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1.  Feasibility of caregiver-directed home-based hand-arm bimanual intensive training: A brief report 
To determine feasibility of a home-based, intensive bimanual intervention with children with unilateral spastic cerebral palsy.
Eleven children (aged 29–54 months) received 90 hours of home hand-arm bimanual intensive therapy (H-HABIT) provided by their trained caregivers. Parenting stress levels and compliance were monitored using the Parenting Stress Index and daily logs. Quality of bimanual performance and changes in performance/satisfaction of functional goals were assessed using the Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM), respectively, at two pretreatment baseline sessions and two posttreatment sessions (immediate and six months).
Ten children completed the study with caregivers completing on average 85.6 hours of H-HABIT. Daily logs indicated high caregiver compliance. Stress levels remained stable across the intervention. Children demonstrated significant improvements in the AHA and COPM.
H-HABIT is a feasible intervention for improving hand function and merits further investigation in a randomized-control trial.
PMCID: PMC4511850  PMID: 25180530
Bimanual training; family focused; hand rehabilitation; hemiplegia; home-based therapy; unilateral cerebral palsy; upper-limb function
2.  Photosynthetic Response of Soybean to Microclimate in 26-Year-Old Tree-Based Intercropping Systems in Southern Ontario, Canada 
PLoS ONE  2015;10(6):e0129467.
In order to study the effect of light competition and microclimatic modifications on the net assimilation (NA), growth and yield of soybean (Glycine max L.) as an understory crop, three 26-year-old soybean-tree (Acer saccharinum Marsh., Populus deltoides X nigra, Juglans nigra L.) intercropping systems were examined. Tree competition reduced photosynthetically active radiation (PAR) incident on soybeans and reduced net assimilation, growth and yield of soybean. Soil moisture of 20 cm depth close (< 3 m) to the tree rows was also reduced. Correlation analysis showed that NA and soil water content were highly correlated with growth and yield of soybean. When compared with the monoculture soybean system, the relative humidity (RH) of the poplar-soybean, silver maple-soybean, and black walnut-soybean intercropped systems was increased by 7.1%, 8.0% and 5.9%, soil water content was reduced by 37.8%, 26.3% and 30.9%, ambient temperature was reduced by 1.3°C, 1.4°C and 1.0°C, PAR was reduced by 53.6%, 57.9% and 39.9%, and air CO2 concentration was reduced by 3.7μmol·mol-1, 4.2μmol·mol-1 and 2.8μmol·mol-1, respectively. Compared to the monoculture, the average NA of soybean in poplar, maple and walnut treatments was also reduced by 53.1%, 67.5% and 46.5%, respectively. Multivariate stepwise regression analysis showed that PAR, ambient temperature and CO2 concentration were the dominant factors influencing net photosynthetic rate.
PMCID: PMC4459881  PMID: 26053375
3.  Percutaneous Ultrasound Guided Implantation of VX2 for Creation of a Rabbit Hepatic Tumor Model 
PLoS ONE  2015;10(4):e0123888.
Creation of a VX2 tumor model has traditionally required a laparotomy and surgical implantation of tumor fragments. Open surgical procedures are invasive and require long procedure times and recovery that can result in post-operative morbidity and mortality. The purpose of this study is to report the results of a percutaneous ultrasound guided method for creation of a VX2 model in rabbit livers. A total of 27 New Zealand white rabbits underwent a percutaneous ultrasound guided approach, where a VX2 tumor fragment was implanted in the liver. Magnetic resonance imaging was used to assess for tumor growth and necropsy was performed to determine rates of tract seeding and metastatic disease. Ultrasound guided tumor implantation was successful in all 27 rabbits. One rabbit died 2 days following the implantation procedure. Two rabbits had no tumors seen on follow-up imaging. Therefore, tumor development was seen in 24/26 (92%) rabbits. During the follow-up period, tract seeding was seen in 8% of rabbits and 38% had extra-hepatic metastatic disease. Therefore, percutaneous ultrasound guided tumor implantation safely provides reliable tumor growth for establishing hepatic VX2 tumors in a rabbit model with decreased rates of tract seeding, compared to previously reported methods.
