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1.  Evaluation of clinical performance of a novel urine-based HPV detection assay among women attending a colposcopy clinic 
Background
Human papillomavirus (HPV) testing in urine offers a convenient approach for cervical cancer screening but has previously suffered from limited clinical sensitivity.
Objectives
We evaluated clinical performance of the prototype Trovagene HPV test, a novel polymerase chain reaction assay that targets the E1 region of the HPV genome and detects and amplifies short fragments of cell-free HPV DNA in urine.
Study design
We conducted a pilot study among seventy two women referred to colposcopy following abnormal screening. Participants provided a urine sample prior to clinician-collected cervical sampling and colposcopically-directed punch biopsy. Trovagene HPV test results on urine samples were compared with cervical and urine testing by Linear Array HPV Genotyping Test (LA-HPV) for detection of histologically-confirmed cervical precancerous lesions.
Results
There was high concordance between urine samples tested by the Trovagene HPV test and corresponding cervical (87.5%) and urine (81.9%) samples tested by LA-HPV. The Trovagene HPV test had high sensitivity (92.3% for detecting CIN2/3, and 100% for CIN3), comparable to LA-HPV testing on cervical samples (96.0% and 100%, respectively), and higher than LA-HPV testing on urine samples (80.8% and 90.0%, respectively). In this referral population, the specificity of the Trovagene urine HPV test was non-significantly lower (29% f CIN2/3 and 25% for CIN3) than corresponding estimates of LA-HPV testing on cervical (36% and 28%, respectively) and urine (42% and 38%, respectively) samples.
Conclusions
This pilot study suggests that the Trovagene HPV test has high sensitivity for urine-based detection of cervical precancer and merits evaluation in larger studies.
doi:10.1016/j.jcv.2014.04.016
PMCID: PMC4146457  PMID: 24881489
human papillomavirus; cervical cancer; urine; screening
2.  Serum Levels of Human MIC-1/GDF15 Vary in a Diurnal Pattern, Do Not Display a Profile Suggestive of a Satiety Factor and Are Related to BMI 
PLoS ONE  2015;10(7):e0133362.
The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC-1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels altered slightly in response to a meal, but comparison with variation its serum levels over a 24hour period suggested that these changes are likely to be due to bimodal diurnal variation which can alter serum MIC-1/GDF15 levels by about plus or minus 10% from the mesor. The lack of a rapid and substantial postprandial increase in MIC-1/GDF15 serum levels suggests that MIC1/GDF15 is unlikely to act as a satiety factor. Taken together, our findings suggest that MIC-1/GDF15 may be a physiological regulator of energy homeostasis in man, most probably due to actions on long-term regulation of energy homeostasis.
doi:10.1371/journal.pone.0133362
PMCID: PMC4514813  PMID: 26207898
3.  Acute Outcomes after Introduction of a Standardized Clinical Assessment and Management Plan (SCAMP) for Balloon Aortic Valvuloplastyin Congenital Aortic Stenosis 
Congenital heart disease  2013;9(4):316-325.
Introduction
Standardization of care can reduce practice variation, optimize resource utilization and improve clinical outcomes. We have created a standardized clinical assessment and management plan (SCAMP) for patients having balloon aortic valvuloplasty (BAV) for congenital aortic stenosis (AS). This study compares acute outcomes of BAV at our institution before and after introduction of this SCAMP.
Methods
In this retrospective matched cohort study each SCAMP patient was matched to 4 historical controls. Outcomes were categorized based on the combination of residual AS and AR as: 1)Optimal: gradient ≤ 35 mmHg and trivial or no AR, 2)Adequate: gradient ≤ 35 mmHg and mild AR, 3)Inadequate: gradient > 35 mmHg and/or moderate or severe AR.
