bluuebunny/crossref_metadata_2025 huggingface dataset:
The contribution of preintervention blood pressure, VO2max, BMI, autonomic function and gender to exercise-induced changes in heart rate variability
Authors: Grant Catharina C , Janse van Rensburg Dina C
Published: May 2013

Introduction

The quantification of heart rate variability (HRV) is a tool to assess the interaction between exercise and autonomic control, as well as the pathophysiology of diseases affecting autonomic function. Little is known about the influence of genetically influenced physiology on exercise-induced changes in autonomic cardiac regulation. It was theorised that preintervention values for blood pressure, VO2max, body mass index (BMI), autonomic function and gender contribute significantly to the exercise-induced changes in HRV.

Methods

A 12-week, medium-to-high intensity exercise intervention was completed by 183 volunteers (18–22 years). Data were sampled at baseline and after 12 weeks. Standard time domain, frequency domain and Poincaré HRV quantification techniques were implemented. Regression analysis was performed to determine the influences of the predictors (baseline values for low frequency  (LF), high frequency (HF), BMI, VO2max, gender, blood pressure) on the exercise-induced response of the dependent variables (changes in HRV-indicator values).

Results

Parameters found to be significant (p<0.05) predictors of exercise-induced changes were LF, HF and systolic blood pressure in, respectively, 10, 5 and 2 of the 12 regressions performed. The results indicated that the independent variables contribute between 12.83% and 29.82%, depending on the specific HRV indicator, to the exercise-induced changes in the autonomic nervous system.

Conclusions

Preintervention autonomic status, as represented specifically by LF, is the most important determinant of cardiac autonomic response to an exercise intervention in a healthy study population. Baseline autonomic function could thus be a significant confounder in the outcome of exercise study results.
A systematic review of the effect of red blood cell transfusion on mortality: evidence from large-scale observational studies published between 2006 and 2010
Authors: Hopewell Sally , Omar Omar , Hyde Chris , Yu Ly-Mee , Doree Carolyn , Murphy Mike F
Published: May 2013

Objective

To carry out a systematic review of recently published large-scale observational studies assessing the effects of red blood cell transfusion (RBCT) on mortality, with particular emphasis on the statistical methods used to adjust for confounding. Given the limited number of randomised trials of the efficacy of RBCT, clinicians often use evidence from observational studies. However, confounding factors, for example, individuals receiving blood generally being sicker than those who do not, make their interpretation challenging.

Design

Systematic review.

Information sources

We searched MEDLINE and EMBASE for studies published from 1 January 2006 to 31 December 2010.

Eligibility criteria for included studies

We included prospective cohort, case–control studies or retrospective analyses of databases or disease registers where the effect of risk factors for mortality or survival was examined. Studies must have included more than 1000 participants receiving RBCT for any cause. We assessed the effects of RBCT versus no RBCT and different volumes and age of RBCT.

Results

–32 studies were included in the review; 23 assessed the effects of RBCT versus no RBCT; 5 assessed different volumes and 4 older versus newer RBCT. There was a considerable variability in the patient populations, study designs and level of statistical adjustment. Overall, most studies showed a higher rate of mortality when comparing patients who received RBCT with those who did not, even when these rates were adjusted for confounding; the majority of these increases were statistically significant. The same pattern was observed in studies where protection from bias was likely to be greater, such as prospective studies.

Conclusions

Recent observational studies do show a consistently adverse effect of RBCT on mortality. Whether this is a true effect remains uncertain as it is possible that even the best conducted adjustments cannot completely eliminate the impact of confounding.
Injecting drug users, sex workers and men who have sex with men: a national cross-sectional study to develop a framework and prevalence estimates for national HIV/AIDS programmes in the Republic of Serbia
Authors: Comiskey Catherine , Dempsey Orla , Simic Danijela , Baroš Sladjana
Published: May 2013

Objective

The aim of this study was to develop a framework and best estimates of prevalence for the most at risk populations (MARPs) for HIV/AIDS to include sex workers (SW), men who have sex with men (MSM) and injecting drug users (IDUs) in order to evaluate national HIV/AIDS programmatic targets across the Republic of Serbia.

Design

A national, cross-sectional study and direct enumeration, multiplier and benchmark methods with integrated bio-behavioural surveys, capture/recapture and methods with Wald and Clopper-Pearson CIs were used.

Setting

This study was carried out in the three largest cities and main regions of Serbia, the capital city, Belgrade, (population 1 639 121 persons), the Vojvodina region with main city Novi Sad (population 335 701) and the rest of Serbia with main city Nis (population 257 867).

Participants

A total of 1301 respondents from the defined MARPs completed the survey in the 2009/2010 period across the three cities.

Primary outcome measures

Estimates of the hidden numbers at risk of HIV/AIDS.

Results

It was estimated that there were 1775–6027 SW between 18 and 49 years in Serbia in 2009. For MSM, national estimates for 2009 ranged from 20 789 to 90 104 individuals aged between 20 and 49 years. For IDU, a possible range of 12 682–48 083 individuals aged between 15 and 59 years in 2009 was estimated.

