Exercise During Chemotherapy for Cancer: A Systematic Review.

Exercise prehabilitation may improve the tolerance and effectiveness of anticancer treatments such as chemotherapy. This systematic review assesses the impact of exercise on chemotherapy outcomes and identifies research priorities. Nineteen studies (1418 patients) were reviewed, including 11 randomised controlled trials and eight observational studies. Exercise led to improvements in body composition, fitness, strength and quality of life (QoL) across studies. Exercise can be safely and effectively delivered during chemotherapy. Limited standardisation and small sample sizes highlight the need for larger, better-designed studies to optimise this low-cost intervention.

'Unable to have a proper conversation over the phone about my concerns': a multimethods evaluation of the impact of COVID-19 on routine childhood vaccination services in London, UK.

OBJECTIVES: Investigating the completion rate of 12-month vaccinations and parental perspectives on vaccine services during COVID-19. STUDY-DESIGN: Service evaluation including parental questionnaire. METHODS: Uptake of 12-month vaccinations in three London general practices during three periods: pre-COVID (1/3/2018-28/2/2019, n = 826), during COVID (1/3/2019-28/2/2020, n = 775) and post-COVID first wave (1/8/2020-31/1/2021, n = 419). Questionnaire of parents whose children were registered at the practices (1/4/2019-1/22/2021, n = 1350). RESULTS: Comparing pre-COVID and both COVID cohorts, the completion rates of 12-month vaccines were lower. Haemophilus influenzae type B/meningococcal group C (Hib/MenC) vaccination uptake was 5.6% lower (89.0% vs 83.4%, P=<0.001), meningococcal group B (MenB) booster uptake was 4.4% lower (87.3% vs 82.9%, P = 0.006), pneumococcal conjugate vaccine (PCV) booster uptake was 6% lower (88.0% vs 82.0%, P < 0.001) and measles, mumps and rubella (MMR) vaccine uptake was 5.2% lower (89.1% vs 83.9%, P = 0.003). Black/Black-British ethnicity children had increased odds of missing their 12-month vaccinations compared to White ethnicity children (adjusted odds ratio 0.43 [95% confidence interval 0.24-0.79, P = 0.005; 0.36 [0.20-0.65], P < 0.001; 0.48 [0.27-0.87], P = 0.01; 0.40 [0.22-0.73], P = 0.002; for Hib/MenC, MenB booster, PCV booster and MMR. Comparing pre-COVID and COVID periods, vaccinations coded as not booked increased for MMR (10%), MenB (7%) and PCV booster (8%). Parents reported changes to vaccination services during COVID-19, including difficulties booking and attending appointments and lack of vaccination reminders. CONCLUSION: A sustained decrease in 12-month childhood vaccination uptake disproportionally affected Black/Black British ethnicity infants during the first wave of the pandemic. Vaccination reminders and availability of healthcare professionals to discuss parental vaccine queries are vital to maintaining uptake.

Making a move in exercise referral: co-development of a physical activity referral scheme.

Background: Translational research is required to ensure exercise referral schemes (ERSs) are evidence-based and reflect local needs. This article reports process data from the co-development phase of an ERS, providing an insight into (i) factors that must be considered when translating evidence to practice in an ERS setting, and (ii) challenges and facilitators of conducting participatory research involving multiple stakeholders. Methods: An ERS was iteratively co-developed by a multidisciplinary stakeholder group (commissioners, managers, practitioners, patients and academics) via five participatory meetings and an online survey. Audio data (e.g. group discussions) and visual data (e.g. whiteboard notes) were recorded and analysed using NVivo-10 electronic software. Results: Factors to consider when translating evidence to practice in an ERS setting included (i) current ERS culture; (ii) skills, safety and accountability; and (iii) resources and capacity. The co-development process was facilitated by needs-analysis, open questions, multidisciplinary debate and reflective practice. Challenges included contrasting views, irregular attendance and (mis)perceptions of evaluation. Conclusion: The multidisciplinary co-development process highlighted cultural and pragmatic issues related to exercise referral provision, resulting in an evidence-based intervention framework designed to be implemented within existing infrastructures. Further work is required to establish the feasibility and effectiveness of the co-developed intervention in practice.