Results
All 23 SCAMP patients achieved a residual AS gradient ≤ 35 mmHg; the median residual AS gradient for the SCAMP group was lower (25 (10 – 35) mmHg) than in matched controls (30 (0 – 65) mmHg; p=0.005). The two groups did not differ with regard to degree of AR grade after BAV. Compared to controls, SCAMP patients were more likely to have an optimal result, and less likely to have an inadequate result (52% versus34% and 17% versus 45%, respectively; p=0.02)
Conclusions
A SCAMP for BAV resulted in optimal acute results in half of the initial 23 patients enrolled, and outcomes in this group were better than those of matched historical controls. Whether these improved acute outcomes translate into better long term outcomes for this patient population remains to be seen.
doi:10.1111/chd.12142
PMCID: PMC4107194  PMID: 24127834
aortic stenosis; balloon aortic valvuloplasty; congenital heart disease
4.  Pharmacodynamic Evaluation of the Activities of Six Parenteral Vancomycin Products Available in the United States 
A recent report found that generic parenteral vancomycin products may not have in vivo efficacies equivalent to those of the innovator in a neutropenic murine thigh infection model despite having similar in vitro microbiological activities and murine serum pharmacokinetics. We compared the in vitro and in vivo activities of six of the parenteral vancomycin products available in the United States. The in vitro assessments for the potencies of the vancomycin products included MIC/minimal bactericidal concentration (MBC) determinations, quantifying the impact of human and murine serum on the MIC values, and time-kill studies. Also, the potencies of the vancomycin products were quantified with a biological assay, and the human and mouse serum protein binding rates for the vancomycin products were measured. The in vivo studies included dose-ranging experiments with the 6 vancomycin products for three isolates of Staphylococcus aureus in a neutropenic mouse thigh infection model. The pharmacokinetics of the vancomycin products were assessed in infected mice by population pharmacokinetic modeling. No differences were seen across the vancomycin products with regard to any in vitro evaluation. Inhibitory sigmoid maximal bacterial kill (Emax) modeling of the relationship between vancomycin dosage and the killing of the bacteria in mice in vivo yielded similar Emax and EC50 (drug exposure driving one-half Emax) values for bacterial killing. Further, there were no differences in the pharmacokinetic clearances of the 6 vancomycin products from infected mice. There were no important pharmacodynamic differences in the in vitro or in vivo activities among the six vancomycin products evaluated.
doi:10.1128/AAC.03710-14
PMCID: PMC4291350  PMID: 25385113
5.  The V-Y Advancement Flap Is Equivalent to the Mustardé Flap for Ectropion Prevention in the Reconstruction of Moderate-Size Lid-Cheek Junction Defects 
Plastic and reconstructive surgery  2013;131(1):28e-36e.
Background
Lid-cheek junction defects represent a reconstructive challenge because of the susceptibility of the lower eyelid to ectropion. To minimize the inferior tension placed on the lid margin, classic teaching advocates for the use of cervicofacial rotation-advancement flaps as popularized by Mustardé. Despite this approach, ectropion can still be problematic, and elevation of the cheek poses its own set of potential complications. An inferior-to-superior V-Y advancement flap has also been described, but its use is often limited because of the perceived increased risk of ectropion. This study attempts to define this risk by investigating the incidence of postoperative ectropion between cervicofacial and V-Y flaps for the reconstruction of lid-cheek junction defects.
Methods
All patients who underwent reconstruction of lid-cheek junction defects performed by the senior author (D.L.B.) between January of 2002 and March of 2009 were reviewed retrospectively. Only cervicofacial (n = 11) and V-Y flaps (n = 23) were included in the analysis. Patient demographics, defect size, operative time, hospital stay, and postoperative complications were extracted from the clinical record.
Results
Nine patients in the cervicofacial group (82 percent) and three patients in the V-Y group (13 percent) experienced a postoperative complication (p = 0.0002). Three cases of ectropion were observed, including two patients in the cervicofacial group (18 percent) and one in the V-Y group (4 percent, p = 0.24). All cases resolved with conservative management.
