slight differences in amplitude observed during exercise can be explained by differences in vascular regions which the two techniques assess, our results suggest that VOP can accurately assess LBF kinetics responses during calf plantar-flexion exercise at intensities between 30 and 70% MVC.

A Comparison of Vertical Stiffness Values Calculated from Different Measures of Center of Mass Displacement in Single-Leg Hopping.

This study assessed the agreement between Kvert calculated from 4 different methods of estimating vertical displacement of the center of mass (COM) during single-leg hopping. Healthy participants (N = 38) completed a 10-s single-leg hopping effort on a force plate, with 3D motion of the lower limb, pelvis, and trunk captured. Derived variables were calculated for a total of 753 hop cycles using 4 methods, including: double integration of the vertical ground reaction force, law of falling bodies, a marker cluster on the sacrum, and a segmental analysis method. Bland-Altman plots demonstrated that Kvert calculated using segmental analysis and double integration methods have a relatively small bias (0.93 kN⋅m-1) and 95% limits of agreement (-1.89 to 3.75 kN⋅m-1). In contrast, a greater bias was revealed between sacral marker cluster and segmental analysis (-2.32 kN⋅m-1), sacral marker cluster and double integration (-3.25 kN⋅m-1), and the law of falling bodies compared with all methods (17.26-20.52 kN⋅m-1). These findings suggest the segmental analysis and double integration methods can be used interchangeably for the calculation of Kvert during single-leg hopping. The authors propose the segmental analysis method to be considered the gold standard for the calculation of Kvert during single-leg, on-the-spot hopping.

The effect of resistance training on markers of immune function and inflammation in previously sedentary women recovering from breast cancer: a randomized controlled trial.

The purpose of this randomized controlled trial was to determine the effects of resistance training (RT) on markers of inflammation and immune function in breast cancer survivors. Thirty-nine breast cancer survivors were randomly assigned to a RT (n = 20) or control (n = 19) group. RT performed supervized exercise three times per week. Natural killer cell (NK) and natural killer T-cell (NKT) function, and markers of inflammation (serum TNF-α, IL-6, IL-10, and CRP) were measured before and after training. Changes in NK and NKT cell function were analyzed using ANCOVA, with the change score the dependent variable, and the baseline value of the same variable the covariate. Effect sizes (ES) were calculated via partial eta-squared. We found a significant reduction, and large associated ESs, in the RT group compared to the control group for change in NK cell expression of TNF-α (p = 0.005, ES = 0.21) and NKT cell expression of TNF-α (p = 0.04, ES = 0.12). No differences were observed in any serum marker. Significant improvements in all measurements of strength were found in RT compared to control (p < 0.001; large ESs ranging from 0.32 to 0.51). These data demonstrate that RT has a beneficial effect on the NK and NKT cell expression of TNF-α indicating that RT may be beneficial in improving the inflammatory profile in breast cancer survivors.

Influence of menopause and Type 2 diabetes on pulmonary oxygen uptake kinetics and peak exercise performance during cycling.

We investigated if the magnitude of the Type 2 diabetes (T2D)-induced impairments in peak oxygen uptake (V̇O2) and V̇O2 kinetics was affected by menopausal status. Twenty-two women with T2D (8 premenopausal, 14 postmenopausal), and 22 nondiabetic (ND) women (11 premenopausal, 11 postmenopausal) matched by age (range = 30-59 yr) were recruited. Participants completed four bouts of constant-load cycling at 80% of their ventilatory threshold for the determination of V̇O2 kinetics. Cardiac output (CO) (inert gas rebreathing) was recorded at rest and at 30 s and 240 s during two additional bouts. Peak V̇O2 was significantly (P < 0.05) reduced in both groups with T2D compared with ND counterparts (premenopausal, 1.79 ± 0.16 vs. 1.55 ± 0.32 l/min; postmenopausal, 1.60 ± 0.30 vs. 1.45 ± 0.24 l/min). The time constant of phase II of the V̇O2 response was slowed (P < 0.05) in both groups with T2D compared with healthy counterparts (premenopausal, 29.1 ± 11.2 vs. 43.0 ± 12.2 s; postmenopausal, 33.0 ± 9.1 vs. 41.8 ± 17.7 s). At rest and during submaximal exercise absolute CO responses were lower, but the "gains" in CO larger (both P < 0.05) in both groups with T2D. Our results suggest that the magnitude of T2D-induced impairments in peak V̇O2 and V̇O2 kinetics is not affected by menopausal status in participants younger than 60 yr of age.

Intensity-dependent effect of ageing on fatigue during intermittent contractions of the human calf muscle in males and females.