PMCID: PMC4390313  PMID: 25853660
4.  Endovascular strategy or open repair for ruptured abdominal aortic aneurysm: one-year outcomes from the IMPROVE randomized trial 
Braithwaite, Bruce | Cheshire, Nicholas J. | Greenhalgh, Roger M. | Grieve, Richard | Hassan, Tajek B. | Hinchliffe, Robert | Howell, Simon | Moore, Fionna | Nicholson, Anthony A. | Soong, Chee V. | Thompson, Matt M. | Thompson, Simon G. | Ulug, Pinar | Heatley, Francine | Anjum, Aisha | Kalinowska, Gosia | Sweeting, Michael J. | Thompson, Simon G. | Gomes, Manuel | Grieve, Richard | Powell, Janet T. | Ashleigh, Ray | Gomes, Manuel | Greenhalgh, Roger M. | Grieve, Richard | Hinchliffe, Robert | Sweeting, Michael | Thompson, Matt M. | Thompson, Simon G. | Ulug, Pinar | Roberts, Ian | Bell, Peter R. F. | Cheetham, Anne | Stephany, Jenny | Warlow, Charles | Lamont, Peter | Moss, Jonathan | Tijssen, Jan | Braithwaite, Bruce | Nicholson, Anthony A. | Thompson, Matthew | Ashleigh, Ray | Thompson, Luke | Cheshire, Nicholas J. | Boyle, Jonathan R. | Serracino-Inglott, Ferdinand | Thompson, Matt M. | Hinchliffe, Robert J. | Bell, Rachel | Wilson, Noel | Bown, Matt | Dennis, Martin | Davis, Meryl | Ashleigh, Ray | Howell, Simon | Wyatt, Michael G. | Valenti, Domenico | Bachoo, Paul | Walker, Paul | MacSweeney, Shane | Davies, Jonathan N. | Rittoo, Dynesh | Parvin, Simon D. | Yusuf, Waquar | Nice, Colin | Chetter, Ian | Howard, Adam | Chong, Patrick | Bhat, Raj | McLain, David | Gordon, Andrew | Lane, Ian | Hobbs, Simon | Pillay, Woolagasen | Rowlands, Timothy | El-Tahir, Amin | Asquith, John | Cavanagh, Steve | Dubois, Luc | Forbes, Thomas L. | Ashworth, Emily | Baker, Sara | Barakat, Hashem | Brady, Claire | Brown, Joanne | Bufton, Christine | Chance, Tina | Chrisopoulou, Angela | Cockell, Marie | Croucher, Andrea | Dabee, Leela | Dewhirst, Nikki | Evans, Jo | Gibson, Andy | Gorst, Siobhan | Gough, Moira | Graves, Lynne | Griffin, Michelle | Hatfield, Josie | Hogg, Florence | Howard, Susannah | Hughes, Cían | Metcalfe, David | Lapworth, Michelle | Massey, Ian | Novick, Teresa | Owen, Gareth | Parr, Noala | Pintar, David | Spencer, Sarah | Thomson, Claire | Thunder, Orla | Wallace, Tom | Ward, Sue | Wealleans, Vera | Wilson, Lesley | Woods, Janet | Zheng, Ting
European Heart Journal  2015;36(31):2061-2069.
To report the longer term outcomes following either a strategy of endovascular repair first or open repair of ruptured abdominal aortic aneurysm, which are necessary for both patient and clinical decision-making.
Methods and results
This pragmatic multicentre (29 UK and 1 Canada) trial randomized 613 patients with a clinical diagnosis of ruptured aneurysm; 316 to an endovascular first strategy (if aortic morphology is suitable, open repair if not) and 297 to open repair. The principal 1-year outcome was mortality; secondary outcomes were re-interventions, hospital discharge, health-related quality-of-life (QoL) (EQ-5D), costs, Quality-Adjusted-Life-Years (QALYs), and cost-effectiveness [incremental net benefit (INB)]. At 1 year, all-cause mortality was 41.1% for the endovascular strategy group and 45.1% for the open repair group, odds ratio 0.85 [95% confidence interval (CI) 0.62, 1.17], P = 0.325, with similar re-intervention rates in each group. The endovascular strategy group and open repair groups had average total hospital stays of 17 and 26 days, respectively, P < 0.001. Patients surviving rupture had higher average EQ-5D utility scores in the endovascular strategy vs. open repair groups, mean differences 0.087 (95% CI 0.017, 0.158), 0.068 (95% CI −0.004, 0.140) at 3 and 12 months, respectively. There were indications that QALYs were higher and costs lower for the endovascular first strategy, combining to give an INB of £3877 (95% CI £253, £7408) or €4356 (95% CI €284, €8323).
An endovascular first strategy for management of ruptured aneurysms does not offer a survival benefit over 1 year but offers patients faster discharge with better QoL and is cost-effective.
Clinical trial registration
ISRCTN 48334791.
PMCID: PMC4553715  PMID: 25855369
Aneurysm; Aorta; Rupture; Surgery; Stent grafts; Cost-effectiveness
5.  Localized Hyperthermia with Iron Oxide-Doped Yttrium Microparticles: Steps Towards Image-Guided Thermoradiotherapy in Liver Cancer 
To test whether iron oxide–containing yttrium aluminosilicate microparticles (IO-YAS MPs) can generate localized therapeutic hyperthermia (≥43°C) when injected intra-tumorally in an animal model of liver cancer and whether MP distributions could be visualized with MR imaging.
