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1.  Dynamic MRI in the Diagnosis and Post Surgical Evaluation of Wandering Spleen 
Wandering spleen is a rare but potentially clinically significant entity, and may be a cause for a patient presenting with acute abdomen. Because wandering spleen may present with non-specific symptoms and presentation, it can be a difficult diagnosis to make clinically. This paper describes a case report of the use of dynamic Magnetic Resonance Imaging (MRI) in a young woman to confirm the diagnosis of wandering spleen pre-operatively. The patient underwent a splenopexy and a post-operative MRI confirmed the successful surgical fixation of the patient’s spleen.
PMCID: PMC4242148  PMID: 25426221
wandering spleen; MRI; splenopexy; dynamic MRI
2.  Shock Index and Prediction of Traumatic Hemorrhagic Shock 28-Day Mortality: Data from the DCLHb Resuscitation Clinical Trials 
To assess the ability of the shock index (SI) to predict 28-day mortality in traumatic hemorrhagic shock patients treated in the diaspirin cross-linked hemoglobin (DCLHb) resuscitation clinical trials.
We used data from two parallel DCLHb traumatic hemorrhagic shock efficacy trials, one in U.S. emergency departments, and one in the European Union prehospital setting to assess the relationship between SI values and 28-day mortality.
In the 219 patients, the mean age was 37 years, 64% sustained a blunt injury, 48% received DCLHb, 36% died, and 88% had an SI≥1.0 at study entry. The percentage of patients with an SI≥1.0 dropped by 57% (88 to 38%) from the time of study entry to 120 minutes after study resuscitation (p<0.001). Patients with a SI≥1.0, 1.4, and 1.8 at any time point were 2.3, 2.7, and 3.1 times, respectively, more likely to die by 28 days than were patients with SI values below these cutoffs (p<0.001). Similarly, after 120 minutes of resuscitation, patients with a SI≥1.0 were 3.9× times more likely to die by 28 days (40 vs. 15%, p<0.001). Although the distribution of SI values differed based on treatment group, the receiver operator characeristics data showed no difference in SI predictive ability for 28-day mortality in patients treated with DCLHb.
In these traumatic hemorrhagic shock patients, the shock index correlates with 28-day mortality, with higher SI values indicating greater mortality risk. Although DCLHb treatment did alter the distribution of SI values, it did not influence the ability of the SI to predict 28-day mortality.
PMCID: PMC4251221  PMID: 25493120
3.  Cardiac hypertrophy in mice expressing unphosphorylatable phospholemman 
Cardiovascular Research  2014;104(1):72-82.
Elevation of intracellular Na in the failing myocardium contributes to contractile dysfunction, the negative force–frequency relationship, and arrhythmias. Although phospholemman (PLM) is recognized to form the link between signalling pathways and Na/K pump activity, the possibility that defects in its regulation contribute to elevation of intracellular Na has not been investigated. Our aim was to test the hypothesis that the prevention of PLM phosphorylation in a PLM3SA knock-in mouse (in which PLM has been rendered unphosphorylatable) will exacerbate cardiac hypertrophy and cellular Na overload. Testing this hypothesis should determine whether changes in PLM phosphorylation are simply bystander effects or are causally involved in disease progression.
Methods and results
In wild-type (WT) mice, aortic constriction resulted in hypophosphorylation of PLM with no change in Na/K pump expression. This under-phosphorylation of PLM occurred at 3 days post-banding and was associated with a progressive decline in Na/K pump current and elevation of [Na]i. Echocardiography, morphometry, and pressure-volume (PV) catheterization confirmed remodelling, dilation, and contractile dysfunction, respectively. In PLM3SA mice, expression of Na/K ATPase was increased and PLM decreased such that net Na/K pump current under quiescent conditions was unchanged (cf. WT myocytes); [Na+]i was increased and forward-mode Na/Ca exchanger was reduced in paced PLM3SA myocytes. Cardiac hypertrophy and Na/K pump inhibition were significantly exacerbated in banded PLM3SA mice compared with banded WT.
Decreased phosphorylation of PLM reduces Na/K pump activity and exacerbates Na overload, contractile dysfunction, and adverse remodelling following aortic constriction in mice. This suggests a novel therapeutic target for the treatment of heart failure.
PMCID: PMC4174889  PMID: 25103111
Na/K ATPase; Phospholemman; Hypertrophy; Intracellular sodium
4.  β-Arrestin-2 Deficiency Attenuates Abdominal Aortic Aneurysm Formation in Mice 
Circulation research  2013;112(9):1219-1229.