Prevalence of bronchoconstriction induced by eucapnic voluntary hyperpnoea in recreationally active individuals.

OBJECTIVE: Exercise-induced bronchoconstriction (EIB) is more prevalent in elite athletes than in the general population. Many of these athletes provide a positive eucapnic voluntary hyperpnoea (EVH) challenge without previous diagnosis of EIB. It is unknown whether this is specific to elite athletes or whether the same risk applies to recreationally active individuals. The purpose of this study was to investigate the prevalence of a positive EVH challenge in a population of recreationally active individuals. METHODS: 136 recreationally active individuals (Age: 21.9 ± 3.7 years; Height: 175 ± 9 cm; Weight: 70.9 ± 10.0 kg) without previous history of asthma or EIB, volunteered to take part in the study. All participants completed an EVH challenge, which was deemed positive if FEV1 fell ≥10% from baseline at two consecutive time points, and was reversible following inhalation of a short acting ß2-agonist. RESULTS: 18 of 136 (13.2%) participants had a positive EVH challenge. Of the 18 individuals, the fall in FEV1 from baseline ranged from -12% to -50%. At baseline, percentage predicted FEV1 (97.5 ± 12.5% versus 104.9 ± 10%; p < 0.01), FEV1/FVC ratio (79.5 ± 6.9% versus 87.8 ± 5.5%; p < 0.01), FEF25-75 (3.73 ± 1.00 versus 4.73 ± 1.00 l/s; p < 0.01) and predicted PEF (89.4 ± 8.8% versus 97.5 ± 13.6%; p < 0.05) values for EVH positive participants were significantly lower than EVH negative participants respectively. CONCLUSIONS: Overall, 13.2% of recreationally active individuals with no previous history of asthma presented with a positive EVH challenge. Individuals who are recreationally active may benefit from an objective bronchial provocation challenge, given that self-reported symptoms alone only provide a supportive role towards a valid EIB diagnosis.

Cardiac electromechanical delay is increased during recovery from 40 km cycling but is not mediated by exercise intensity.

Cardiac electrical-mechanical delay (cEMD), left ventricular (LV) function, and cardiac troponin I (cTnI) were assessed after 40 km cycle time trials completed at high (HIGH) and moderate (MOD) intensities in 12 cyclists. Echocardiograms and blood samples were collected before, 10, and 60 min after cycling. cEMD as assessed by time from QRS onset to peak systolic (S') tissue velocity was lengthened after both bouts of cycling but was not mediated by cycling intensity (HIGH: 174 ± 52 vs 198 ± 26 ms; MOD: 151 ± 40 vs 178 ± 52 ms, P < 0.05). Global LV systolic function was unaltered by exercise. cEMD from QRS to peak early (E') diastolic tissue velocity was also increased post-exercise (HIGH: 524 ± 95 vs 664 ± 68 ms; MOD: 495 ± 62 vs 604 ± 91 ms, P < 0.05). Indices of LV diastolic function was reduced after cycling but were not mediated by exercise intensity. cTnI was elevated in two participants after HIGH trial (0.06 ug/L; 0.04 ug/L) and one participant after MOD trial (0.02 ug/L). While cEMD is lengthened and LV diastolic function was reduced post-cycling, altering time-trial intensity had little impact upon cEMD, LV function, and cTnI release.

Do the effects of high intensity 40 km cycling upon left ventricular function and cardiac biomarker during recovery vary with time of day?