Conclusions
No difference in ectropion rate was found between the cervicofacial and V-Y groups. The versatility of the V-Y advancement flap is perhaps underestimated in this clinical context.
CLINICAL QUESTION/LEVEL OF EVIDENCE
Therapeutic, III.
doi:10.1097/PRS.0b013e3182729e22
PMCID: PMC4487805  PMID: 23271551
6.  Expression of the Kynurenine Pathway in Human Peripheral Blood Mononuclear Cells: Implications for Inflammatory and Neurodegenerative Disease 
PLoS ONE  2015;10(6):e0131389.
The kynurenine pathway is a fundamental mechanism of immunosuppression and peripheral tolerance. It is increasingly recognized as playing a major role in the pathogenesis of a wide variety of inflammatory, neurodegenerative and malignant disorders. However, the temporal dynamics of kynurenine pathway activation and metabolite production in human immune cells is currently unknown. Here we report the novel use of flow cytometry, combined with ultra high-performance liquid chromatography and gas chromatography-mass spectrometry, to sensitively quantify the intracellular expression of three key kynurenine pathway enzymes and the main kynurenine pathway metabolites in a time-course study. This is the first study to show that up-regulation of indoleamine 2,3-dioxygenase (IDO-1), kynurenine 3-monoxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) is lacking in lymphocytes treated with interferon gamma. In contrast, peripheral monocytes showed a significant elevation of kynurenine pathway enzymes and metabolites when treated with interferon gamma. Expression of IDO-1, KMO and QPRT correlated significantly with activation of the kynurenine pathway (kynurenine:tryptophan ratio), quinolinic acid concentration and production of the monocyte derived, pro-inflammatory immune response marker: neopterin. Our results also describe an original and sensitive methodological approach to quantify kynurenine pathway enzyme expression in cells. This has revealed further insights into the potential role of these enzymes in disease processes.
doi:10.1371/journal.pone.0131389
PMCID: PMC4482723  PMID: 26114426
7.  Silicon induces minimal thromboinflammatory response during 28-day intravascular implant testing 
Microelectromechanical systems (MEMS) are used to machine miniaturized implantable medical devices. Our group has used MEMS technology to develop hemofiltration membranes for use in renal replacement therapy which possess enhanced selectivity and permeability. The use of silicon in blood-contacting environments may be limited, however, due to contact activation of the coagulation cascade by silicon which form the surface oxides in atmospheric conditions. As well, reports of long-term biocompatibility of blood-contacting silicon devices are lacking. The aims of this pilot study were: 1) to develop a model for investigating the effects of intravascular implants and 2) to characterize the degree of thrombosis and tissue inflammation incited by prolonged implantation of silicon materials. Silicon implants with and without polyethylene glycol (PEG) coatings were surgically implanted transluminally through rat femoral veins. Gore-Tex and stainless steel implants served as controls. Implants were left in vivo for four weeks. All femoral veins remained patent. Veins associated with silicon implants exhibited rare thrombi and occasional mild perivascular inflammation. In contrast, Gore-Tex and stainless steel controls caused moderate vein thrombosis and provoked a moderate to marked cellular infiltrate. Under scanning electron microscopy, bare silicon implants were found to have significant adherent microthrombi, while PEG-treated implants showed no evidence of thrombi. PEG-treated silicon appears to be biocompatible and holds potential as an excellent material with which to construct an implantable, miniaturized hemofiltration membrane.
doi:10.1097/MAT.0b013e3181d98cf8
PMCID: PMC4476785  PMID: 20431483
biocompatibility; biofouling; nanotechnology; MEMS component materials; silicon; artificial kidney; hemofilter
8.  SANCDB: a South African natural compound database 
Background
Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
Description
The current research presents a South African natural compound database, named SANCDB. This is a curated and fully-referenced database containing compound information for 600 natural products extracted directly from journal articles, book chapters and theses. There is a web interface to the database, which is simple and easy to use, while allowing for compounds to be searched by a number of different criteria. Being fully referenced, each compound page contains links to the original referenced work from which the information was obtained. Further, the website provides a submission pipeline, allowing researchers to deposit compounds from their own research into the database.