Abdominal aortic aneurysms (AAAs) are a chronic inflammatory vascular disease for which pharmacological treatments are not available. A mouse model of AAA formation involves chronic infusion of angiotensin II (AngII) and previous studies indicated a primary role for the angiotensin II type 1a (AT1a) receptor, in AAA formation. β-arrestin-2 (βarr2) is a multifunctional scaffolding protein that binds G-protein coupled receptors such as AT1a, and regulates numerous signaling pathways and pathophysiological processes. However, a role for βarr2 in AngII-induced AAA formation is currently unknown.
To determine if βarr2 played a role in AngII-induced AAA formation in mice.
Methods and Results
Treatment of βarr2+/+ and βarr2-/- mice on the hyperlipidemic ApoE-/- background or normolipidemic C57BL/6 background with AngII for 28 days indicated that βarr2 deficiency significantly attenuated AAA formation. βarr2 deficiency attenuated AngII-induced expression of cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1α (MIP1α), and macrophage infiltration. AngII also increased the levels of phosphorylated-extracellular signal-regulated kinase 1/2 (p-ERK1/2) in ApoE-/-/βarr2+/+ aortas, whereas βarr2 deficiency diminished this increase. Furthermore, inhibition of ERK1/2 activation with CI1040 (100mg/kg/day) reduced the level of AngII-induced COX-2 expression in ApoE-/-/βarr2+/+ mice to the level observed in ApoE-/-/βarr2-/- mice. AngII treatment also increased matrix metalloproteinase (MMP) expression and disruption of the elastic layer in ApoE-/-/βarr2+/+ aortas and βarr2-deficiency reduced these effects.
βarr2 contributes to AngII-induced AAA formation in mice by p-ERK1/2-mediated COX-2 induction and increased inflammation. These studies suggest that for the AT1a receptor, G-protein-independent, βarr2-dependent signaling plays a major role in AngII-induced AAA formation.
PMCID: PMC4118213  PMID: 23524589
Aneurysm; β-Arrestin-2; cyclooxygenase-2; angiotensin
5.  Investigating the potential role of TRPA1 in locomotion and cardiovascular control during hypertension 
Radiotelemetry was used to investigate the in vivo cardiovascular and activity phenotype of both TRPA1 (transient receptor potential ankyrin 1) wild-type (WT) and TRPA1 knockout (KO) mice. After baseline recording, experimental hypertension was induced using angiotensin II infusion (1.1 mg−1 kg−1 a day, for 14 days). TRPA1 WT and KO mice showed similar morphological and functional cardiovascular parameters, including similar basal blood pressure (BP), heart rate, size, and function. Similar hypertension was also displayed in response to angiotensin II (156 ± 7 and 165 ± 11 mmHg, systolic BP ± SEM, n = 5–6). TRPA1 KO mice showed increased hypertensive hypertrophy (heart weight:tibia length: 7.3 ± 1.6 mg mm−1 vs. 8.8 ± 1.7 mg mm−1) and presented with blunted interleukin 6 (IL-6) production compared with hypertensive WT mice (151 ± 24 vs. 89 ± 16 pg mL−1). TRPA1 expression in dorsal root ganglion (DRG) neurones was upregulated during hypertension (163% of baseline expression). Investigations utilizing the TRPA1 agonist cinnamaldehyde (CA) on mesenteric arterioles isolated from näive mice suggested a lack of TRPA1-dependent vasoreactivity in this vascular bed; a site with notable ability to alter total peripheral resistance. However, mesenteric arterioles isolated from TRPA1 KO hypertensive mice displayed significantly reduced ability to relax in response to nitric oxide (NO) (P < 0.05). Unexpectedly, naïve TRPA1 KO mice also displayed physical hyperactivity traits at baseline, which was exacerbated during hypertension. In conclusion, our study provides a novel cardiovascular characterization of TRPA1 KO mice in a model of hypertension. Results suggest that TRPA1 has a limited role in global cardiovascular control, but we demonstrate an unexpected capacity for TRPA1 to regulate physical activity.
PMCID: PMC4186440  PMID: 25505598
Blood pressure; cinnamaldehyde; hypertension; locomotion; TRPA1
6.  Design of a Multitasking Robotic Platform with Flexible Arms and Articulated Head for Minimally Invasive Surgery 
This paper describes a multitasking robotic platform for Minimally Invasive Surgery (MIS). The device is designed to be introduced through a standard trocar port. Once the device is inserted to the desired surgical site, it can be reconfigured by lifting an articulated section, and protruding two tendon driven flexible arms. Each of the arms holds an interchangeable surgical instrument. The articulated section features a 2 Degrees-of-Freedom (DoF) universal joint followed by a single DoF yaw joint. It incorporates an on-board camera and LED light source at the distal end, leaving a Ø3mm channel for an additional instrument. The main shaft of the robot is largely hollow, leaving ample space for the insertion of two tendon driven flexible arms integrated with surgical instruments. The ex-vivo and in-vivo experiments demonstrate the potential clinical value of the device for performing surgical tasks through single incision or natural orifice transluminal procedures.