Twenty-one Sprague-Dawley rats implanted with N1-S1 liver tumors were assigned to alternating magnetic field (AMF) exposure following intra-tumoral injection with IO-YAS MPs (n=7), sham surgery (n=7), or baseline iron quantitation (n=7). Three fiber optic probes allowed spatial and temporal monitoring of temperatures during 24 minutes of AMF. T2-weighted turbo spin echo magnetic resonance imaging was performed within 1 hour post-procedure to detect signal voids due to IO-YAS deposition. Hematoxylin and eosin–stained pathologic slides were also obtained and the presence of IO-YAS was evaluated with inductively coupled plasma optical emission spectroscopy.
Following AMF exposure, intra-tumoral temperatures after IO-YAS MP injection achieved therapeutic hyperthermia while those after sham surgery did not (46.6±1.3 vs. 36.8±0.4°C, P<0.0001). Within the treated group, the normal hepatic parenchyma (NHP) and rectal temperatures were 37.4±0.9 and 36.5±1.0°C (P=0.0809) at the conclusion of AMF exposure, respectively. A T2-weighted signal void at the tumor site was observed in 7/7 treated animals and intra-tumoral IO-YAS visualized on subsequent histopathology in each case. The mean ratio of tumor:NHP Fe concentrations attributable to IO-YAS MPs was 108:1.
AMF exposure of intra-tumoral IO-YAS MPs generates localized therapeutic hyperthermia in an animal model of liver cancer. MR detectability and potential for combination brachytherapy warrants further investigation for thermoradiotherapy in liver cancer.
PMCID: PMC3943613  PMID: 24315666
6.  Mycotic thoracic aortic arch aneurysm from haematogenous spread of Clostridium septicum due to metastatic colorectal cancer: a survival guide 
Journal of Surgical Case Reports  2014;2014(11):rju117.
We report the case of a 78-year-old female who was found to have a mycotic thoracic aortic arch aneurysm caused by Clostridium septicum. Subsequent investigations demonstrated adenocarcinoma of the caecum with two liver metastases. The patient underwent a hybrid procedure involving endovascular repair of the aneurysm with a right-to-left carotid crossover bypass and a left carotid to left subclavian bypass to protect the cerebral and left subclavian blood flow. The caecal tumour was later completely excised by laparoscopic right hemicolectomy. The patient then underwent resection for the liver metastases. There was no evidence of tumour recurrence 2 years after her right hemicolectomy. This case emphasizes the importance of the association of C. septicum infection with colorectal malignancy. To our knowledge, this is the first case of a mycotic aortic arch aneurysm caused by C. septicum being successfully treated with a hybrid endovascular repair procedure.
PMCID: PMC4216455  PMID: 25362731
7.  Evaluation of the Quality of Artemisinin-Based Antimalarial Medicines Distributed in Ghana and Togo 
Malaria Research and Treatment  2014;2014:806416.
This study, conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines, reports on the quality of 132 artemisinin-based antimalarial medicines distributed in Ghana and Togo. Three methods were employed in the quality evaluation—basic (colorimetric) tests for establishing the identity of the requisite active pharmaceutical ingredients (APIs), semi-quantitative TLC assay for the identification and estimation of API content, and HPLC assay for a more accurate quantification of API content. From the basic tests, only one sample totally lacked API. The HPLC assay, however, showed that 83.7% of the ACTs and 57.9% of the artemisinin-based monotherapies failed to comply with international pharmacopoeia requirements due to insufficient API content. In most of the ACTs, the artemisinin component was usually the insufficient API. Generally, there was a good correlation between the HPLC and SQ-TLC assays. The overall failure rates for both locally manufactured (77.3%) and imported medicines (77.5%) were comparable. Similarly the unregistered medicines recorded a slightly higher overall failure rate (84.7%) than registered medicines (70.8%). Only two instances of possible cross-border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries.
PMCID: PMC4225840  PMID: 25400975
8.  Learned Manipulation at Unconstrained Contacts Does Not Transfer across Hands 
PLoS ONE  2014;9(9):e108222.
Recent studies about sensorimotor control of the human hand have focused on how dexterous manipulation is learned and generalized. Here we address this question by testing the extent to which learned manipulation can be transferred when the contralateral hand is used and/or object orientation is reversed. We asked subjects to use a precision grip to lift a grip device with an asymmetrical mass distribution while minimizing object roll during lifting by generating a compensatory torque. Subjects were allowed to grasp anywhere on the object’s vertical surfaces, and were therefore able to modulate both digit positions and forces. After every block of eight trials performed in one manipulation context (i.e., using the right hand and at a given object orientation), subjects had to lift the same object in the second context for one trial (transfer trial). Context changes were made by asking subjects to switch the hand used to lift the object and/or rotate the object 180° about a vertical axis. Therefore, three transfer conditions, hand switch (HS), object rotation (OR), and both hand switch and object rotation (HS+OR), were tested and compared with hand matched control groups who did not experience context changes. We found that subjects in all transfer conditions adapted digit positions across multiple transfer trials similar to the learning of control groups, regardless of different changes of contexts. Moreover, subjects in both HS and HS+OR group also adapted digit forces similar to the control group, suggesting independent learning of the left hand. In contrast, the OR group showed significant negative transfer of the compensatory torque due to an inability to adapt digit forces. Our results indicate that internal representations of dexterous manipulation tasks may be primarily built through the hand used for learning and cannot be transferred across hands.