Conclusions

For service planning across Central and Eastern Europe, it is important to highlight how credible estimates can be achieved and compared with numbers within HIV/AIDS-prevention programmes. Within needle exchange programmes, only 5.4–20.5% of the estimated population was observed and this proportion was lower within methadone treatment data. Results have implications for future IDU treatment and HIV incidence and spread across all populations at risk.
INvolvement of breast CAncer patients during oncological consultations: a multicentre randomised controlled trial—the INCA study protocol
Authors: Goss Claudia , Ghilardi Alberto , Deledda Giuseppe , Buizza Chiara , Bottacini Alessandro , Del Piccolo Lidia , Rimondini Michela , Chiodera Federica , Mazzi Maria Angela , Ballarin Mario , Bighelli Irene , Strepparava Maria Grazia , Molino Annamaria , Fiorio Elena , Nortilli Rolando , Caliolo Chiara , Zuliani Serena , Auriemma Alessandra , Maspero Federica , Simoncini Edda Lucia , Ragni Fulvio , Brown Richard , Zimmermann Christa
Published: May 2013

Introduction

Studies on patient involvement show that physicians make few attempts to involve their patients who ask few questions if not facilitated. On the other hand, the patients who participate in the decision-making process show greater treatment adherence and have better health outcomes. Different methods to encourage the active participation during oncological consultation have been described; however, similar studies in Italy are lacking. The aims of the present study are to (1) assess the effects of a preconsultation intervention to increase the involvement of breast cancer patients during the consultation, and (2) explore the role of the attending companions in the information exchange during consultation.

Methods and analysis

All female patients with breast cancer who attend the Oncology Out-patient Services for the first time will provide an informed consent to participate in the study. They are randomly assigned to the intervention or to the control group. The intervention consists of the presentation of a list of relevant illness-related questions, called a question prompt sheet. The primary outcome measure of the efficacy of the intervention is the number of questions asked by patients during the consultation. Secondary outcomes are the involvement of the patient by the oncologist; the patient's perceived achievement of her information needs; the patient's satisfaction and ability to cope; the quality of the doctor–patient relationship in terms of patient-centeredness; and the number of questions asked by the patient's companions and their involvement during the consultation. All outcome measures are supposed to significantly increase in the intervention group.

Ethics and dissemination

The study was approved by the local Ethics Committee of the Hospital Trust of Verona. Study findings will be disseminated through peer-reviewed publications and conference presentations.

Trial registration

ClinicalTrials.gov identifier:NCT01510964
Job strain and supervisor support in primary care health centres and glycaemic control among patients with type 2 diabetes: a cross-sectional study
Authors: Koponen Anne , Vahtera Jussi , Pitkäniemi Janne , Virtanen Marianna , Pentti Jaana , Simonsen-Rehn Nina , Kivimäki Mika , Suominen Sakari
Published: May 2013

Objectives

This study investigates associations between healthcare personnel's perceived job strain, supervisor support and the outcome of care in terms of glycaemic control among patients with type 2 diabetes.

Design

A cross-sectional study from 2006.

Setting

18 primary care health centres (HCs) from five municipalities in Finland.

Participants

Aggregated survey data on perceived job strain and supervisor support from healthcare personnel (doctors, n=122, mean age 45.5 years, nurses, n=300, mean age 47.1 years) were combined with registered data (Electronic Medical Records) from 8975 patients (51% men, mean age 67 years) with type 2 diabetes.

Outcome measure

Poor glycaemic control (glycated haemoglobin (HbA1c) ≥7%).

Results

The mean HbA1c level among patients with type 2 diabetes was 7.1 (SD 1.2, range 4.5–19.1), and 43% had poor glycaemic control (HbA1c ≥7%). Multilevel logistic regression analyses, adjusted for patient's age and sex, and HC and HC service area-level characteristics, showed that patients’ HbA1c-levels were less optimal in high-strain HCs than in low-strain HCs (OR 1.44, 95% CI 1.12 to 1.86). Supervisor support in HCs was not associated with the outcome of care.

Conclusions

The level of job strain among healthcare personnel may play a role in achieving good glycaemic control among patients with type 2 diabetes.
Publication rate for funded studies from a major UK health research funder: a cohort study
Authors: Turner S , Wright D , Maeso R , Cook A , Milne R
Published: May 2013

Objectives

This study aimed to investigate what percentage of National Institute for Health Research (NIHR) Health Technology Assessment (HTA) Programme-funded projects have published their final reports in the programme's journal HTA and to explore reasons for non-publication.

Design

Retrospective cohort study.

Setting

Failure to publish findings from research is a significant area of research waste. It has previously been suggested that potentially over 50% of studies funded are never published.

Participants

All NIHR HTA projects with a planned submission date for their final report for publication in the journal series on or before 9 December 2011 were included.

Primary and secondary outcome measures

The projects were classified according to the type of research, whether they had been published or not; if not yet published, whether they would be published in the future or not. The reasons for non-publication were investigated.

Results

628 projects were included: 582 (92.7%) had published a monograph; 19 (3%) were expected to publish a monograph; 13 (2.1%) were discontinued studies and would not publish; 12 (1.9%) submitted a report which did not lead to a publication as a monograph; and two (0.3%) did not submit a report. Overall, 95.7% of HTA studies either have published or will publish a monograph: 94% for those commissioned in 2002 or before and 98% for those commissioned after 2002. Of the 27 projects for which there will be no report, the majority (21) were commissioned in 2002 or before. Reasons why projects failed to complete included failure to recruit; issues concerning the organisation where the research was taking place; drug licensing issues; staffing issues; and access to data.