PMCID: PMC3988875  PMID: 24748998
7.  A Hand-held Instrument for in vivo Probe-based Confocal Laser Endomicroscopy during Minimally Invasive Surgery 
Probe-based confocal laser endomicroscopy (pCLE) provides high resolution imaging of tissue in vivo. Maintaining a steady contact between target tissue and pCLE probe tip is important for image consistency. In this paper, a new prototype hand-held instrument for in vivo pCLE during Minimally Invasive Surgery (MIS) is presented. The proposed instrument incorporates adaptive force sensing and actuation, allowing improved image consistency and force control, thus minimizing tissue deformation and induced micro-structural variations. The performance and accuracy of the contact force control are evaluated in detailed laboratory settings and in vivo validation of the device during transanal microsurgery in a live porcine model further demonstrates the potential clinical value of the device.
PMCID: PMC3988877  PMID: 24748997
hand-held imaging probe; force adaptive control; confocal endomicroscopy; pCLE; tissue characterization; TEM; TEO
8.  Dimensionality Reduction in Controlling Articulated Snake Robot for Endoscopy Under Dynamic Active Constraints 
This paper presents a real-time control framework for a snake robot with hyper-kinematic redundancy under dynamic active constraints for minimally invasive surgery. A proximity query (PQ) formulation is proposed to compute the deviation of the robot motion from predefined anatomical constraints. The proposed method is generic and can be applied to any snake robot represented as a set of control vertices. The proposed PQ formulation is implemented on a graphic processing unit, allowing for fast updates over 1 kHz. We also demonstrate that the robot joint space can be characterized into lower dimensional space for smooth articulation. A novel motion parameterization scheme in polar coordinates is proposed to describe the transition of motion, thus allowing for direct manual control of the robot using standard interface devices with limited degrees of freedom. Under the proposed framework, the correct alignment between the visual and motor axes is ensured, and haptic guidance is provided to prevent excessive force applied to the tissue by the robot body. A resistance force is further incorporated to enhance smooth pursuit movement matched to the dynamic response and actuation limit of the robot. To demonstrate the practical value of the proposed platform with enhanced ergonomic control, detailed quantitative performance evaluation was conducted on a group of subjects performing simulated intraluminal and intracavity endoscopic tasks.
PMCID: PMC3985322  PMID: 24741371
Dynamic active constraints (DACs); haptic interaction; hyper-redundant robot; proximity queries (PQs); snake robot
9.  Mechanism and consequence of the autoactivation p38α Mitogen-activated Protein Kinase promoted by TAB1 
Nature structural & molecular biology  2013;20(10):10.1038/nsmb.2668.
p38α Mitogen-activated Protein Kinase (p38α) is activated by a variety of mechanisms, including autophosphorylation initiated by TGFβ-activated kinase 1 binding protein 1 (TAB1) during myocardial ischemia and other stresses. Chemical genetic approaches and co-expression in mammalian, bacterial and cell-free systems revealed that mouse p38α autophosphorylation occurs in cis by direct interaction with TAB1(371-416). In isolated rat cardiac myocytes and perfused mouse hearts TAT-TAB1(371-416) rapidly activates p38 and profoundly perturbs function. Crystal structures and characterization in solution revealed a bipartite docking site for TAB1 in the p38α C-terminal kinase lobe. TAB1 binding stabilizes active p38α and induces rearrangements within the activation segment by helical extension of the Thr-Gly-Tyr motif that allows auto-phosphorylation in cis. Interference with p38α recognition by TAB1 abolishes its cardiac toxicity. Potentially, such intervention could circumvent the drawbacks seen when pharmacological inhibitors of p38 catalytic activity are used clinically.
PMCID: PMC3822283  PMID: 24037507
10.  Supported Palladium Nanoparticles Synthesized by Living Plants as a Catalyst for Suzuki-Miyaura Reactions 
PLoS ONE  2014;9(1):e87192.
The metal accumulating ability of plants has previously been used to capture metal contaminants from the environment; however, the full potential of this process is yet to be realized. Herein, the first use of living plants to recover palladium and produce catalytically active palladium nanoparticles is reported. This process eliminates the necessity for nanoparticle extraction from the plant and reduces the number of production steps compared to traditional catalyst palladium on carbon. These heterogeneous plant catalysts have demonstrated high catalytic activity in Suzuki coupling reactions between phenylboronic acid and a range of aryl halides containing iodo-, bromo- and chloro- moieties.