PMCID: PMC4169447  PMID: 25233091
9.  Differences in Fat and Muscle Mass Associated With a Functional Human Polymorphism in a Post-Transcriptional BMP2 Gene Regulatory Element 
Journal of cellular biochemistry  2009;107(6):1073-1082.
A classic morphogen, bone morphogenetic protein 2 (BMP2) regulates the differentiation of pluripotent mesenchymal cells. High BMP2 levels promote osteogenesis or chondrogenesis and low levels promote adipogenesis. BMP2 inhibits myogenesis. Thus, BMP2 synthesis is tightly controlled. Several hundred nucleotides within the 3′ untranslated regions of BMP2 genes are conserved from mammals to fishes indicating that the region is under stringent selective pressure. Our analyses indicate that this region controls BMP2 synthesis by post-transcriptional mechanisms. A common A to C single nucleotide polymorphism (SNP) in the BMP2 gene (rs15705, +A1123C) disrupts a putative post-transcriptional regulatory motif within the human ultra-conserved sequence. In vitro studies indicate that RNAs bearing the A or C alleles have different protein binding characteristics in extracts from mesenchymal cells. Reporter genes with the C allele of the ultra-conserved sequence were differentially expressed in mesenchymal cells. Finally, we analyzed MRI data from the upper arm of 517 healthy individuals aged 18–41 years. Individuals with the C/C genotype were associated with lower baseline subcutaneous fat volumes (P = 0.0030) and an increased gain in skeletal muscle volume (P = 0.0060) following resistance training in a cohort of young males. The rs15705 SNP explained 2–4% of inter-individual variability in the measured parameters. The rs15705 variant is one of the first genetic markers that maybe exploited to facilitate early diagnosis, treatment, and/or prevention of diseases associated with poor fitness. Furthermore, understanding the mechanisms by which regulatory polymorphisms influence BMP2 synthesis will reveal novel pharmaceutical targets for these disabling conditions.
PMCID: PMC4147943  PMID: 19492344
Bone Morphogenetic Protein 2 (BMP2); Messenger RNA (mRNA); Post-Transcriptional Gene Regulation; Mesenchymal Cells; Single Nucleotide Polymorphism (SNP); Fitness; Population Genetics
10.  Splenic abscess rupture postappendicectomy 
BMJ Case Reports  2012;2012:bcr0120125705.
The authors present a case of splenic abscess rupture postappendicectomy. Splenic abscess is rare with a reported incidence of 0.05%–0.7%. It is extremely unusual for a splenic abscess to result in splenic rupture. Contiguous spread, in this case from postappendix perforation, can cause splenic abscess formation. Postemergency splenectomy, the patient required admission to intensive therapy unit for 5 days but made a good postoperative recovery. This case is important to report as this is a rare postoperative complication of generalised peritonitis and this case highlights that astute diagnosis and management of the deteriorating surgical patient and rapid mobilisation of theatre are lifesaving.
PMCID: PMC3416992  PMID: 22802559
11.  Engineering of Nanoscale Contrast Agents for Optical Coherence Tomography 
Optical coherence tomography has emerged as valuable imaging modalityin ophthalmology and other fields by enabling high-resolution three-dimensional imaging of tissue. In this paper, we review recent progress in the field of contrast-enhanced optical coherence tomography (OCT). We discuss exogenous and endogenous sources of OCT contrast, focusing on their use with standard OCT systems as well as emerging OCT-based imaging modalities. We include advances in the processing of OCT data that generate improved tissue contrast, including spectroscopic OCT (SOCT), as well as work utilizing secondary light sources and/or detection mechanisms to create and detect enhanced contrast, including photothermal OCT (PTOCT) and photoacoustic OCT (PAOCT). Finally, we conclude with a discussion of the translational potential of these developments as well as barriers to their clinical use.
PMCID: PMC4083612  PMID: 25009761
12.  Stroke Experiences in Weblogs: A Feasibility Study of Sex Differences 
Research on cerebral stroke symptoms using hospital records has reported that women experience more nontraditional symptoms of stroke (eg, mental status change, pain) than men do. This is an important issue because nontraditional symptoms may delay the decision to get medical assistance and increase the difficulty of correct diagnosis. In the present study, we investigate sex differences in the stroke experience as described in stories on weblogs.
The goal of this study was to investigate the feasibility of using the Internet as a source of data for basic research on stroke experiences.