Twelve healthy participants performed two identical high-intensity 40 km cycling trials (morning and evening) under controlled laboratory conditions. Echocardiograms and venous blood samples were collected before and after each exercise bout. Cardiac electro-mechanical-delay (cEMD) was measured as QRS-complex onset to peak systolic (S') and early diastolic (E') tissue velocities. Myocardial strain and strain rates were assessed in longitudinal, circumferential and radial planes at the left ventricular apex and base. Cardiac troponin I (cTnI) and N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) were assessed as biomarkers of cardiomyocyte damage and wall stress. cEMD was lengthened after both morning (S': 160 ± 30 vs. 193 ± 27; E': 478 ± 60 vs. 620 ± 87, P < 0.05) and evening (S': 155 ± 29 vs. 195 ± 31; E': 488 ± 42 vs. 614 ± 61, P < 0.05) trials. A reduction in peak S' (morning: 6.96 ± 1.12 vs. 6.66 ± 0.89; evening: 7.09 ± 0.94 vs. 7.02 ± 0.76) was correlated with cEMD (r = -0.335, P < 0.05). Peak longitudinal strain was reduced, atrial strain rates were sporadically increased in both trials post-cycling. cTnI was elevated in only two participants (0.04 µg · L(-1), 0.03 µg · L(-1)), whilst NT-proBNP was below the clinical cut-off point in all participants. Prolonged-cycling resulted in a lengthening of cEMD, small changes in aspects of left ventricular deformation and sporadic increases in cardiac biomarkers. None of these effects were moderated by time-of-day.

Prevalence of electrocardiographic abnormalities in West-Asian and African male athletes.

OBJECTIVES: To evaluate the electrocardiographic (ECG) characteristics of West-Asian, black and Caucasian male athletes competing in Qatar using the 2010 recommendations for 12-lead ECG interpretation by the European Society of Cardiology (ESC). DESIGN: Cardiovascular screening with resting 12-lead ECG analysis of 1220 national level athletes (800 West-Asian, 300 black and 120 Caucasian) and 135 West-Asian controls was performed. RESULTS: Ten per cent of athletes presented with 'uncommon' ECG findings. Black African descent was an independent predictor of 'uncommon' ECG changes when compared with West-Asian and Caucasian athletes (p<0.001). Black athletes also demonstrated a significantly greater prevalence of lateral T-wave inversions than both West-Asian and Caucasian athletes (6.1% vs 1.6% and 0%, p<0.05). The rate of 'uncommon' ECG changes between West-Asian and Caucasian athletes was comparable (7.9% vs 5.8%, p>0.05). Seven athletes (0.6%) were identified with a disease associated with sudden death; this prevalence was two times higher in black athletes than in West-Asian athletes (1% vs 0.5%), and no cases were reported in Caucasian athletes and West-Asian controls. Eighteen West-Asian and black athletes were identified with repolarisation abnormalities suggestive of a cardiomyopathy, but ultimately, none were diagnosed with a cardiac disease. CONCLUSION: West-Asian and Caucasian athletes demonstrate comparable rates of ECG findings. Black African ethnicity is positively associated with increased frequencies of 'uncommon' ECG traits. Future work should examine the genetic mechanisms behind ECG and myocardial adaptations in athletes of diverse ethnicity, aiding in the clinical differentiation between physiological remodelling and potential cardiomyopathy or ion channel disorders.

Significance of deep T-wave inversions in asymptomatic athletes with normal cardiovascular examinations: practical solutions for managing the diagnostic conundrum.

Preparticipation screening programmes for underlying cardiac pathologies are now commonplace for many international sporting organisations. However, providing medical clearance for an asymptomatic athlete without a family history of sudden cardiac death (SCD) is especially challenging when the athlete demonstrates particularly abnormal repolarisation patterns, highly suggestive of an inherited cardiomyopathy or channelopathy. Deep T-wave inversions of ≥ 2 contiguous anterior or lateral leads (but not aVR, and III) are of major concern for sports cardiologists who advise referring team physicians, as these ECG alterations are a recognised manifestation of hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). Subsequently, inverted T-waves may represent the first and only sign of an inherited heart muscle disease, in the absence of any other features and before structural changes in the heart can be detected. However, to date, there remains little evidence that deep T-wave inversions are always pathognomonic of either a cardiomyopathy or an ion channel disorder in an asymptomatic athlete following long-term follow-up. This paper aims to provide a systematic review of the prevalence of T-wave inversion in athletes and examine T-wave inversion and its relationship to structural heart disease, notably HCM and ARVC with a view to identify young athletes at risk of SCD during sport. Finally, the review proposes clinical management pathways (including genetic testing) for asymptomatic athletes demonstrating significant T-wave inversion with structurally normal hearts.