Ageing reduces fatigue during submaximal intermittent contractions, but the influence of intensity on this ageing effect in males and females is not clear. Younger males (n = 8; 23 ± 2 years), younger females (n = 8; 22 ± 1 years), older males (n = 8; 67 ± 5 years) and older females (n = 10; 64 ± 7 years) completed intermittent calf contractions at four submaximal intensities (30-70 %MVC) for up to 20 min. MVC was assessed during exercise at 30-60 s intervals and its linear rate of decline represented fatigue. Individual relationships between intensity and fatigue (%MVC min(-1)) were fitted to a biphasic function consisting of a linear and nonlinear component. There was no age × sex × intensity interaction for fatigue (3-way ANOVA, P = 0.46). However, there were significant interactive effects of age and sex on endurance at 70 %MVC, fatigue at 70 %MVC and the linear component of the intensity-fatigue relationship. Endurance was lower and fatigue and its linear component were greater (P < 0.05) in younger males compared with other groups, but not different between younger and older females. This suggests that there is an intensity-dependent effect of human ageing on fatigue during submaximal exercise that is specific to males.

The effect of pH on fatigue during submaximal isometric contractions of the human calf muscle.

PURPOSE: This study examined whether changes in pH throughout the physiologic range would have a differential effect on central and peripheral factors associated with fatigue and force production during submaximal lower limb isometric exercise to task failure. METHODS: Eight males completed three experimental trials [0.2 g kg(-1) ammonia chloride (ACD); 0.3 g kg(-1) calcium carbonate (PLA); or 0.3 g kg(-1) sodium bicarbonate (ALK)], each consisting of submaximal calf contractions at 55% of maximal voluntary contraction (MVC) to task failure. Every minute of the task subjects performed an MVC, coupled with stimulation of the tibial nerve during and immediately post MVC. RESULTS: Time to task failure was not different between trials (ACD 531 ± 166 s, PLA 592 ± 163 s, ALK 596 ± 150 s; p = 0.31). MVC force in all trials declined 29 % from the start of exercise to the fifth minute (mean decline of 371 ± 26 N; p < 0.001), however was not different between trials (p = 0.21). Fatigue was mediated in all trials by central and peripheral factors, as declines in voluntary activation, V/M-wave in the soleus and the potentiated resting twitch amplitudes were evident throughout the task (p < 0.05). Central fatigue appeared to be muscle specific, as reductions in central drive (V/M-wave and rate of sEMG rise) persisted in the soleus but not the medial gastrocnemius. CONCLUSIONS: These data suggest that calf fatigue associated with intermittent, isometric contractions to task failure is unaffected by alterations in pH; however, central drive reductions may be muscle specific.

'Candidatus Phytoplasma palmicola', associated with a lethal yellowing-type disease of coconut (Cocos nucifera L.) in Mozambique.

In this study, the taxonomic position and group classification of the phytoplasma associated with a lethal yellowing-type disease (LYD) of coconut (Cocos nucifera L.) in Mozambique were addressed. Pairwise similarity values based on alignment of nearly full-length 16S rRNA gene sequences (1530 bp) revealed that the Mozambique coconut phytoplasma (LYDM) shared 100% identity with a comparable sequence derived from a phytoplasma strain (LDN) responsible for Awka wilt disease of coconut in Nigeria, and shared 99.0-99.6% identity with 16S rRNA gene sequences from strains associated with Cape St Paul wilt (CSPW) disease of coconut in Ghana and Côte d'Ivoire. Similarity scores further determined that the 16S rRNA gene of the LYDM phytoplasma shared <97.5% sequence identity with all previously described members of 'Candidatus Phytoplasma'. The presence of unique regions in the 16S rRNA gene sequence distinguished the LYDM phytoplasma from all currently described members of 'Candidatus Phytoplasma', justifying its recognition as the reference strain of a novel taxon, 'Candidatus Phytoplasma palmicola'. Virtual RFLP profiles of the F2n/R2 portion (1251 bp) of the 16S rRNA gene and pattern similarity coefficients delineated coconut LYDM phytoplasma strains from Mozambique as novel members of established group 16SrXXII, subgroup A (16SrXXII-A). Similarity coefficients of 0.97 were obtained for comparisons between subgroup 16SrXXII-A strains and CSPW phytoplasmas from Ghana and Côte d'Ivoire. On this basis, the CSPW phytoplasma strains were designated members of a novel subgroup, 16SrXXII-B.

Assessment of calf muscle fatigue during submaximal exercise using transcranial magnetic stimulation versus transcutaneous motor nerve stimulation.