Conclusions

The percentage of HTA projects for which a monograph is published is high. The advantages of funding organisations requiring publication in their own journal include avoidance of publication bias and research waste.
Comparison of health confidence in rural, suburban and urban areas in the UK and the USA: a secondary analysis
Authors: Haven Kristen , Celaya Martín F , Pierson Jaclyn , Weisskopf Aron J , MacKinnon Neil J
Published: May 2013

Objective

Confidence in healthcare may influence the patients’ utilisation of healthcare resources and perceptions of healthcare quality. We sought to determine whether self-reported confidence in healthcare differed between the UK and the USA, as well as by rurality or urbanicity.

Design

A secondary analysis of a subset of survey questions regarding self-reported confidence in healthcare from the 2010 Commonwealth Fund International Health Policy Survey.

Setting

Telephone survey of participants from the UK and the USA.

Participants

Our final analysis included 1511 UK residents (688 rural, 446 suburban, 372 urban, 5 uncategorised) and 2501 US residents (536 rural, 1294 suburban, 671 urban).

Outcome measures

Questions assessed respondents’ confidence in the effectiveness and affordability of the treatment. We compared survey outcomes from these questions between, and within, the two regions and among, and within, residence types (rural, suburban and urban).

Results

Significant differences were found in self-reported confidence in healthcare between the UK and US, among residence types, and between the two regions within residence types. Reported levels were higher in the UK. Within regions, significant differences by residence type were found for the US, but not the UK. Within the US, suburban respondents had the highest self-reported confidence in healthcare.

Conclusions

Significant differences exist between the UK and US in confidence in healthcare. In the US, but not in the UK, self-reported confidence is related to residence type. Within countries, significant differences by residence type were found for the US, but not the UK. Our findings warrant the examination of causes for relative confidence levels in healthcare between regions and among US residence types.
Role of public and private funding in the rising caesarean section rate: a cohort study
Authors: Einarsdóttir Kristjana , Haggar Fatima , Pereira Gavin , Leonard Helen , de Klerk Nick , Stanley Fiona J , Stock Sarah
Published: May 2013

Objective

The caesarean section rates have been rising in the developed world for over two decades. This study assessed the involvement of the public and private health sectors in this increase.

Design

Population-based, retrospective cohort study.

Setting

Public and private hospitals in Western Australia.

Participants

Included in this study were 155 646 births to nulliparous women during 1996–2008.

Main outcome measures

Caesarean section rates were calculated separately for four patient type groups defined according to mothers’ funding source at the time of birth (public/private) and type of delivery hospital (public/private). The average annual per cent change (AAPC) for the caesarean section rates was calculated using joinpoint regression.

Results

Overall, there were 45 903 caesarean sections performed (29%) during the study period, 24 803 in-labour and 21 100 prelabour. Until 2005, the rate of caesarean deliveries increased most rapidly on average annually for private patients delivering in private hospitals (AAPC=6.5%) compared with public patients in public hospitals (AAPC=4.3%, p<0.0001). This increase could mostly be attributed to an increase in prelabour caesarean deliveries for this group of women and could not be explained by an increase in breech deliveries, placenta praevia or multiple pregnancies.

Conclusions

Our results indicate that an increase in the prelabour caesarean delivery rate for private patients in private hospitals has been driving the increase in the caesarean section rate for nulliparous women since 1996. Future research with more detailed information on indication for the prelabour caesarean section is needed to understand the reasons for these findings.
The association between height and birth order: evidence from 652 518 Swedish men
Authors: Myrskylä Mikko , Silventoinen Karri , Jelenkovic Aline , Tynelius Per , Rasmussen Finn
Published: May 2013

Background

Birth order is associated with outcomes such as birth weight and adult socioeconomic position (SEP), but little is known about the association with adult height. This potential birth order-height association is important because height predicts health, and because the association may help explain population-level height trends. We studied the birth order-height association and whether it varies by family characteristics or birth cohort.

Methods

We used the Swedish Military Conscription Register to analyse adult height among 652 518 men born in 1951–1983 using fixed effects regression models that compare brothers and account for genetic and social factors shared by brothers. We stratified the analysis by family size, parental SEP and birth cohort. We compared models with and without birth weight and birth length controls.

Results

Unadjusted analyses showed no differences between the first two birth orders but in the fixed effects regression, birth orders 2, 3 and 4 were associated with 0.4, 0.7 and 0.8 cm (p<0.001 for each) shorter height than birth order 1, respectively. The associations were similar in large and small and high-SEP and low-SEP families, but were attenuated in recent cohorts. Birth characteristics did not explain these associations.

Conclusions

Birth order is an important determinant of height. The height difference between birth orders 3 and 1 is larger than the population-level height increase achieved over 10 years. The attenuation of the effect over cohorts may reflect improvements in living standards. Decreases in family size may explain some of the secular-height increases in countries with decreasing fertility.
Resolution of trigeminal neuralgia by coil embolization of a persistent primitive trigeminal artery aneurysm
Authors: Ladner Travis R , Ehtesham Moneeb , Davis Brandon J , Khan Imad S , Ghiassi Mayshan , Ghiassi Mahan , Singer Robert J
Published: May 2013