Stroke experiences described in blogs were identified by using StoryUpgrade, a program that searches blog posts using a fictional prototype story. In this study, the prototype story was a description of a stroke experience. Retrieved stories coded by the researchers as relevant were used to update the search query and retrieve more stories using relevance feedback. Stories were coded for first- or third-person narrator, traditional and nontraditional patient symptoms, type of stroke, patient sex and age, delay before seeking medical assistance, and delay at hospital and in treatment.
There were 191 relevant stroke stories of which 174 stories reported symptoms (52.3% female and 47.7% male patients). There were no sex differences for each traditional or nontraditional stroke symptom by chi-square analysis (all Ps>.05). Type of narrator, however, affected report of traditional and nontraditional symptoms. Female first-person narrators (ie, the patient) were more likely to report mental status change (56.3%, 27/48) than male first-person narrators (36.4%, 16/44), a marginally significant effect by logistic regression (P=.056), whereas reports of third-person narrators did not differ for women (27.9%, 12/43) and men (28.2%, 11/39) patients. There were more reports of at least 1 nontraditional symptom in the 92 first-person reports (44.6%, 41/92) than in the 82 third-person reports (25.6%, 21/82, P=.006). Ischemic or hemorrhagic stroke was reported in 67 and 29 stories, respectively. Nontraditional symptoms varied with stroke type with 1 or more nontraditional symptoms reported for 79.3% (23/29) of hemorrhagic stroke patients and 53.7% (36/67) of ischemic stroke patients (P=.001).
The results replicate previous findings based on hospital interview data supporting the reliability of findings from weblogs. New findings include the effect of first- versus third-person narrator on sex differences in the report of nontraditional symptoms. This result suggests that narrator is an important variable to be examined in future studies. A fragmentary data problem limits some conclusions because important information, such as age, was not consistently reported. Age trends strengthen the feasibility of using the Internet for stroke research because older adults have significantly increased their Internet use in recent years.
PMCID: PMC3978549  PMID: 24647327
cerebral stroke; signs and symptoms; sex differences; Internet; blogging
13.  Improvements in hand function after intensive bimanual training are not associated with corticospinal tract dysgenesis in children with unilateral cerebral palsy 
Experimental Brain Research  2014;232(6):2001-2009.
Unilateral cerebral palsy (CP) results from damage to the developing brain that occurs within the first 2 years of life. Previous studies found associations between asymmetry in the size of the corticospinal tract (CST) from the two hemispheres and severity of hand impairments in children with unilateral CP. The extent to which CST damage affects the capacity for hand function improvement is unknown. This study examines the association between an estimate of CST dysgenesis and (1) hand function and (2) the efficacy of intensive bimanual training in improving hand function. Children with unilateral CP, age 3.6–14.9 years, n = 35, received intensive bimanual training. Children engaged in bimanual functional/play activities (6 h/day, 15 days). Peduncle asymmetry, an estimate of CST dysgenesis, was measured on T1-weighted magnetic resonance imaging scans. Hand function was measured pre- and post-treatment using the assisting hand assessment (AHA) and Jebsen–Taylor test of hand function (JTTHF). AHA and JTTHF improved post-treatment (p < 0.001). Peduncle asymmetry was correlated with baseline AHA and JTTHF (p < 0.001) but not with AHA or JTTHF improvement post-training (R2 < 0.1, p > 0.2). An estimate of CST dysgenesis is correlated with baseline hand function but is a poor predictor of training efficacy, possibly indicating a flexibility of developing motor systems to mediate recovery.
PMCID: PMC4037561  PMID: 24623352
Bimanual training; Rehabilitation; Corticospinal; Motor development
14.  Molecular Imaging of Retinal Disease 
Imaging of the eye plays an important role in ocular therapeutic discovery and evaluation in preclinical models and patients. Advances in ophthalmic imaging instrumentation have enabled visualization of the retina at an unprecedented resolution. These developments have contributed toward early detection of the disease, monitoring of disease progression, and assessment of the therapeutic response. These powerful technologies are being further harnessed for clinical applications by configuring instrumentation to detect disease biomarkers in the retina. These biomarkers can be detected either by measuring the intrinsic imaging contrast in tissue, or by the engineering of targeted injectable contrast agents for imaging of the retina at the cellular and molecular level. Such approaches have promise in providing a window on dynamic disease processes in the retina such as inflammation and apoptosis, enabling translation of biomarkers identified in preclinical and clinical studies into useful diagnostic targets. We discuss recently reported and emerging imaging strategies for visualizing diverse cell types and molecular mediators of the retina in vivo during health and disease, and the potential for clinical translation of these approaches.
PMCID: PMC3601716  PMID: 23421501
15.  Precision Grip in Congenital and Acquired Hemiparesis: Similarities in Impairments and Implications for Neurorehabilitation 
Background: Patients with congenital and acquired hemiparesis incur long-term functional deficits, among which the loss of prehension that may impact their functional independence. Identifying, understanding, and comparing the underlying mechanisms of prehension impairments represent an opportunity to better adapt neurorehabilitation.