Conclusions
SANCDB is currently the only web-based NP database in Africa. It aims to provide a useful resource for the in silico screening of South African NPs for drug discovery purposes. The database is supported by a submission pipeline to allow growth by entries from researchers. As such, we currently present SANCDB the starting point of a platform for a community-driven, curated database to further natural products research in South Africa. SANCDB is freely available at https://sancdb.rubi.ru.ac.za/.
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-015-0080-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13321-015-0080-8
PMCID: PMC4471313  PMID: 26097510
South Africa; Natural products; Chemical databases
9.  SANCDB: a South African natural compound database 
Background
Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
Description
The current research presents a South African natural compound database, named SANCDB. This is a curated and fully-referenced database containing compound information for 600 natural products extracted directly from journal articles, book chapters and theses. There is a web interface to the database, which is simple and easy to use, while allowing for compounds to be searched by a number of different criteria. Being fully referenced, each compound page contains links to the original referenced work from which the information was obtained. Further, the website provides a submission pipeline, allowing researchers to deposit compounds from their own research into the database.
Conclusions
SANCDB is currently the only web-based NP database in Africa. It aims to provide a useful resource for the in silico screening of South African NPs for drug discovery purposes. The database is supported by a submission pipeline to allow growth by entries from researchers. As such, we currently present SANCDB the starting point of a platform for a community-driven, curated database to further natural products research in South Africa. SANCDB is freely available at https://sancdb.rubi.ru.ac.za/.
Electronic supplementary material
The online version of this article (doi:10.1186/s13321-015-0080-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s13321-015-0080-8
PMCID: PMC4471313  PMID: 26097510
South Africa; Natural products; Chemical databases
10.  Lipid binding promotes oligomerization and focal adhesion activity of vinculin 
The Journal of Cell Biology  2014;207(5):643-656.
PIP2 binds vinculin and directs its oligomerization, which promotes proper focal adhesion structure and function.
Adherens junctions (AJs) and focal adhesion (FA) complexes are necessary for cell migration and morphogenesis, and for the development, growth, and survival of all metazoans. Vinculin is an essential regulator of both AJs and FAs, where it provides links to the actin cytoskeleton. Phosphatidylinositol 4,5-bisphosphate (PIP2) affects the functions of many targets, including vinculin. Here we report the crystal structure of vinculin in complex with PIP2, which revealed that PIP2 binding alters vinculin structure to direct higher-order oligomerization and suggests that PIP2 and F-actin binding to vinculin are mutually permissive. Forced expression of PIP2-binding–deficient mutants of vinculin in vinculin-null mouse embryonic fibroblasts revealed that PIP2 binding is necessary for maintaining optimal FAs, for organization of actin stress fibers, and for cell migration and spreading. Finally, photobleaching experiments indicated that PIP2 binding is required for the control of vinculin dynamics and turnover in FAs. Thus, through oligomerization, PIP2 directs a transient vinculin sequestration at FAs that is necessary for proper FA function.
doi:10.1083/jcb.201404128
PMCID: PMC4259812  PMID: 25488920
11.  Prenatal Diagnosis of Transposition of the Great Arteries over a 20-Year Period: Improved but Imperfect 
Objective
To evaluate temporal trends in prenatal diagnosis of transposition of the great arteries with intact ventricular septum (TGA/IVS) and its impact on neonatal morbidity and mortality.
Methods
Newborns with TGA/IVS referred for surgical management to our center over a 20-year period (1992 – 2011) were included. The study time was divided into 5 four-year periods, and the primary outcome was rate of prenatal diagnosis. Secondary outcomes included neonatal pre-operative status and perioperative survival.