PURPOSE: Few studies have assessed the time-dependent response of fatigue (i.e., loss of force) during submaximal exercise without the use of maximum contractions. There is unexplored potential in the use of the superimposed muscle twitch (SIT), evoked by transcranial magnetic stimulation (TMS) or motor nerve stimulation (MNS), to assess fatigue during voluntary submaximal contractions. For the human triceps surae muscles, there are also no data on TMS-evoked twitches. METHODS: To optimise the TMS stimulus for assessment of fatigue, we first tested the effects of TMS power (40, 55, 70, 85, 100% max) on SIT force during contractions (0-100% MVC in 10% increments) in six subjects. Then, we compared SIT responses (TMS and MNS) during submaximal contractions and MVCs (all at 60 s intervals) during a continuous protocol of intermittent contractions (30% MVC) consisting of consecutive 5 min periods of baseline, fatigue (ischaemia) and recovery. RESULTS: For TMS, SIT force increased as a diminishing function of TMS power (P < 0.05), the relationships between SIT force and the force of voluntary contraction at all TMS powers were parabolic, and SIT force was maximised at ~20-40% MVC. During intermittent contractions, MVC and SIT forces were stable during baseline, decreased similarly during ischaemia by 40-50% (P < 0.05), and recovered similarly to baseline values (P > 0.05) before the end of the protocol. CONCLUSION: TMS can be used to evoke twitches during submaximal contractions of the human calf muscle and, along with MNS, used to assess fatigue during submaximal exercise.

Cyclin E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients.

Clinical benefits from trastuzumab and other anti-HER2 therapies in patients with HER2 amplified breast cancer remain limited by primary or acquired resistance. To identify potential mechanisms of resistance, we established trastuzumab-resistant HER2 amplified breast cancer cells by chronic exposure to trastuzumab treatment. Genomewide copy-number variation analyses of the resistant cells compared with parental cells revealed a focal amplification of genomic DNA containing the cyclin E gene. In a cohort of 34 HER2(+) patients treated with trastuzumab-based therapy, we found that cyclin E amplification/overexpression was associated with a worse clinical benefit (33.3% compared with 87.5%, P < 0.02) and a lower progression-free survival (6 mo vs. 14 mo, P < 0.002) compared with nonoverexpressing cyclin E tumors. To dissect the potential role of cyclin E in trastuzumab resistance, we studied the effects of cyclin E overexpression and cyclin E suppression. Cyclin E overexpression resulted in resistance to trastuzumab both in vitro and in vivo. Inhibition of cyclin E activity in cyclin E-amplified trastuzumab resistant clones, either by knockdown of cyclin E expression or treatment with cyclin-dependent kinase 2 (CDK2) inhibitors, led to a dramatic decrease in proliferation and enhanced apoptosis. In vivo, CDK2 inhibition significantly reduced tumor growth of trastuzumab-resistant xenografts. Our findings point to a causative role for cyclin E overexpression and the consequent increase in CDK2 activity in trastuzumab resistance and suggest that treatment with CDK2 inhibitors may be a valid strategy in patients with breast tumors with HER2 and cyclin E coamplification/overexpression.

Effects of intensity and training on cardiovascular responses to the Valsalva maneouvre.

OBJECTIVES: To establish the effect of intensity of effort during Valsalva's manoeuvre (VM) on blood pressure and heart rate responses. METHODS: Fourteen participants consisting of eight powerlifters and six controls completed four 15-s VMs at 30 and 50% maximum expiratory pressure. Expiratory pressure (EP), systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) were recorded continuously during manoeuvres and response amplitudes were related to well-established phases (I-IV). RESULTS: For all participants, SBP and DBP responses during Phase I were significantly higher at 50% EPmax than 30% EPmax. Phase II responses were significantly higher at 50% EPmax than 30% EPmax for HR (39.9 ± 24.3 vs. 24.5 ± 12.5 bpm), SBP (43.6 ± 24.6 vs. 35.3 ± 18.3 mm Hg) and DBP (26.7 ± 7.1 vs. 21.1 ± 7.4 mm Hg). For Phase IV, only the HR response was affected significantly by intensity. These intensity-dependent effects were similar between powerlifters and controls. Powerlifters had significantly greater Phase II responses (HR, SBP and DBP), but in the whole group these cardiovascular responses were also significantly correlated with expiratory pressure (mm Hg) at 30% EPmax (r=0.59-0.84) and 50% EPmax (r=0.53-0.82) which was higher in powerlifters than controls. CONCLUSIONS: This study demonstrates that heart rate and blood pressure responses during Phase II are affected by the relative intensity of VM, whereas during Phase IV only heart rate is affected. The higher Phase II responses in powerlifters can be attributed to the higher expiratory pressures they developed.