Ethnic differences in physiological cardiac adaptation to intense physical exercise in highly trained female athletes.

BACKGROUND: Ethnicity is an important determinant of cardiovascular adaptation in athletes. Studies in black male athletes reveal a higher prevalence of electric repolarization and left ventricular hypertrophy than observed in white males; these frequently overlap with those observed in cardiomyopathy and have important implications in the preparticipation cardiac screening era. There are no reports on cardiac adaptation in highly trained black females, who comprise an increasing population of elite competitors. METHODS AND RESULTS: Between 2004 and 2009, 240 nationally ranked black female athletes (mean age 21+/-4.6 years old) underwent 12-lead ECG and 2-dimensional echocardiography. The results were compared with 200 white female athletes of similar age and size participating in similar sports. Black athletes demonstrated greater left ventricular wall thickness (9.2+/-1.2 versus 8.6+/-1.2 mm, P<0.001) and left ventricular mass (187.2+/-42 versus 172.3+/-42 g, P=0.008) than white athletes. Eight black athletes (3%) exhibited a left ventricular wall thickness >11 mm (12 to 13 mm) compared with none of the white athletes. All athletes revealed normal indices of systolic and diastolic function. Black athletes exhibited a higher prevalence of T-wave inversions (14% versus 2%, P<0.001) and ST-segment elevation (11% versus 1%, P<0.001) than white athletes. Deep T-wave inversions (-0.2 mV) were observed only in black athletes and were confined to the anterior leads (V(1) through V(3)). CONCLUSIONS: Systematic physical exercise in black female athletes is associated with greater left ventricular hypertrophy and higher prevalence of repolarization changes than in white female athletes of similar age and size participating in identical sporting disciplines. However, a maximal left ventricular wall thickness >13 mm or deep T-wave inversions in the inferior and lateral leads are rare and warrant further investigation.

Biological markers of cardiac damage are not related to measures of cardiac systolic and diastolic function using cardiovascular magnetic resonance and echocardiography after an acute bout of prolonged endurance exercise.

OBJECTIVES: Seventeen male participants (mean (SD) (range): age 33.5 (6.5) years (46-26 years), body mass 80 (9.2) kg (100-63 kg), height 1.81 (0.06) m (1.93- 1.70 m)) ran a marathon to investigate the relationship between systolic function (using cardiac magnetic resonance (CMR)) and diastolic function (using echocardiography) against biomarkers of cardiac damage. METHODS: Echocardiographic and cardiac troponin I (cTnI)/N-terminal pro-B-type natriuretic peptide (NTproBNP) data were collected 24 h premarathon, immediately postmarathon and 6 h postmarathon. CMR data were collected 24 h premarathon and at 6 h postmarathon. RESULTS: Body mass was significantly reduced postmarathon (80 (9.2) vs 78.8 (8.6) kg; p<0.001). There was a significant E/A reduction postmarathon (1.11 (0.34) vs 1.72 (0.44); p<0.05) that remained depressed 6 h postmarathon (1.49 (0.43); p<0.05). CMR demonstrated left ventricular end-diastolic and end-systolic volumes were reduced postmarathon, with a preserved stroke volume. Left ventricular ejection fraction 6 h postmarathon significantly increased (64.4% (4.2%) vs 67.4% (5%); p<0.05). There were significant elevations in cTnI (0.00 vs 0.04 (0.03) µg/l; p<0.05) and NTproBNP (37.4 (24.15) ng/l vs 59.34 (43.3) ng/l; p<0.05) immediately postmarathon. Eight runners had cTnI elevations immediately postmarathon above acute myocardial infarction cutoff levels (≥0.03 µg/l). No correlations between cTnI/NTproBNP and measures of diastolic function (E, A, E/A, isovolumic relaxation time, E deceleration time and E/E') or measures of systolic function (stroke volume or ejection fraction) were observed immediately postmarathon or 6 h postmarathon. CONCLUSIONS: Biomarkers of cardiac damage after prolonged exercise are not associated with either systolic or diastolic functional measures.

Inhibition of platelet-rich arterial thrombus in vivo: acute antithrombotic effect of intravenous HMG-CoA reductase therapy.