The persistent primitive trigeminal artery (PTA) is a rare anastomosis between the carotid artery and basilar artery. While most PTAs are asymptomatic, lateral variants can occasionally compress the trigeminal nerve and precipitate trigeminal neuralgia. Aneurysms of the PTA are exceptionally rare in the literature and have not previously been associated with trigeminal neuralgia. We present the first case of an aneurysm of the PTA causing trigeminal neuralgia. The patient underwent coil embolization of the aneurysm which relieved her symptoms. We propose embolization as a viable therapeutic option for the resolution of trigeminal neuralgia when the condition is secondary to irritation by the high velocity pulsatile flow of an aneurysm.
Prevalence of and risk factors for chronic arthralgia and rheumatoid-like polyarthritis more than 2 years after infection with chikungunya virus
Authors: Essackjee Khadijah , Goorah Smita , Ramchurn Satish Kumar , Cheeneebash Jayrani , Walker-Bone Karen
Published: May 2013

Objectives

Chikungunya virus (CHIKV), transmitted to humans from infected mosquitoes, causes acute fever, arthralgia and rash. There is increasing evidence that it also causes longer-term rheumatic symptoms. In a circumscribed part of Mauritius where infectivity was high, a cohort of inhabitants was surveyed with the objectives of assessing the prevalence of and risk factors for chronic musculoskeletal symptoms and for a rheumatoid arthritis-like condition at 27.5 months after initial infection.

Methods

Participants were recruited May–November 2008 and invited to complete a questionnaire. CHIKV was diagnosed clinically. The primary outcomes for the analyses were (a) self-reported ongoing musculoskeletal symptoms and (b) fulfilment of modified diagnostic criteria for rheumatoid arthritis. Risk factors for these outcomes were explored in univariate analyses using logistic regression. Subsequently, multivariate logistic regression was used to identify factors that were independently associated with the outcomes.

Results

173 individuals were identified with CHIKV, of whom 136 (78.6%) reported persisting musculoskeletal symptoms 27.5 months after infection. Persistent symptoms were associated with older age at time of infection, female gender and baseline symmetrical distribution of joint symptoms. We found that 5% of those infected with CHIKV fulfilled a modified version of the American College of Rheumatology criteria for rheumatoid arthritis 27.5 months after infection.

Conclusions

CHIKV is associated with a high prevalence of persistent rheumatic symptoms. Physicians need to be aware of CHIKV as a cause of acute and chronic rheumatic symptoms.
Tissue-specific effects of acetylcholine in the canine heart
Authors: Calloe Kirstine , Goodrow Robert , Olesen Søren-Peter , Antzelevitch Charles , Cordeiro Jonathan M.
Published: May 2013

Acetylcholine (ACh) release from the vagus nerve slows heart rate and atrioventricular conduction. ACh stimulates a variety of receptors and channels, including an inward rectifying current [ACh-dependent K+ current ( IK,ACh)]. The effect of ACh in the ventricle is still debated. We compared the effect of ACh on action potentials in canine atria, Purkinje, and ventricular tissue as well as on ionic currents in isolated cells. Action potentials were recorded from ventricular slices, Purkinje fibers, and arterially perfused atrial preparations. Whole cell currents were recorded under voltage-clamp conditions, and unloaded cell shortening was determined on isolated cells. The effect of ACh (1–10 μM) as well as ACh plus tertiapin, an IK,ACh-specific toxin, was tested. In atrial tissue, ACh hyperpolarized the membrane potential and shortened the action potential duration (APD). In Purkinje and ventricular tissues, no significant effect of ACh was observed. Addition of ACh to atrial cells activated a large inward rectifying current (from −3.5 ± 0.7 to −23.7 ± 4.7 pA/pF) that was abolished by tertiapin. This current was not observed in other cell types. A small inhibition of Ca2+ current ( ICa) was observed in the atria, endocardium, and epicardium after ACh. ICa inhibition increased at faster pacing rates. At a basic cycle length of 400 ms, ACh (1 μM) reduced ICa to 68% of control. In conclusion, IK,ACh is highly expressed in atria and is negligible/absent in Purkinje, endocardial, and epicardial cells. In all cardiac tissues, ACh caused rate-dependent inhibition of ICa.
Flow restoration post revascularization predicted by stenosis indexes: sensitivity to hemodynamic variability
Authors: Algranati Dotan , Kassab Ghassan S. , Lanir Yoram
Published: May 2013

The expected blood flow improvement following a coronary intervention is inversely related to the stenotic-to-normal flow ratio Qs/Qn. Since Qn cannot be measured prior to intervention, treatment decisions rely on stenosis-severity indexes, e.g., area stenosis (%AS), hyperemic stenosis resistance (HSR), and fractional flow reserve (FFR), where treatment cut-off levels have been established for each index based on presence of inducible ischemia. Here, we studied the dependence of these indexes-predicted Qs/Qn under physiological perturbations of stenosis features and of hemodynamic and mechanical conditions. Dynamic coronary flow was simulated based on measured coronary morphometric data and a physics-based computational model. Simulations were used to evaluate the relationship between each index level and Qs/Qn. Under each perturbation, an independence measure (IM) was calculated for each index based on the relative change in Qs/Qn associated with each perturbation. The results show that while %AS prediction of Qs/Qn is largely independent (IM > 90%) of physiological changes in heart rate, venous pressure, and lesion length and location on the epicardial tree, HSR is also independent of changes in left ventricle pressure. FFR-predicted Qs/Qn is also independent of changes in aortic pressure, blood hematocrit, and stenotic vessel stiffness. Nevertheless, independence of all indexes is substantially compromised (IM < 70%) under changes in vasculature stiffness. Specifically, a physiological stiffening elevates Qs/Qn value by 21% at the FFR cut-off value (0.75). These findings suggest that the current FFR cut-off value for treatment of stenotic lesions overestimates the benefit of coronary intervention in patients with a stiffer coronary vasculature (e.g., diabetics, hypertensives).
Functional role of peripheral opioid receptors in the regulation of cardiac spinal afferent nerve activity during myocardial ischemia
Authors: Fu Liang-Wu , Longhurst John C.
Published: May 2013