Results
Of the 340 patients, 81 (24%) had a prenatal diagnosis. Prenatal diagnosis increased over the study period from 6% to 41% (p<0.001). Prenatally diagnosed patients underwent a balloon atrial septostomy (BAS) earlier than postnatally diagnosed patients (0 vs. 1 day, p<0.001) and fewer required mechanical ventilation (56% vs. 69%, p=0.03). There were no statistically significant differences in pre-operative acidosis (16% vs. 26%, p=0.1) and need for preoperative ECMO (2% vs. 3%, p=1.0). There was also no significant mortality difference (1 pre-operative and no post-operative deaths among prenatally diagnosed patients, as compared to 4 pre-operative and 6 post-operative deaths among postnatally diagnosed patients).
Conclusion
The prenatal detection rate of TGA/IVS has improved but still remains below 50%, suggesting the need for strategies to increase detection rates. The mortality rate was not statistically different between pre- and postnatally diagnosed patients; however, there were significant pre-operative differences with regard to earlier BAS and less mechanical ventilation. Ongoing study is required to elucidate whether prenatal diagnosis confers long-term benefit.
doi:10.1002/uog.14751
PMCID: PMC4452393  PMID: 25484180
Prenatal diagnosis; transposition of the great arteries; outflow tract view; survival; metabolic acidosis
12.  Seeking a Mechanism for the Toxicity of Oligomeric α-Synuclein 
Biomolecules  2015;5(2):282-305.
In a number of neurological diseases including Parkinson’s disease (PD), α‑synuclein is aberrantly folded, forming abnormal oligomers, and amyloid fibrils within nerve cells. Strong evidence exists for the toxicity of increased production and aggregation of α-synuclein in vivo. The toxicity of α-synuclein is popularly attributed to the formation of “toxic oligomers”: a heterogenous and poorly characterized group of conformers that may share common molecular features. This review presents the available evidence on the properties of α-synuclein oligomers and the potential molecular mechanisms of their cellular disruption. Toxic α-synuclein oligomers may impact cells in a number of ways, including the disruption of membranes, mitochondrial depolarization, cytoskeleton changes, impairment of protein clearance pathways, and enhanced oxidative stress. We also examine the relationship between α-synuclein toxic oligomers and amyloid fibrils, in the light of recent studies that paint a more complex picture of α-synuclein toxicity. Finally, methods of studying and manipulating oligomers within cells are described.
doi:10.3390/biom5020282
PMCID: PMC4496673  PMID: 25816357
α-synuclein; neurodegeneration; Parkinson’s disease; aggregation; toxic oligomers; amyloid fibrils
13.  Muscle cell derived angiopoietin-1 contributes to both myogenesis and angiogenesis in the ischemic environment 
Recent strategies to treat peripheral arterial disease (PAD) have focused on stem cell based therapies, which are believed to result in local secretion of vascular growth factors. Little is known, however, about the role of ischemic endogenous cells in this context. We hypothesized that ischemic muscle cells (MC) are capable of secreting growth factors that act as potent effectors of the local cellular regenerative environment. Both muscle and endothelial cells (ECs) were subjected to experimental ischemia, and conditioned medium (CM) from each was collected and analyzed to assess myogenic and/or angiogenic potential. In muscle progenitors, mRNA expression of VEGF and its cognate receptors (Nrp1, Flt, Flk) was present and decreased during myotube formation in vitro, and EC CM or VEGF increased myoblast proliferation. Angiopoietin-1 (Ang-1), Tie1, and Tie2 mRNA increased during MC differentiation in vitro. Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. Myotube formation was enhanced by MC CM and inhibited by EC CM. Ang-1 protein was present in CM from MCs isolated from both the genetically ischemia-susceptible BALB/c and ischemia-resistant C57BL/6 mouse strains, and chimeric Tie2 receptor trapping in situ ablated Ang-1's myogenic effects in vitro. Ang-1 or MC CM enhanced myotube formation in a mixed isolate of muscle progenitors as well as a myoblast co-culture with pluripotent mesenchymal cells (10T1/2) and this effect was abrogated by viral expression of the extracellular domain of Tie2 (AdsTie2). Furthermore, mesh/tube formation by HUVECs was enhanced by Ang-1 or MC CM and abrogated by Tie2 chimeric receptor trapping. Our results demonstrate the ability of muscle and endothelial cell-derived vascular growth factors, particularly Ang-1, to serve as multi-functional stimuli regulating crosstalk between blood vessels and muscle cells during regeneration from ischemic myopathy.