OBJECTIVE: To test the hypothesis that statins will acutely inhibit platelet thrombus formation, intravenous lovastatin was assessed in our well-characterized porcine carotid injury model. METHODS AND RESULTS: The first carotid artery was crush-injured and harvested after 30 minutes. Pigs then received intravenous lovastatin (100 microg/kg bolus+100 microg/kg/h infusion, n=6) or saline (n=11) before injury of the second carotid artery. Thrombus size was quantified by scintillation detection of autologous (111)In-platelets. Sequential carotid injury produced a thrombus more than 50% greater in volume in the second (3149+/-2053 x 10(6)/cm(2)) relative to the first injured artery (2081+/-1552 x 10(6)/cm(2); P=0.04) in control pigs. This augmentation was inhibited by intravenous lovastatin which acutely reduced platelet deposition (944+/-246 x 10(6)/cm(2)) relative to saline control (P=0.02). Flow chamber closure times increased on average by 2.45-fold in response to whole blood lovastatin incubation. Lovastatin (P<0.05) and simvastatin (P<0.05) reduced platelet dense granule secretion in vitro. CONCLUSIONS: Sequential arterial injury augments the thrombotic response suggesting that the propensity for arterial thrombosis is at least partially acquired. This thrombotic augmentation can be acutely attenuated by intravenous lovastatin which may result from a pleiotropic impact on platelet function. These results appear to be a class effect of 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors.

Cardiovascular function and the veteran athlete.

The cardiovascular benefits of exercise are well known. In contrast, the impact of lifelong endurance exercise is less well understood. Long-term high-intensity endurance exercise is associated with changes in cardiac morphology together with electrocardiographic alterations that are believed to be physiologic in nature. Recent data however has suggested a number of deleterious adaptive changes in cardiac structure, function and electrical activity, together with peripheral and cerebral vascular structure and function. This review serves to detail knowledge in relation to; (1) Cardiac structure and function in veteran endurance athletes focusing on the differentiation of physiological and pathological changes in cardiac remodelling; (2) Cardiac electrical activity and the veteran endurance athlete with attention to arrhythmias, the substrate for arrhythmia generation and the clinical significance of such arrhythmias; (3) Peripheral and cerebral vascular structure and function in ageing and endurance-trained individuals; and (4) directions for future research.

The effect of prolonged endurance exercise upon blood pressure regulation during a postexercise orthostatic challenge.

OBJECTIVE: To investigate the regulation of blood pressure in response to an orthostatic challenge in athletes running a marathon. METHODS: 10 experienced male runners (mean (SD) age 29 (4) years) were tested on the day prior to the 2004 London Marathon, and again immediately postrace (race time 210 (36) min). In addition, 6 of the subjects were retested 24 h postrace. During each examination, beat-to-beat systolic arterial blood pressure (SBP) and heart rate (HR) were measured, and stroke volume (SV), cardiac output (CO) and total peripheral resistance (TPR) were estimated via arterial transmural pressure waveforms during 3 min in a supine position and then during 3 min of upright, unsupported standing. Data were averaged over 20 s epochs, and the final 20 s of each posture were compared prerace and postrace via repeated measures 2-way ANOVA. RESULTS: Prerace SBP in standing increased only moderately when compared with supine values (2 (9) mm Hg, NS). This was accompanied by an increase in HR (13 (7) beats/min, p<0.05), as well as a decrease in SV (16 (9) ml, p<0.05). However, there was little change in CO (-0.13 (0.97) litres/min, NS) or TPR (0.047 (0.280) medical units (MU), NS). Postrace SBP significantly decreased from supine to standing (-15 (20) mm Hg, p<0.05). The change in SBP was accompanied by an increase in HR (19 (6) beats/min, p<0.05) and a reduction in SV (26 (14) ml, p<0.05) and CO (-1.02 (1.39) litres/min, p = 0.05). Postrace there was no change in TPR (0.366 (0.607) MU, NS) upon standing. The orthostatic adjustments in SBP, HR and CO were greater than at prerace (p<0.05). The postrace orthostatic challenge resulted in only one subject experiencing presyncopal symptoms. At 24 h postrace, cardiovascular responses to an orthostatic challenge mirrored those at prerace. CONCLUSIONS: Following prolonged exercise, a fall in systolic blood pressure during orthostasis results from an inadequately compensated decrease in SV and resultant CO during standing.