Objective: The present review aims to provide a better understanding of precision grip deficits in congenital and acquired hemiparesis and to determine whether the severity and type of fine motor control impairments depend on whether or not the lesions are congenital or acquired in adulthood.
Methods: Using combinations of the following key words: fingertip force, grip force, precision grip, cerebral palsy, stroke, PubMed, and Scopus databases were used to search studies from 1984 to 2013.
Results: Individuals with both congenital and acquired hemiparesis were able to some extent to use anticipatory motor control in precision grip tasks, even if this control was impaired in the paretic hand. In both congenital and acquired hemiparesis, the ability to plan efficient anticipatory motor control when the less-affected hand is used provides a possibility to remediate impairments in anticipatory motor control of the paretic hand.
Conclusion: Surprisingly, we observed very few differences between the results of studies in children with congenital hemiplegia and stroke patients. We suggest that the underlying specific strategies of neurorehabilitation developed for each one could benefit the other.
PMCID: PMC4074995  PMID: 25071502
fingertip force; grip force; precision grip; cerebral palsy; stroke
16.  Effects of Visual Cues of Object Density on Perception and Anticipatory Control of Dexterous Manipulation 
PLoS ONE  2013;8(10):e76855.
Anticipatory force planning during grasping is based on visual cues about the object’s physical properties and sensorimotor memories of previous actions with grasped objects. Vision can be used to estimate object mass based on the object size to identify and recall sensorimotor memories of previously manipulated objects. It is not known whether subjects can use density cues to identify the object’s center of mass (CM) and create compensatory moments in an anticipatory fashion during initial object lifts to prevent tilt. We asked subjects (n = 8) to estimate CM location of visually symmetric objects of uniform densities (plastic or brass, symmetric CM) and non-uniform densities (mixture of plastic and brass, asymmetric CM). We then asked whether subjects can use density cues to scale fingertip forces when lifting the visually symmetric objects of uniform and non-uniform densities. Subjects were able to accurately estimate an object’s center of mass based on visual density cues. When the mass distribution was uniform, subjects could scale their fingertip forces in an anticipatory fashion based on the estimation. However, despite their ability to explicitly estimate CM location when object density was non-uniform, subjects were unable to scale their fingertip forces to create a compensatory moment and prevent tilt on initial lifts. Hefting object parts in the hand before the experiment did not affect this ability. This suggests a dichotomy between the ability to accurately identify the object’s CM location for objects with non-uniform density cues and the ability to utilize this information to correctly scale their fingertip forces. These results are discussed in the context of possible neural mechanisms underlying sensorimotor integration linking visual cues and anticipatory control of grasping.
PMCID: PMC3797765  PMID: 24146935
17.  Using Cell-ID 1.4 with R for Microscope-Based Cytometry 
This unit describes a method for quantifying various cellular features (e.g., volume, total and subcellular fluorescence localization) from sets of microscope images of individual cells. It includes procedures for tracking cells over time. One purposefully defocused transmission image (sometimes referred to as bright-field or BF) is acquired to segment the image and locate each cell. Fluorescent images (one for each of the color channels to be analyzed) are then acquired by conventional wide-field epifluorescence or confocal microscopy. This method uses the image processing capabilities of Cell-ID (Gordon et al., 2007, as updated here) and data analysis by the statistical programming framework R (R-Development-Team, 2008), which we have supplemented with a package of routines for analyzing Cell-ID output. Both Cell-ID and the analysis package are open-source.
PMCID: PMC3485637  PMID: 23026908
image processing; fluorescence microscopy; Cell-ID; R
18.  RGD-Binding Integrins in Prostate Cancer: Expression Patterns and Therapeutic Prospects against Bone Metastasis 
Cancers  2012;4(4):1106-1146.
Prostate cancer is the third leading cause of male cancer deaths in the developed world. The current lack of highly specific detection methods and efficient therapeutic agents for advanced disease have been identified as problems requiring further research. The integrins play a vital role in the cross-talk between the cell and extracellular matrix, enhancing the growth, migration, invasion and metastasis of cancer cells. Progression and metastasis of prostate adenocarcinoma is strongly associated with changes in integrin expression, notably abnormal expression and activation of the β3 integrins in tumour cells, which promotes haematogenous spread and tumour growth in bone. As such, influencing integrin cell expression and function using targeted therapeutics represents a potential treatment for bone metastasis, the most common and debilitating complication of advanced prostate cancer. In this review, we highlight the multiple ways in which RGD-binding integrins contribute to prostate cancer progression and metastasis, and identify the rationale for development of multi-integrin antagonists targeting the RGD-binding subfamily as molecularly targeted agents for its treatment.