doi:10.3389/fphys.2015.00161
PMCID: PMC4436568  PMID: 26042050
paracrine; angiogenesis; regeneration; muscle; progenitor cell; ischemia; vascular disease
14.  Optical and SPION-Enhanced MR Imaging Shows that trans-Stilbene Inhibitors of NF-κB Concomitantly Lower Alzheimer’s Disease Plaque Formation and Microglial Activation in AβPP/PS-1 Transgenic Mouse Brain 
Alzheimer’s disease (AD) is associated with a microglia-dependent neuroinflammatory response against plaques containing the fibrous protein amyloid-β (Aβ). Activation of microglia, which closely associate with Aβ plaques, engenders the release of pro-inflammatory cytokines and the internalization of Aβ fibrils. Since the pro-inflammatory transcription factor NF-κB is one of the major regulators of Aβ-induced inflammation, we treated transgenic amyloid-β protein protein/presenilin-1 (AβPP/PS1) mice for one year with a low dose (0.01% by weight in the diet) of either of two trans-stilbene NF-κB inhibitors, resveratrol or a synthetic analog LD55. The 3D distribution of Aβ plaques was measured ex vivo in intact brains at 60 μm resolution by quantitative magnetic resonance imaging (MRI) using blood-brain barrier-permeable, anti-AβPP-conjugated superparamagentic iron oxide nanoparticles (SPIONs). The MRI measurements were confirmed by optical microscopy of thioflavin-stained brain tissue sections and indicated that supplementation with either of the two trans-stilbenes lowered Aβ plaque density in the cortex, caudoputamen, and hippocampus by 1.4 to 2-fold. The optical measurements also included the hippocampus and indicated that resveratrol and LD55 reduced average Aβ plaque density by 2.3-fold and 3.1-fold, respectively. Ex vivo measurements of the regional distribution of microglial activation by Iba-1 immunofluorescence of brain tissue sections showed that resveratrol and LD55 reduced average microglial activation by 4.2-fold and 3.5-fold, respectively. Since LD55 lacked hydroxyl groups but both resveratrol and LD55 concomitantly reduced both Aβ plaque burden and neuroinflammation to a similar extent, it appears that the antioxidant potential of resveratrol is not an important factor in plaque reduction.
doi:10.3233/JAD-131031
PMCID: PMC4407807  PMID: 24413613
LD55; magnetic resonance imaging; microglia; neuroinflammation; NF-κB; resveratrol; SPIONs; transgenic mice
15.  The effects of paired associative stimulation on knee extensor motor excitability of individuals post-stroke: A pilot study 
Objective
Paired associative stimulation (PAS) modulates bilateral distal lower limb motor pathways during walking. We assessed the effects of inhibitory PAS applied to the vastus medialis (VM) motor pathways of chronic stroke patients.
Methods
PAS consisted of 120 electrical stimuli applied to the femoral nerve paired with transcranial magnetic stimulation (TMS) of the lower limb primary motor cortex so that the estimated arrival of the afferent volley occurred 8 ms after delivery of the magnetic stimulus. Stimulus pairs were delivered to the non-paretic VM motor system of 11 chronic stroke patients and the right limb motor system of 11 non-impaired subjects at 0.19 Hz. The effects of PAS on VM motor pathway excitability and muscle activity were assessed during pedaling. TMS-induced motor evoked potential (MEP) amplitudes and the percent of VM activity in the flexion phase of active pedaling (%FLEXVM) was examined before and after PAS.