Energy expenditure in the Race Across America (RAAM).

Energy Expenditure was measured with doubly labelled water technique during heavy sustained exercise with an official finishing team in the Race Across America. Energy Intake was also calculated to produce an energy balance for the race. A team of 4 cyclists (Mean +/-SD age: 37+4 yr; body height: 182+8 cm; body mass: 80.8+6.6 kg) completed the race in a relay fashion. The team completed the race in 6 days 10 h and 51 min. Total mean energy expenditure was found to be 43,401 kcals (181,711 kJ) with a mean daily energy expenditure of 6,420 kcals (26,879 kJ). Total mean energy intake from all food and drink consumed was calculated at 29,506 kcals (123,536 kJ) with a mean daily energy intake of 4 918 kcals (20,591 kJ). This resulted in a total mean energy deficit of 13,878 kcals (58,104 kJ) with a mean daily energy deficit of 1,503 kcals (6,293 kJ). The high energy expenditure highlights the need for correct and practical dietary strategies and challenges nutritionists to devise high energy diets that not only contain the correct macronutrient balance, but are also palatable to the cyclists, thus encouraging a high energy intake.

Aggregation and microparticle production through toll-like receptor 4 activation in platelets from recently menopausal women.

Bacterial infection may increase risk for thrombosis and atherosclerosis. Human platelets express toll-like receptor 4 (TLR4), the receptor for gram-negative bacterial lipopolysaccharide (LPS). Experiments were designed to evaluate direct, acute effects of TLR4 activation on aggregation, secretion, and generation of prothrombogenic microparticles in vitro on platelets derived from healthy women at risk for development of cardiovascular disease because of their hormonal status. Platelet-rich plasma from recently menopausal women was incubated with ultrapure Escherichia coli LPS in the absence or presence of antibodies that neutralize the human TLR4. Incubating platelets with LPS (100 ng/mL) for 5 minutes decreased aggregation and dense granule adenosine triphosphate secretion induced by thrombin receptor agonist peptide (TRAP) but not by adenosine diphosphate or collagen. The antibody to TLR4 blocked this effect of LPS. TLR4 activation increased phosphorylation of p38 mitogen-activated protein kinase and decreased production of prothrombotic phosphatidylserine and P-selectin-positive microparticles in response to TRAP. Therefore, acute, direct activation of TLR4 reduces platelet reactivity to TRAP stimulation in vitro. Increased thrombotic and cardiovascular risk with bacterial infection most likely reflects the sum of TLR4 activation on other blood and vascular cells to release proinflammatory cytokines/chemokines, which indirectly affect platelet reactivity.

The role of lactate in the exercise-induced human growth hormone response: evidence from McArdle disease.

PURPOSE: Increased blood lactate concentration has been suggested as a primary stimulus for the exercise-induced growth hormone response (EIGR). Patients with McArdle disease are unable to produce lactate in response to exercise and thus offer a unique model to assess the role of lactate in the EIGR. Accordingly, McArdle's patients were exercised to test the hypothesis that lactate is a major stimulus of the EIGR. METHODS: 11 patients with McArdle disease (3 male, 8 female; age: 35.5 (SD 13.9) years, height: 166 (8) cm, body mass: 75.2 (13.1) kg) were recruited for the study. The patients walked initially at 0.42 m/s, increasing by 0.14 m/s per 3 min stage. Exercise was terminated when participants completed 3 minutes at 1.80 m/s or when a Borg CR10 pain scale rating of "4" was reached. Stages were separated by 60 s for capillary blood sampling for analysis of hGH and blood lactate concentration. RESULTS: McArdle's patients' blood lactate levels remained at resting levels (0.3-1.2 mmol/l) as exercise intensity increased. Nine out of 11 participants failed to demonstrate an EIGR obtaining hGH values below the clinical definition of a response (>3 microg/l). CONCLUSION: The absence of an EIGR in nine out of 11 participants suggests that lactate could play a major role in the EIGR in humans.