Thinly myelinated Aδ-fiber and unmyelinated C-fiber cardiac sympathetic (spinal) sensory nerve fibers are activated during myocardial ischemia to transmit the sensation of angina pectoris. Although recent observations showed that myocardial ischemia increases the concentrations of opioid peptides and that the stimulation of peripheral opioid receptors inhibits chemically induced visceral and somatic nociception, the role of opioids in cardiac spinal afferent signaling during myocardial ischemia has not been studied. The present study tested the hypothesis that peripheral opioid receptors modulate cardiac spinal afferent nerve activity during myocardial ischemia by suppressing the responses of cardiac afferent nerve to ischemic mediators like bradykinin and extracellular ATP. The nerve activity of single unit cardiac afferents was recorded from the left sympathetic chain (T2–T5) in anesthetized cats. Forty-three ischemically sensitive afferent nerves (conduction velocity: 0.32–3.90 m/s) with receptive fields in the left and right ventricles were identified. The responses of these afferent nerves to repeat ischemia or ischemic mediators were further studied in the following protocols. First, epicardial administration of naloxone (8 μmol), a nonselective opioid receptor antagonist, enhanced the responses of eight cardiac afferent nerves to recurrent myocardial ischemia by 62%, whereas epicardial application of vehicle (PBS) did not alter the responses of seven other cardiac afferent nerves to ischemia. Second, naloxone applied to the epicardial surface facilitated the responses of seven cardiac afferent nerves to epicardial ATP by 76%. Third, administration of naloxone enhanced the responses of seven other afferent nerves to bradykinin by 85%. In contrast, in the absence of naloxone, cardiac afferent nerves consistently responded to repeated application of ATP ( n = 7) or bradykinin ( n = 7). These data suggest that peripheral opioid peptides suppress the responses of cardiac sympathetic afferent nerves to myocardial ischemia and ischemic mediators like ATP and bradykinin.
Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle
Authors: Crecelius Anne R. , Kirby Brett S. , Luckasen Gary J. , Larson Dennis G. , Dinenno Frank A.
Published: May 2013

A monophasic increase in skeletal muscle blood flow is observed after a brief single forearm contraction in humans, yet the underlying vascular signaling pathways remain largely undetermined. Evidence from experimental animals indicates an obligatory role of vasodilation via K+-mediated smooth muscle hyperpolarization, and human data suggest little to no independent role for nitric oxide (NO) or vasodilating prostaglandins (PGs). We tested the hypothesis that K+-mediated vascular hyperpolarization underlies the rapid vasodilation in humans and that combined inhibition of NO and PGs would have a minimal effect on this response. We measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance 10 s before and for 30 s after a single 1-s dynamic forearm contraction at 10%, 20%, and 40% maximum voluntary contraction in 16 young adults. To inhibit K+-mediated vasodilation, BaCl2 and ouabain were infused intra-arterially to inhibit inwardly rectifying K+ channels and Na+-K+-ATPase, respectively. Combined enzymatic inhibition of NO and PG synthesis occurred via NG-monomethyl-l-arginine (l-NMMA; NO synthase) and ketorolac (cyclooxygenase), respectively. In protocol 1 ( n = 8), BaCl2 + ouabain reduced peak vasodilation (range: 30–45%, P < 0.05) and total postcontraction vasodilation (area under the curve, ∼55–75% from control) at all intensities. Contrary to our hypothesis, l-NMMA + ketorolac had a further impact (peak: ∼60% and area under the curve: ∼80% from control). In protocol 2 ( n = 8), the order of inhibitors was reversed, and the findings were remarkably similar. We conclude that K+-mediated hyperpolarization and NO and PGs, in combination, significantly contribute to contraction-induced rapid vasodilation and that inhibition of these signaling pathways nearly abolishes this phenomenon in humans.
Uncoupling the mitochondria facilitates alternans formation in the isolated rabbit heart
Authors: Smith Rebecca M. , Visweswaran Ramjay , Talkachova Iryna , Wothe Jillian K. , Tolkacheva Elena G.
Published: May 2013

Alternans of action potential duration (APD) and intracellular calcium ([Ca2+]i) transients in the whole heart are thought to be markers of increased propensity to ventricular fibrillation during ischemia-reperfusion injuries. During ischemia, ATP production is affected and the mitochondria become uncoupled, which may affect alternans formation in the heart. The aim of our study was to investigate the role of mitochondria on the formation of APD and [Ca2+]i alternans in the isolated rabbit heart. We performed dual voltage and [Ca2+]i optical mapping of isolated rabbit hearts under control conditions, global no-flow ischemia ( n = 6), and after treatment with 50 nM of the mitochondrial uncoupler FCCP ( n = 6). We investigated the formation of alternans of APD, [Ca2+]i amplitude (CaA), and [Ca2+]i duration (CaD) under different rates of pacing. We found that treatment with FCCP leads to the early occurrence of APD, CaD, and CaA alternans; an increase of intraventricular APD but not CaD heterogeneity; and significant reduction in conduction velocity compared with that of control. Furthermore, we demonstrated that FCCP and global ischemia have similar effects on the prolongation of [Ca2+]i transients, whereas ischemia induces a significantly larger reduction of APD compared with that in FCCP treatment. In conclusion, our results demonstrate that uncoupling of mitochondria leads to an earlier occurrence of alternans in the heart. Thus, in conditions of mitochondrial stress, as seen during myocardial ischemia, uncoupled mitochondria may be responsible for the formation of both APD and [Ca2+]i alternans in the heart, which in turn creates a substrate for ventricular arrhythmias.
Modeling serotonin uptake in the lung shows endothelial transporters dominate over cleft permeation
Authors: Jardine Bartholomew , Bassingthwaighte James B.
Published: May 2013