PMCID: PMC3712721  PMID: 24213501
integrin; RGD; prostate carcinoma; bone metastasis
19.  Coordination of Fingertip Forces During Precision Grip in Premanifest Huntington’s Disease 
Precision grip control is important for accurate object manipulation and requires coordination between horizontal (grip) and vertical (load) fingertip forces. Manifest Huntington’s disease (HD) subjects demonstrate excessive and highly variable grip force and delayed coordination between grip and load forces. Because the onset of these impairments is unknown, we examined precision grip control in premanifest HD (pre-HD) subjects. Fifteen pre-HD and 15 age- and sex-matched controls performed the precision grip task in a seated position. Subjects grasped and lifted an object instrumented with a force transducer that measured horizontal grip and vertical load forces. Outcomes were preload time, loading time, maximum grip force, mean static grip force, and variability for all measures. We compared outcomes across groups and correlated grip measures with the Unified Huntington’s Disease Rating Scale and predicted age of onset. Variability of maximum grip force (P < .0001) and variability of static grip force (P < .00001) were higher for pre-HD subjects. Preload time (P < .007) and variability of preload time (P < .006) were higher in pre-HD subjects. No differences were seen in loading time across groups. Variability of static grip force (r2 = 0.23) and variability of preload time (r2 = 0.59) increased with predicted onset and were correlated with tests of cognitive function. Our results indicate that pre-HD patients have poor regulation of the transition between reach and grasp and higher variability in force application and temporal coordination during the precision grip task. Force and temporal variability may be good markers of disease severity because they were correlated with predicted onset of disease.
PMCID: PMC3116202  PMID: 21394785
Huntington’s disease; premanifest; precision grip; motor control
20.  Recommendations for standardization and phenotype definitions in genetic studies of osteoarthritis: the TREAT-OA consortium 
To address the need for standardization of osteoarthritis (OA) phenotypes by examining the effect of heterogeneity among symptomatic (SOA) and radiographic osteoarthritis (ROA) phenotypes.
Descriptions of OA phenotypes of the 28 studies involved in the TREAT-OA consortium were collected. To investigate whether different OA definitions result in different association results, we created hip OA definitions used within the consortium in the Rotterdam Study-I and tested the association of hip OA with gender, age and BMI using one-way ANOVA. For radiographic OA, we standardized the hip, knee and hand ROA definitions and calculated prevalence's of ROA before and after standardization in 9 cohort studies. This procedure could only be performed in cohort studies and standardization of SOA definitions was not feasible at this moment.
In this consortium, all studies with symptomatic OA phenotypes (knee, hip and hand) used a different definition and/or assessment of OA status. For knee, hip and hand radiographic OA 5, 4 and 7 different definitions were used, respectively. Different hip OA definitions do lead to different association results. For example, we showed in the Rotterdam Study-I that hip OA defined as “at least definite JSN and one definite osteophyte” was not associated with gender (p=0.22), but defined as “at least one definite osteophyte” was significantly associated with gender (p=3×10−9). Therefore, a standardization process was undertaken for radiographic OA definitions. Before standardization a wide range of ROA prevalence's was observed in the 9 cohorts studied. After standardization the range in prevalence of knee and hip ROA was small. Standardization of SOA phenotypes was not possible due to the case-control design of the studies.
Phenotype definitions influence the prevalence of OA and association with clinical variables. ROA phenotypes within the TREAT-OA consortium were standardized to reduce heterogeneity and improve power in future genetics studies.
PMCID: PMC3236091  PMID: 21059398
21.  Tactile/proprioceptive integration during arm localization is intact in individuals with Parkinson’s disease 
Neuroscience letters  2009;470(1):38.
It has been theorized that sensorimotor processing deficits underlie Parkinson’s disease (PD) motor impairments including movement under proprioceptive control. However, it is possible that these sensorimotor processing deficits exclude tactile/proprioception sensorimotor integration: prior studies show improved movement accuracy in PD with endpoint tactile feedback, and good control in tactile-driven precision-grip tasks.
To determine whether tactile/proprioceptive integration in particular is affected by PD, nine subjects with PD (off-medication, UPDRS motor=19-42) performed an arm-matching task without visual feedback. In some trials one arm touched a static tactile cue that conflicted with dynamic proprioceptive feedback from biceps brachii muscle vibration. This sensory conflict paradigm has characterized tactile/proprioceptive integration in healthy subjects as specific to the context of tactile cue mobility assumptions and the intention to move the arm.
We found that the individuals with PD had poorer arm-matching acuracy than age-matched control subjects. However, PD-group accuracy improved with tactile feedback. Furthermore, sensory conflict conditions were resolved in the same context-dependent fashion by both subject groups. We conclude that the somatosensory integration mechanism for prioritizing tactile and proprioception feedback in this task are not disrupted by PD, and are not related to the observed proprioceptive deficits.