PMCID: PMC3906157  PMID: 24489869
11.  Cochlear Implant Rehabilitation in Older Adults: Literature Review and Proposal of a Conceptual Framework 
Hearing loss is a prevalent consequence of aging and also poses special challenges for older adults. Particularly when superimposed on other age-related conditions, presbycusis (age-related hearing loss) places the older adult at risk for social isolation and associated psychological and general health sequelae. The increasing cognitive demand of verbal communication, as well as the diminished sense of social and physical connectedness, can furthermore contribute to a feeling of vulnerability and poor health that worsens with advancing presbycusis. This cascade of downstream effects of hearing loss has implications for the self-assessment of health related quality of life (HRQL) and resulting estimates of associated costs. There is accumulating evidence of a potential role for cochlear implants (CI) in older adults with poor word understanding despite conventional hearing aid (HA) usage. In our review of the literature we identify strong evidence for the restoration of communication capacity in the deaf and hard of hearing geriatric population, little published work on communication performance in the real world and HRQL, and significant gaps of knowledge regarding how CI rehabilitation interacts with changing psychosocial and functional status. We therefore propose a broader conceptual framework than is currently available for the role of CI rehabilitation in the management of severe-to-profound hearing loss in older adults. We posit that the use of such a model in future investigations is needed to guide multidisciplinary investigations into the unique challenges of hearing loss in older adults as well as open new opportunities for innovation.
PMCID: PMC3902638  PMID: 22974240
presbycusis; hearing loss; aging; older adults; cochlear implant; communication; conceptual framework; cascade
12.  Improving the Modeling of Disease Data from the Government Surveillance System: A Case Study on Malaria in the Brazilian Amazon 
PLoS Computational Biology  2013;9(11):e1003312.
The study of the effect of large-scale drivers (e.g., climate) of human diseases typically relies on aggregate disease data collected by the government surveillance network. The usual approach to analyze these data, however, often ignores a) changes in the total number of individuals examined, b) the bias towards symptomatic individuals in routine government surveillance, and; c) the influence that observations can have on disease dynamics. Here, we highlight the consequences of ignoring the problems listed above and develop a novel modeling framework to circumvent them, which is illustrated using simulations and real malaria data. Our simulations reveal that trends in the number of disease cases do not necessarily imply similar trends in infection prevalence or incidence, due to the strong influence of concurrent changes in sampling effort. We also show that ignoring decreases in the pool of infected individuals due to the treatment of part of these individuals can hamper reliable inference on infection incidence. We propose a model that avoids these problems, being a compromise between phenomenological statistical models and mechanistic disease dynamics models; in particular, a cross-validation exercise reveals that it has better out-of-sample predictive performance than both of these alternative models. Our case study in the Brazilian Amazon reveals that infection prevalence was high in 2004–2008 (prevalence of 4% with 95% CI of 3–5%), with outbreaks (prevalence up to 18%) occurring during the dry season of the year. After this period, infection prevalence decreased substantially (0.9% with 95% CI of 0.8–1.1%), which is due to a large reduction in infection incidence (i.e., incidence in 2008–2010 was approximately one fifth of the incidence in 2004–2008).We believe that our approach to modeling government surveillance disease data will be useful to advance current understanding of large-scale drivers of several diseases.
Author Summary
Disease data collected by the government surveillance system are frequently used to understand the influence of large-scale phenomena (e.g., climate) on human health because these data often have a large temporal and/or geographical span. The down side is that a) these data are often biased towards individuals that come to the health facilities (i.e., symptomatic individuals); and b) the number of individuals examined can vary substantially regardless of concurrent changes in prevalence or incidence (e.g., due to shortage of personnel or supplies in health facilities), directly impacting the number of disease cases detected. Current modeling approaches typically ignore these peculiarities of the government data. Furthermore, current approaches do not take into account that observations directly influence disease dynamics since individuals with a positive diagnosis are often subsequently treated for the disease. In this article, we develop a novel model to circumvent these shortcomings and apply it to simulated data, highlighting how inference on infection incidence and prevalence might be misleading when some of the issues mentioned above are ignored. Finally, we illustrate this model using malaria data from the Brazilian Amazon, revealing the strong role of precipitation on infection prevalence seasonality and striking patterns in infection incidence.
PMCID: PMC3820532  PMID: 24244127
13.  Inference for Size Demography from Point Pattern Data using Integral Projection Models 
Population dynamics with regard to evolution of traits has typically been studied using matrix projection models (MPMs). Recently, to work with continuous traits, integral projection models (IPMs) have been proposed. Imitating the path with MPMs, IPMs are handled first with a fitting stage, then with a projection stage. Fitting these models has so far been done only with individual-level transition data. These data are used to estimate the demographic functions (survival, growth, fecundity) that comprise the kernel of the IPM specification. Then, the estimated kernel is iterated from an initial trait distribution to project steady state population behavior under this kernel. When trait distributions are observed over time, such an approach does not align projected distributions with these observed temporal benchmarks.