A four-region (capillary plasma, endothelium, interstitial fluid, cell) multipath model was configured to describe the kinetics of blood-tissue exchange for small solutes in the lung, accounting for regional flow heterogeneity, permeation of cell membranes and through interendothelial clefts, and intracellular reactions. Serotonin uptake data from the Multiple indicator dilution “bolus sweep” experiments of Rickaby and coworkers (Rickaby DA, Linehan JH, Bronikowski TA, Dawson CA. J Appl Physiol 51: 405–414, 1981; Rickaby DA, Dawson CA, and Linehan JH. J Appl Physiol 56: 1170–1177, 1984) and Malcorps et al. (Malcorps CM, Dawson CA, Linehan JH, Bronikowski TA, Rickaby DA, Herman AG, Will JA. J Appl Physiol 57: 720–730, 1984) were analyzed to distinguish facilitated transport into the endothelial cells (EC) and the inhibition of tracer transport by nontracer serotonin in the bolus of injectate from the free uninhibited permeation through the clefts into the interstitial fluid space. The permeability-surface area products (PS) for serotonin via the inter-EC clefts were ∼0.3 ml·g−1·min−1, low compared with the transporter-mediated maximum PS of 13 ml·g−1·min−1(with Km= ∼0.3 μM and Vmax= ∼4 nmol·g−1·min−1). The estimates of serotonin PS values for EC transporters from their multiple data sets were similar and were influenced only modestly by accounting for the cleft permeability in parallel. The cleft PS estimates in these Ringer-perfused lungs are less than half of those for anesthetized dogs (Yipintsoi T. Circ Res 39: 523–531, 1976) with normal hematocrits, but are compatible with passive noncarrier-mediated transport observed later in the same laboratory (Dawson CA, Linehan JH, Rickaby DA, Bronikowski TA. Ann Biomed Eng 15: 217–227, 1987; Peeters FAM, Bronikowski TA, Dawson CA, Linehan JH, Bult H, Herman AG. J Appl Physiol 66: 2328–2337, 1989) The identification and quantitation of the cleft pathway conductance from these studies affirms the importance of the cleft permeation.
Efficacy and Mechanism-of-Action of a Novel Superagonist Interleukin-15: Interleukin-15 Receptor αSu/Fc Fusion Complex in Syngeneic Murine Models of Multiple Myeloma
Authors: Xu Wenxin , Jones Monica , Liu Bai , Zhu Xiaoyun , Johnson Christopher B. , Edwards Ana C. , Kong Lin , Jeng Emily K. , Han Kaiping , Marcus Warren D. , Rubinstein Mark P. , Rhode Peter R. , Wong Hing C.
Published: May 2013

ALT-803, a complex of an interleukin (IL)-15 superagonist mutant and a dimeric IL-15 receptor αSu/Fc fusion protein, was found to exhibit significantly stronger in vivo biologic activity on NK and T cells than IL-15. In this study, we show that a single dose of ALT-803, but not IL-15 alone, eliminated well-established 5T33P and MOPC-315P myeloma cells in the bone marrow of tumor-bearing mice. ALT-803 treatment also significantly prolonged survival of myeloma-bearing mice and provided resistance to rechallenge with the same tumor cells through a CD8+ T-cell–dependent mechanism. ALT-803 treatment stimulated CD8+ T cells to secrete large amounts of IFN-γ and promoted rapid expansion of CD8+CD44high memory T cells in vivo. These memory CD8+ T cells exhibited ALT-803–mediated upregulation of NKG2D (KLRK1) but not PD-1 (PDCD1) or CD25 (IL2RA) on their cell surfaces. ALT-803–activated CD8+ memory T cells also exhibited nonspecific cytotoxicity against myeloma and other tumor cells in vitro, whereas IFN-γ had no direct effect on myeloma cell growth. ALT-803 lost its antimyeloma activity in tumor-bearing IFN-γ knockout mice but retained the ability to promote CD8+CD44high memory T-cell proliferation, indicating that ALT-803–mediated stimulation of CD8+CD44high memory T cells is IFN-γ–independent. Thus, besides well-known IL-15 biologic functions in host immunity, this study shows that IL-15–based ALT-803 could activate CD8+CD44high memory T cells to acquire a unique innate-like phenotype and secrete IFN-γ for nonspecific tumor cell killing. This unique immunomodulatory property of ALT-803 strongly supports its clinical development as a novel immunotherapeutic agent against cancer and viral infections. Cancer Res; 73(10); 3075–86. ©2013 AACR.
CIP4 Controls CCL19-Driven Cell Steering and Chemotaxis in Chronic Lymphocytic Leukemia
Authors: Malet-Engra Gema , Viaud Julien , Ysebaert Loïc , Farcé Manon , Lafouresse Fanny , Laurent Guy , Gaits-Iacovoni Frédérique , Scita Giorgio , Dupré Loïc
Published: May 2013

Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of nonsolid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein Cdc42-interacting protein 4 (CIP4) as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells, where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 mitogen-activated protein kinase (MAPK). Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells by controlling the dynamics of microspike-containing protrusions and cell steering. Cancer Res; 73(11); 3412–24. ©2013 AACR.
KDM4/JMJD2 Histone Demethylases: Epigenetic Regulators in Cancer Cells
Authors: Berry William L. , Janknecht Ralf
Published: May 2013

Lysine methylation is one of the most prominent histone posttranslational modifications that regulate chromatin structure. Changes in histone lysine methylation status have been observed during cancer formation, which is thought to be a consequence of the dysregulation of histone lysine methyltransferases or the opposing demethylases. KDM4/JMJD2 proteins are demethylases that target histone H3 on lysines 9 and 36 and histone H1.4 on lysine 26. This protein family consists of three ∼130-kDa proteins (KDM4A-C) and KDM4D/JMJD2D, which is half the size, lacks the double PHD and Tudor domains that are epigenome readers and present in the other KDM4 proteins, and has a different substrate specificity. Various studies have shown that KDM4A/JMJD2A, KDM4B/JMJD2B, and/or KDM4C/JMJD2C are overexpressed in breast, colorectal, lung, prostate, and other tumors and are required for efficient cancer cell growth. In part, this may be due to their ability to modulate transcription factors such as the androgen and estrogen receptor. Thus, KDM4 proteins present themselves as novel potential drug targets. Accordingly, multiple attempts are under way to develop KDM4 inhibitors, which could complement the existing arsenal of epigenetic drugs that are currently limited to DNA methyltransferases and histone deacetylases. Cancer Res; 73(10); 2936–42. ©2013 AACR.
β1 Integrin Targeting Potentiates Antiangiogenic Therapy and Inhibits the Growth of Bevacizumab-Resistant Glioblastoma
Authors: Carbonell W. Shawn , DeLay Michael , Jahangiri Arman , Park Catherine C. , Aghi Manish K.
Published: May 2013

Antiangiogenic therapies like bevacizumab offer promise for cancer treatment, but acquired resistance, which often includes an aggressive mesenchymal phenotype, can limit the use of these agents. Upregulation of β1 integrin (ITGB1) occurs in some bevacizumab-resistant glioblastomas (BRG) whereby, mediating tumor–microenvironment interactions, we hypothesized that it may mediate a mesenchymal-type resistance to antiangiogenic therapy. Immunostaining analyses of β1 integrin and its downstream effector kinase FAK revealed upregulation in 75% and 86% of BRGs, respectively, compared with pretreatment paired specimens. Furthermore, flow cytometry revealed eight-fold more β1 integrin in primary BRG cells compared with cells from bevacizumab-naïve glioblastomas (BNG). Fluorescence recovery after photobleaching of cells engineered to express a β1-GFP fusion protein indicated that the mobile β1 integrin fraction was doubled, and half-life of β1 integrin turnover in focal adhesions was reduced markedly in BRG cells compared with bevacizumab-responsive glioblastoma multiforme cells. Hypoxia, which was increased with acquisition of bevacizumab resistance, was associated with increased β1 integrin expression in cultured BNG cells. BRGs displayed an aggressive mesenchymal-like phenotype in vitro. We found that growth of BRG xenograft tumors was attenuated by the β1 antibody, OS2966, allowing a 20-fold dose reduction of bevacizumab per cycle in this model. Intracranial delivery of OS2966 through osmotic pumps over 28 days increased tumor cell apoptosis, decreased tumor cell invasiveness, and blunted the mesenchymal morphology of tumor cells. We concluded that β1 integrin upregulation in BRGs likely reflects an onset of hypoxia caused by antiangiogenic therapy, and that β1 inhibition is well tolerated in vivo as a tractable strategy to disrupt resistance to this therapy. Cancer Res; 73(10); 3145–54. ©2013 AACR.
Multivalent Scaffold Proteins as Superagonists of TRAIL Receptor 2–Induced Apoptosis
Authors: Swers Jeffery S. , Grinberg Luba , Wang Lin , Feng Hui , Lekstrom Kristen , Carrasco Rosa , Xiao Zhan , Inigo Ivan , Leow Ching Ching , Wu Herren , Tice David A. , Baca Manuel
Published: May 2013