Kinetic analysis of interaction of BRCA1 tandem breast cancer c-terminal domains with phosphorylated peptides reveals two binding conformations.

Tandem breast cancer C-terminal (BRCT) domains, present in many DNA repair and cell cycle checkpoint signaling proteins, are phosphoprotein binding modules. The best-characterized tandem BRCT domains to date are from the protein BRCA1 (BRCA1-BRCT), an E3 ubiquitin ligase that has been linked to breast and ovarian cancer. While X-ray crystallography and NMR spectroscopy studies have uncovered the structural determinants of specificity of BRCA1-BRCT for phosphorylated peptides, a detailed kinetic and thermodynamic characterization of the interaction is also required to understand how structure and dynamics are connected and therefore better probe the mechanism of phosphopeptide recognition by BRCT domains. Through a global analysis of binding kinetics data obtained from surface plasmon resonance (SPR) and stopped-flow fluorescence spectroscopy, we show that the recognition mechanism is complex and best modeled by two equilibrium conformations of BRCA1-BRCT in the free state that both interact with a phosphopeptide, with dissociation constants ( K d) in the micromolar range. We show that the apparent global dissociation constant derived from this kinetic analysis is similar to the K d values measured using steady-state SPR, isothermal titration calorimetry, and fluorescence anisotropy. The dynamic nature of BRCA1-BRCT may facilitate the binding of BRCA1 to different phosphorylated protein targets.

Dynamic control of higher-order modes in hollow-core photonic crystal fibers.

We present a versatile method for selective mode coupling into higher-order modes of photonic crystal fibers, using holograms electronically generated by a spatial light modulator. The method enables non-mechanical and completely repeatable changes in the coupling conditions. We have excited higher order modes up to LP(31) in hollow-core photonic crystal fibers. The reproducibility of the coupling allows direct comparison of the losses of different guided modes in both hollow-core bandgap and kagome-lattice photonic crystal fibers. Our results are also relevant to applications in which the intensity distribution of the light inside the fiber is important, such as particle- or atom-guidance.

Estrogen, inflammation, and platelet phenotype.

BACKGROUND: Although exogenous estrogenic therapies increase the risk of thrombosis, the effects of estrogen on formed elements of blood are uncertain. OBJECTIVE: This article examines the genomic and nongenomic actions of estrogen on platelet phenotype that may contribute to increased thrombotic risk. METHODS: To determine aggregation, secretion, protein expression, and thrombin generation, platelets were collected from experimental animals of varying hormonal status and from women enrolled in the Kronos Early Estrogen Prevention Study. RESULTS: Estrogen receptor beta predominates in circulating platelets. Estrogenic treatment in ovariectomized animals decreased platelet aggregation and adenosine triphosphate (ATP) secretion. However, acute exposure to 17beta-estradiol did not reverse decreases in platelet ATP secretion invoked by lipopolysaccharide. Thrombin generation was positively correlated to the number of circulating microvesicles expressing phosphatidylserine. CONCLUSION: Assessing the effect of estrogen treatments on blood platelets may lead to new ways of identifying women at risk for adverse thrombotic events with such therapies.

Efficacy of personal symptom and family history questionnaires when screening for inherited cardiac pathologies: the role of electrocardiography.

AIMS: This study sought to confirm the efficacy of using resting 12-lead ECG alongside personal symptom and family history questionnaires and physical examination when screening for diseases with the potential to cause sudden cardiac death in the young. METHODS AND RESULTS: 1074 national and international junior athletes (mean age 15.8 (SD 0.7) years, range 10 to 27) and 1646 physically active schoolchildren (16.1 (SD 2.1) years, range 14 to 20) were screened using personal and family history questionnaires, physical examination and resting 12-lead ECG. Nine participants with a positive diagnosis of a disease associated with sudden cardiac death were identified. None of the participants diagnosed with a disease associated with sudden cardiac death were symptomatic or had a family history of note. CONCLUSION: Family history and personal symptom questionnaires alone are inadequate to identify people with diseases associated with sudden cardiac death. Use of the 12-lead ECG is essential when screening for cardiac pathology in the young.