The contribution here, focusing on size distributions, is to address this issue. Our concern is that the above approach introduces an inherent mismatch in scales. The redistribution kernel in the IPM proposes a mechanistic description of population level redistribution. A kernel of the same functional form, fitted to data at the individual level, would provide a mechanistic model for individual-level processes. Resulting parameter estimates and the associated estimated kernel are at the wrong scale and do not allow population-level interpretation.
Our approach views the observed size distribution at a given time as a point pattern over a bounded interval. We build a three-stage hierarchical model to infer about the dynamic intensities used to explain the observed point patterns. This model is driven by a latent deterministic IPM and we introduce uncertainty by having the operating IPM vary around this deterministic specification. Further uncertainty arises in the realization of the point pattern given the operating IPM. Fitted within a Bayesian framework, such modeling enables full inference about all features of the model. Such dynamic modeling, optimized by fitting data observed over time, is better suited to projection.
Exact Bayesian model fitting is very computationally challenging; we offer approximate strategies to facilitate computation. We illustrate with simulated data examples as well as well as a set of annual tree growth data from Duke Forest in North Carolina. A further example shows the benefit of our approach, in terms of projection, compared with the foregoing individual level fitting.
PMCID: PMC3819200  PMID: 24223480
density dependence; Fourier transform; hierarchical model; integro-difference equation; Laplace approximation; nonhomogeneous Poisson process; spectral domain
14.  Thymosin β4-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing 
Nature communications  2013;4:2081.
The downstream consequences of inflammation in the adult mammalian heart are formation of a non-functional scar, pathological remodelling and heart failure. In zebrafish, hydrogen peroxide (H2O2) released from a wound is the initial instructive chemotactic cue for the infiltration of inflammatory cells, however, the identity of a subsequent resolution signal(s), to attenuate chronic inflammation, remains unknown. Here we reveal that Thymosin β4-Sulfoxide inhibits interferon-γ, and increases monocyte dispersal and cell death, lies downstream of H2O2 in the wounded fish and triggers depletion of inflammatory macrophages at the injury site. This function is conserved in the mouse and observed after cardiac injury, where it promotes wound healing and reduced scarring. In human T cell/CD14+ monocyte co-cultures, Tβ4-SO inhibits IFN-γ and increases monocyte dispersal and cell death, likely by stimulating superoxide production. Thus, Tβ4-SO is a putative target for therapeutic modulation of the immune response, resolution of fibrosis and cardiac repair.
PMCID: PMC3797509  PMID: 23820300
15.  Timing of Cochlear Implantation and Parents’ Global Ratings of Children’s Health and Development 
To assess children’s health-related quality of life (HRQL) and development after cochlear implant (CI) surgery, and compare improvements between different age of implantation categories.
Prospective, longitudinal study comparing outcomes of deaf children post-CI with hearing controls.
Six US CI centers.
Deaf children who received CI (n=188) and hearing children of comparable ages (n=97).
CI before 5 years of age.
Parental ratings of global HRQL and development, as assessed over the first 4 years of follow-up using visual analog scales. Development scores assess parental views of children’s growth and development, motor skills, ability to express themselves and communicate with others, and learning abilities. Associations of baseline child and family characteristics with post-CI HRQL and development were investigated using multivariable analysis, controlling for factors that influence post-CI language learning.
Baseline deficits of CI candidates relative to hearing controls were larger in development than HRQL. Development scores improved significantly by four years after CI, particularly in the youngest CI recipients. Developmental deficits of older CI recipients with early, extended hearing aid use were only partially remediated by CI. Overall, no significant health deficits were observed in CI children after four years. Cognition and speech recognition were positively associated with both HRQL and development.
Parental perspectives on quality of their child’s life and development provide practical insight into the optimal timing of interventions for early onset deafness. Validity of parental global assessments is supported by clinical measures of speech perception and language learning and comparison with a well-validated health status instrument.
PMCID: PMC3677526  PMID: 22588232
16.  Using Hierarchical Bayes to Understand Movement, Health, and Survival in the Endangered North Atlantic Right Whale 
PLoS ONE  2013;8(6):e64166.