Activation of TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) can induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in normal cells. The natural ligand and agonistic antibodies show antitumor activity in preclinical models of cancer, and this had led to significant excitement in the clinical potential of these agents. Unfortunately, this optimism has been tempered by trial data that, thus far, are not showing clear signs of efficacy in cancer patients. The reasons for discrepant preclinical and clinical observations are not understood, but one possibility is that the current TRAILR2 agonists lack sufficient potency to achieve a meaningful response in patients. Toward addressing that possibility, we have developed multivalent forms of a new binding scaffold (Tn3) that are superagonists of TRAILR2 and can induce apoptosis in tumor cell lines at subpicomolar concentrations. The monomer Tn3 unit was a fibronectin type III domain engineered for high-affinity TRAILR2 binding. Multivalent presentation of this basic unit induced cell death in TRAILR2-expressing cell lines. Optimization of binding affinity, molecular format, and valency contributed to cumulative enhancements of agonistic activity. An optimized multivalent agonist consisting of 8 tandem Tn3 repeats was highly potent in triggering cell death in TRAIL-sensitive cell lines and was 1 to 2 orders of magnitude more potent than TRAIL. Enhanced potency was also observed in vivo in a tumor xenograft setting. The TRAILR2 superagonists described here have the potential for superior clinical activity in settings insensitive to the current therapeutic agonists that target this pathway. Mol Cancer Ther; 12(7); 1235–44. ©2013 AACR.
Aerosol Administration of Phospho-Sulindac Inhibits Lung Tumorigenesis
Authors: Cheng Ka Wing , Wong Chi C. , Alston Ninche , Mackenzie Gerardo G. , Huang Liqun , Ouyang Nengtai , Xie Gang , Wiedmann Timothy , Rigas Basil
Published: May 2013

Phospho-sulindac is a sulindac derivative with promising anticancer activity in lung cancer, but its limited metabolic stability presents a major challenge for systemic therapy. We reasoned that inhalation delivery of phospho-sulindac might overcome first-pass metabolism and produce high levels of intact drug in lung tumors. Here, we developed a system for aerosolization of phospho-sulindac and evaluated the antitumor efficacy of inhaled phospho-sulindac in an orthotopic model of human non–small cell lung cancer (A549 cells). We found that administration by inhalation delivered high levels of phospho-sulindac to the lungs and minimized its hydrolysis to less active metabolites. Consequently, inhaled phospho-sulindac (6.5 mg/kg) was highly effective in inhibiting lung tumorigenesis (75%; P < 0.01) and significantly improved the survival of mice bearing orthotopic A549 xenografts. Mechanistically, phospho-sulindac suppressed lung tumorigenesis by (i) inhibiting EGF receptor (EGFR) activation, leading to profound inhibition of Raf/MEK/ERK and PI3K/AKT/mTOR survival cascades; (ii) inducing oxidative stress, which provokes the collapse of mitochondrial membrane potential and mitochondria-dependent cell death; and (iii) inducing autophagic cell death. Our data establish that inhalation delivery of phospho-sulindac is an efficacious approach to the control of lung cancer, which merits further evaluation. Mol Cancer Ther; 12(8); 1417–28. ©2013 AACR.
Antiproliferative Effects of Continued Mitogen-Activated Protein Kinase Pathway Inhibition following Acquired Resistance to BRAF and/or MEK Inhibition in Melanoma
Authors: Carlino Matteo S. , Gowrishankar Kavitha , Saunders Catherine A.B. , Pupo Gulietta M. , Snoyman Stephanie , Zhang Xu Dong , Saw Robyn , Becker Therese M. , Kefford Richard F. , Long Georgina V. , Rizos Helen
Published: May 2013

Inhibitors of the mitogen-activated protein kinases (MAPK), BRAF, and MAP–ERK kinase (MEK) induce tumor regression in the majority of patients with BRAF-mutant metastatic melanoma. The clinical benefit of MAPK inhibitors is restricted by the development of acquired resistance with half of those who benefit having progressed by 6 to 7 months and long-term responders uncommon. There remains no agreed treatment strategy on disease progression in these patients. Without published evidence, fears of accelerated disease progression on inhibitor withdrawal have led to the continuation of drugs beyond formal disease progression. We now show that treatment with MAPK inhibitors beyond disease progression can provide significant clinical benefit, and the withdrawal of these inhibitors led to a marked increase in the rate of disease progression in two patients. We also show that MAPK inhibitors retain partial activity in acquired resistant melanoma by examining drug-resistant clones generated to dabrafenib, trametinib, or the combination of these drugs. All resistant sublines displayed a markedly slower rate of proliferation when exposed to MAPK inhibitors, and this coincided with a reduction in MAPK signaling, decrease in bromodeoxyuridine incorporation, and S-phase inhibition. This cytostatic effect was also associated with diminished levels of cyclin D1 and p-pRb. Two short-term melanoma cultures generated from resistant tumor biopsies also responded to MAPK inhibition, with comparable inhibitory changes in proliferation and MAPK signaling. These data provide a rationale for the continuation of BRAF and MEK inhibitors after disease progression and support the development of clinical trials to examine this strategy. Mol Cancer Ther; 12(7); 1332–42. ©2013 AACR.
A Supplementary Source for the Study of Mamluk Social History: The Taqārīẓ*
Authors: Levanoni Amalia
Published: May 2013

Abstract

The taqārīẓ were part of an established system of academic recognition and the ʿulamāʾ patronage networks and at times, they could also be a powerful satirical weapon used by the learned elite members to denigrate and exclude a colleague. The large collection of the satire taqārīẓ written for the panegyric Biography composed in 819/1416 by Šams al-Dīn Muḥammad b. Nāhiḍ for the Mamluk sultan al-Muʾayyad Šayḫ is explored in this article as a supplementary source to the historical narratives for the study of the ʿulamāʾ milieu during the strained period of the transition from Turkish to Circassian sultanate (784/1382). Placing these taqārīẓ in the context of the increasing social insecurity entailed by the political reshuffles, reveals the growing anxiety of the incumbent learned elites over their positions and status in the administration of justice, the academe (madāris) and the waqf institution—the spheres where they exercised their hegemony of knowledge and religious power—and the strategies they adopted for their social survival.