PMCID: PMC2814986  PMID: 20036715
Parkinson’s disease; proprioception; touch; sensory integration
22.  The Alpha Project, a model system for systems biology research 
IET systems biology  2008;2(5):222-233.
One goal of systems biology is to understand how genome-encoded parts interact to produce quantitative phenotypes. The Alpha Project is a medium-scale, interdisciplinary systems biology effort that aims to achieve this goal by understanding fundamental quantitative behaviors of a prototypic signal transduction pathway, the yeast pheromone response system from Saccharomyces cerevisiae. The Alpha Project distinguishes itself from many other systems biology projects by studying a tightly-bounded and well-characterized system that is easily modified by genetic means, and by focusing on deep understanding of a discrete number of important and accessible quantitative behaviors. During the project, we have developed tools to measure the appropriate data and develop models at appropriate levels of detail for studying a number of these quantitative behaviors. We also have developed transportable experimental tools and conceptual frameworks for understanding other signaling systems. In particular, we have begun to interpret system behaviors and their underlying molecular mechanisms through the lens of information transmission, a principal function of signaling systems. The Alpha Project demonstrates that interdisciplinary studies that identify key quantitative behaviors and measure important quantities, in the context of well-articulated abstractions of system function and appropriate analytical frameworks, can lead to deeper biological understanding. Our experience may provide a productive template for system biology investigations of other cellular systems.
PMCID: PMC2806158  PMID: 19045818
23.  Cell-ID Software for Microscope-Based Cytometry 
This unit describes a method to quantify, from sets of microscope images, various cellular parameters from individual cells, and includes procedures to track cells over time. For example, the user can measure cell volume, total and subcellular localization (nuclear, plasma membrane) of fluorescence for multiple fluorescence channels. This method uses the image processing capabilities of Cell-ID (Gordon et al., 2007) and data analysis by the statistical programming framework R, both open source software packages. The first step for successful cytometry entails acquiring at least one set of images for each field of cells. Each set is composed of one purposefully defocused transmission image (sometimes referred to as brightfield, or BF) that will be used to locate each cell, and one fluorescence image for each of the color channels to be analyzed. Images may be conventional wide-field epifluorescence or confocal microscopy images. Cell-ID processes the images and outputs a tab-delimited file with information extracted from each cell, for each time point and each fluorescence channel. Finally, the user analyzes the data using R (R-Development-Team, 2008), which we have supplemented with a package tailored to analyze Cell-ID output.
PMCID: PMC2784696  PMID: 18972382
image processing; fluorescence microscopy; Cell-ID; R
24.  Fus3 generates negative feedback that improves information transmission in yeast pheromone response 
Nature  2008;456(7223):755-761.
Haploid Saccharomyces cerevisiae yeast cells use a prototypic cell signaling system to transmit information about the extracellular concentration of mating pheromone secreted by potential mating partners. The ability for cells to respond distinguishably to different pheromone concentrations depends on how much information about pheromone concentration the system can transmit. Here we show that the MAPK Fus3 mediates fast-acting negative feedback that adjusts the dose-response of downstream system response to match that of receptor-ligand binding. This “dose-response alignment”, defined by a linear relationship between receptor occupancy and downstream response, can improve the fidelity of information transmission by making downstream responses corresponding to different receptor occupancies more distinguishable and reducing amplification of stochastic noise during signal transmission. We also show that one target of the feedback is a novel signal-promoting function of the RGS protein Sst2. Our work suggests that negative feedback is a general mechanism used in signaling systems to align dose-responses and thereby increase the fidelity of information transmission.
PMCID: PMC2716709  PMID: 19079053
25.  Fingertip force control during bimanual object lifting in hemiplegic cerebral palsy 
In the present study we examined unimanual and bimanual fingertip force control during grasping in children with hemiplegic cerebral palsy (CP). Participants lifted, transported and released an object with one hand or both hands together in order to examine the effect on fingertip force control for each hand separately and to determine whether any benefit exists for the affected hand when it performed the task concurrently with the less-affected hand. Seven children with hemiplegic CP performed the task while their movement and fingertip force control were measured. In the bimanual conditions, the weight of the instrumented objects was equal or unequal. The durations of the all temporal phases for the less-affected hand were prolonged during bimanual control compared to unimanual control. We observed close synchrony of both hands when the task was performed with both hands, despite large differences in duration between both hands when they performed separately. There was a marginal benefit for two of the five force related variables for the affected hand (grip force at onset of load force, and peak grip force) when it transported the object simultaneously with the less-affected hand. Collectively, these results corroborate earlier findings of reaching studies that showed slowing down of the less-affected hand when it moved together with the affected hand. A new finding that extends these studies is that bimanual tasks may have the potential to facilitate force control of the affected hand. The implications of these findings for recent rehabilitative therapies in children with CP that make use of bimanual training are discussed.
PMCID: PMC2668615  PMID: 18224309

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