Body condition is an indicator of health, and it plays a key role in many vital processes for mammalian species. While evidence of individual body condition can be obtained, these observations provide just brief glimpses into the health state of the animal. An analytical framework is needed for understanding how health of animals changes over space and time.Through knowledge of individual health we can better understand the status of populations. This is particularly important in endangered species, where the consequences of disruption of critical biological functions can push groups of animals rapidly toward extinction. Here we built a state-space model that provides estimates of movement, health, and survival. We assimilated 30+ years of photographic evidence of body condition and three additional visual health parameters in individual North Atlantic right whales, together with survey data, to infer the true health status as it changes over space and time. We also included the effect of reproductive status and entanglement status on health. At the population level, we estimated differential movement patterns in males and females. At the individual level, we estimated the likely animal locations each month. We estimated the relationship between observed and latent health status. Observations of body condition, skin condition, cyamid infestation on the blowholes, and rake marks all provided measures of the true underlying health. The resulting time series of individual health highlight both normal variations in health status and how anthropogenic stressors can affect the health and, ultimately, the survival of individuals. This modeling approach provides information for monitoring of health in right whales, as well as a framework for integrating observational data at the level of individuals up through the health status of the population. This framework can be broadly applied to a variety of systems – terrestrial and marine – where sporadic observations of individuals exist.
PMCID: PMC3675107  PMID: 23762237
17.  Cardiac Physiologic and Genetic Predictors of Hyperoxia-Induced Acute Lung Injury in Mice 
Exposure of mice to hyperoxia produces pulmonary toxicity similar to acute lung injury/acute respiratory distress syndrome, but little is known about the interactions within the cardiopulmonary system. This study was designed to characterize the cardiopulmonary response to hyperoxia, and to identify candidate susceptibility genes in mice. Electrocardiogram and ventilatory data were recorded continuously from 4 inbred and 29 recombinant inbred strains during 96 hours of hyperoxia (100% oxygen). Genome-wide linkage analysis was performed in 27 recombinant inbred strains against response time indices (TIs) calculated from each cardiac phenotype. Reductions in minute ventilation, heart rate (HR), low-frequency (LF) HR variability (HRV), high-frequency HRV, and total power HRV were found in all mice during hyperoxia exposure, but the lag time before these changes began was strain dependent. Significant (chromosome 9) or suggestive (chromosomes 3 and 5) quantitative trait loci were identified for the HRTI and LFTI. Functional polymorphisms in several candidate susceptibility genes were identified within the quantitative trait loci and were associated with hyperoxia susceptibility. This is the first study to report highly significant interstrain variation in hyperoxia-induced changes in minute ventilation, HR, and HRV, and to identify polymorphisms in candidate susceptibility genes that associate with cardiac responses. Results indicate that changes in HR and LF HRV could be important predictors of subsequent adverse outcome during hyperoxia exposure, specifically the pathogenesis of acute lung injury. Understanding the genetic mechanisms of these responses may have significant diagnostic clinical value.
PMCID: PMC3359944  PMID: 22052878
heart rate; hyperoxia; genome-wide mapping
18.  Patent foramen ovale and scuba diving: a practical guide for physicians on when to refer for screening 
Divers are taught some basic physiology during their training. There is therefore some underlying knowledge and understandable concern in the diving community about the presence of a patent foramen ovale (PFO) as a cause of decompression illness (DCI). There is an agreement that PFO screening should not be done routinely on all divers; however, when to screen selected divers is not clear. We present the basic physiology and current existing guidelines for doctors, advice on the management and identify which groups of divers should be referred for consideration of PFO screening. Venous bubbles after diving and right to left shunts are common, but DCI is rare. Why this is the case is not clear, but the divers look to doctors for guidance on PFO screening and closure; both of which are not without risks. Ideally, we should advise and apply guidelines that are consistent and based on best available evidence. We hope this guideline and flow chart helps address these issues with regard to PFOs and diving.
PMCID: PMC3710076  PMID: 23849539
Patent foramen ovale; Decompression illness; Arterial gas embolism; Screening
19.  Conservation Efforts May Increase Malaria Burden in the Brazilian Amazon 
PLoS ONE  2013;8(3):e57519.
Large-scale forest conservation projects are underway in the Brazilian Amazon but little is known regarding their public health impact. Current literature emphasizes how land clearing increases malaria incidence, leading to the conclusion that forest conservation decreases malaria burden. Yet, there is also evidence that proximity to forest fringes increases malaria incidence, which implies the opposite relationship between forest conservation and malaria. We compare the effect of these environmental factors on malaria and explore its implications.
Methods and Findings
Using a large malaria dataset (∼1,300,000 positive malaria tests collected over ∼4.5 million km2), satellite imagery, permutation tests, and hierarchical Bayesian regressions, we show that greater forest cover (as a proxy for proximity to forest fringes) tends to be associated with higher malaria incidence, and that forest cover effect was 25 times greater than the land clearing effect, the often cited culprit of malaria in the region. These findings have important implications for land use/land cover (LULC) policies in the region. We find that cities close to protected areas (PA’s) tend to have higher malaria incidence than cities far from PA’s. Using future LULC scenarios, we show that avoiding 10% of deforestation through better governance might result in an average 2-fold increase in malaria incidence by 2050 in urban health posts.
Our results suggest that cost analysis of reduced carbon emissions from conservation efforts in the region should account for increased malaria morbidity, and that conservation initiatives should consider adopting malaria mitigation strategies. Coordinated actions from disparate science fields, government ministries, and global initiatives (e.g., Reduced Emissions from Deforestation and Degradation; Millenium Development Goals; Roll Back Malaria; and Global Fund to Fight AIDS, Tuberculosis and Malaria), will be required to decrease malaria toll in the region while preserving these important ecosystems.
PMCID: PMC3590219  PMID: 23483912
20.  The relative efficacy of imatinib, dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia: a systematic review and network meta-analysis 
Dasatinib 100 mg daily and nilotinib 600/800 mg daily have been compared to imatinib as first line treatments for CML in two recent randomised studies. However, no head to head evidence exists of the relative efficacy of dasatinib and nilotinib.
We conducted a systematic literature review and used the data extracted to perform an indirect comparison meta-analysis of the three interventions.
Data from eight clinical studies (3,520 individuals) were included, all of which were of good quality (low risk of bias). At six months, the odds of complete cytogenetic response (CCyR) for dasatinib and nilotinib were approximately three times those for imatinib (range 2.77 to 3.06, all values not significant). At twelve months datatinib and nilotinib were significantly better than imatinib for both CCyR and major molecular response (MMR) (CCyR odds range 2.06 to 2.41, MMR odds range 2.09 to 2.87). At eighteen months dasatinib and nilotinib were again significantly better in terms of CCyR than imatinib (response odds 1.55 to 2.01). When dasatinib and nilotinib were compared to each other, for both clinical endpoints at all time points the response odds were not significantly different.
On the basis of a systematic review of the current literature base, dasatinib 100 mg, nilotinib 600 mg and nilotinib 800 mg should be viewed as equivalent in terms of complete cytogenetic and major molecular response.
PMCID: PMC3585848  PMID: 23422286
Dasatinib; CML; Chronic myeloid leukaemia; Network meta-analysis; Systematic review; Relative efficacy
21.  Individual-scale inference to anticipate climate-change vulnerability of biodiversity 
Anticipating how biodiversity will respond to climate change is challenged by the fact that climate variables affect individuals in competition with others, but interest lies at the scale of species and landscapes. By omitting the individual scale, models cannot accommodate the processes that determine future biodiversity. We demonstrate how individual-scale inference can be applied to the problem of anticipating vulnerability of species to climate. The approach places climate vulnerability in the context of competition for light and soil moisture. Sensitivities to climate and competition interactions aggregated from the individual tree scale provide estimates of which species are vulnerable to which variables in different habitats. Vulnerability is explored in terms of specific demographic responses (growth, fecundity and survival) and in terms of the synthetic response (the combination of demographic rates), termed climate tracking. These indices quantify risks for individuals in the context of their competitive environments. However, by aggregating in specific ways (over individuals, years, and other input variables), we provide ways to summarize and rank species in terms of their risks from climate change.
PMCID: PMC3223806  PMID: 22144386
biodiversity; climate change; forest dynamics; hierarchical models; model selection; risk analysis
22.  An overview of the contribution of fatness and fitness factors, and the role of exercise, in the formation of health status for individuals who are overweight 
Over the last half century there has been an epidemic of diminished health status induced by what seems as a concurrent rise in a population of individuals that are overfat. During the past few decades, the use of exercise has become a staple in the prevention and treatment options for the retarding the development of health issues pertaining to individuals who are overweight, overfatness or experience obesity. However, there are few studies and reviews look at the global issues surrounding the metabolic and hormone consequences of overfatness and the interaction of exercise with adiposity in humans developing the health status for the individual. This review offers an insight into our current understanding of health issues pertaining to metabolic and hormonal disruption related to overfatness and the treatment effect that exercise, especially resistance exercise, can have on impacting the health status, and overall well-being, for individuals who are overfat, regardless of body compositional changes leading toward a lessening of diseased state, and eventually a return to a normal health status for the individual.
PMCID: PMC3602007  PMID: 23497464
Fatness; Fitness; Exercise; Health status
23.  Multispectral image alignment using a three channel endoscope in vivo during minimally invasive surgery 
Biomedical Optics Express  2012;3(10):2567-2578.
Sequential multispectral imaging is an acquisition technique that involves collecting images of a target at different wavelengths, to compile a spectrum for each pixel. In surgical applications it suffers from low illumination levels and motion artefacts. A three-channel rigid endoscope system has been developed that allows simultaneous recording of stereoscopic and multispectral images. Salient features on the tissue surface may be tracked during the acquisition in the stereo cameras and, using multiple camera triangulation techniques, this information used to align the multispectral images automatically even though the tissue or camera is moving. This paper describes a detailed validation of the set-up in a controlled experiment before presenting the first in vivo use of the device in a porcine minimally invasive surgical procedure. Multispectral images of the large bowel were acquired and used to extract the relative concentration of haemoglobin in the tissue despite motion due to breathing during the acquisition. Using the stereoscopic information it was also possible to overlay the multispectral information on the reconstructed 3D surface. This experiment demonstrates the ability of this system for measuring blood perfusion changes in the tissue during surgery and its potential use as a platform for other sequential imaging modalities.
PMCID: PMC3469985  PMID: 23082296
(170.2150) Endoscopic imaging; (170.3010) Image reconstruction techniques; (170.6510) Spectroscopy, tissue diagnostics
24.  A tissue biopsy-based epigenetic multiplex PCR assay for prostate cancer detection 
BMC Urology  2012;12:16.
PSA-directed prostate cancer screening leads to a high rate of false positive identifications and an unnecessary biopsy burden. Epigenetic biomarkers have proven useful, exhibiting frequent and abundant inactivation of tumor suppressor genes through such mechanisms. An epigenetic, multiplex PCR test for prostate cancer diagnosis could provide physicians with better tools to help their patients. Biomarkers like GSTP1, APC and RASSF1 have demonstrated involvement with prostate cancer, with the latter two genes playing prominent roles in the field effect. The epigenetic states of these genes can be used to assess the likelihood of cancer presence or absence.
An initial test cohort of 30 prostate cancer-positive samples and 12 cancer-negative samples was used as basis for the development and optimization of an epigenetic multiplex assay based on the GSTP1, APC and RASSF1 genes, using methylation specific PCR (MSP). The effect of prostate needle core biopsy sample volume and age of formalin-fixed paraffin-embedded (FFPE) samples was evaluated on an independent follow-up cohort of 51 cancer-positive patients. Multiplexing affects copy number calculations in a consistent way per assay. Methylation ratios are therefore altered compared to the respective singleplex assays, but the correlation with patient outcome remains equivalent. In addition, tissue-biopsy samples as small as 20 μm can be used to detect methylation in a reliable manner. The age of FFPE-samples does have a negative impact on DNA quality and quantity.
The developed multiplex assay appears functionally similar to individual singleplex assays, with the benefit of lower tissue requirements, lower cost and decreased signal variation. This assay can be applied to small biopsy specimens, down to 20 microns, widening clinical applicability. Increasing the sample volume can compensate the loss of DNA quality and quantity in older samples.
PMCID: PMC3431995  PMID: 22672250
GSTP1; APC; RASSF1; Methylation; Epigenetics; Prostate cancer; Diagnosis; Multiplex; Singleplex; MSP
25.  Between-Site Differences in the Scale of Dispersal and Gene Flow in Red Oak 
PLoS ONE  2012;7(5):e36492.
Nut-bearing trees, including oaks (Quercus spp.), are considered to be highly dispersal limited, leading to concerns about their ability to colonize new sites or migrate in response to climate change. However, estimating seed dispersal is challenging in species that are secondarily dispersed by animals, and differences in disperser abundance or behavior could lead to large spatio-temporal variation in dispersal ability. Parentage and dispersal analyses combining genetic and ecological data provide accurate estimates of current dispersal, while spatial genetic structure (SGS) can shed light on past patterns of dispersal and establishment.
Methodology and Principal Findings
In this study, we estimate seed and pollen dispersal and parentage for two mixed-species red oak populations using a hierarchical Bayesian approach. We compare these results to those of a genetic ML parentage model. We also test whether observed patterns of SGS in three size cohorts are consistent with known site history and current dispersal patterns. We find that, while pollen dispersal is extensive at both sites, the scale of seed dispersal differs substantially. Parentage results differ between models due to additional data included in Bayesian model and differing genotyping error assumptions, but both indicate between-site dispersal differences. Patterns of SGS in large adults, small adults, and seedlings are consistent with known site history (farmed vs. selectively harvested), and with long-term differences in seed dispersal. This difference is consistent with predator/disperser satiation due to higher acorn production at the low-dispersal site. While this site-to-site variation results in substantial differences in asymptotic spread rates, dispersal for both sites is substantially lower than required to track latitudinal temperature shifts.
Animal-dispersed trees can exhibit considerable spatial variation in seed dispersal, although patterns may be surprisingly constant over time. However, even under favorable conditions, migration in heavy-seeded species is likely to lag contemporary climate change.
PMCID: PMC3341347  PMID: 22563504

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