Results
Inhibitory PAS reduced VM MEP amplitudes in the target limb (p < 0.05) of both groups, while post-PAS paretic VM MEP amplitudes increased for some patients and decreased for others. Group mean paretic limb %FLEXVM was not altered by inhibitory PAS.
Conclusions
These results indicate PAS can be used to manipulate motor cortical excitability in proximal lower limb representations, however the sign of induced modulation was unpredictable and cyclic muscle activity was not modified.
Significance
The study has important implications for the development of therapies involving non-invasive brain stimulation to modify abnormal motor behavior following stroke.
doi:10.1016/j.clinph.2010.11.006
PMCID: PMC4403861  PMID: 21130032
Stroke; Transcranial magnetic stimulation; Cortical plasticity; Paired associative stimulation; Locomotion; Cycling
16.  Limitations of Risk Score Models in Patients with Acute Chest Pain 
Objectives
Cardiac multidetector computed tomography (CMCT) has potential to be used as a screening test for patients with acute chest pain, but several tools are already used to risk-stratify this population. Risk models exist that stratify need for intensive-care (Goldman), short-term prognosis (Thrombolysis in Myocardial Infarction, TIMI), and one-year events (Sanchis). We applied these cardiovascular risk models to candidates for CMCT and assessed sensitivity for prediction of in-hospital NSTEMI. We hypothesized that none of the models would achieve a sensitivity of 90% or greater, thereby justifying use of CMCT in patients with acute chest pain.
Methods
We analyzed TIMI, Goldman, and Sanchis in 148 consecutive patients with chest pain, non-diagnostic ECG, and negative initial cardiac biomarkers who previously met inclusion and exclusion criteria for the ROMICAT Study. NSTEMI was adjudicated and risk scores were categorized based on established criteria. Risk score agreement was assessed with weighted kappa statistics.
Results
Overall 17/148 (11%) patients had NSTEMI. For all risk models, sensitivity was poor (range 35–53%) and 95% confidence intervals did not cross above 77%. Agreement to risk-classify patients was poor to moderate (weighted kappa range 0.18–0.43). Patients categorized as “low risk” had non-zero rates of NSTEMI using all three scoring models (range 8–9%).
Conclusions
Available risk scores had poor sensitivity to detect NSTEMI in patients with acute chest pain. Because of the small number of patients in this data set, these findings require confirmation in larger studies.
doi:10.1016/j.ajem.2008.01.022
PMCID: PMC4394743  PMID: 19041532
Chest pain; computed tomography; myocardial infarction; risk
17.  The Relationship of Serum Macrophage Inhibitory Cytokine – 1 Levels with Gray Matter Volumes in Community-Dwelling Older Individuals 
PLoS ONE  2015;10(4):e0123399.
Using circulating inflammatory markers and magnetic resonance imaging (MRI), recent studies have associated inflammation with brain volumetric measures. Macrophage Inhibitory Cytokine–1 (MIC-1/GDF15) is a divergent transforming growth factor – beta (TGF-β) superfamily cytokine. To uncover the underlying mechanisms of the previous finding of a negative association between MIC-1/GDF15 serum levels and cognition, the present study aimed to examine the relationship of circulating MIC-1/GDF15 levels with human brain gray matter (GM) volumes, in a community-dwelling sample aged 70–90 years over two years (Wave 1: n = 506, Wave 2: n = 327), of which the age-related brain atrophy had been previously well defined. T1-weighted MRI scans were obtained at both waves and analyzed using the FMRIB Software Library and FreeSurfer. The results showed significantly negative associations between MIC-1/GDF15 serum levels and both subcortical and cortical GM volumes. GM volumes of the whole brain, cortex, temporal lobe, thalamus and accumbens showed significant mediating effects on the associations between MIC-1/GDF15 serum levels and global cognition scores. Increases in MIC-1/GDF15 serum levels were associated with decreases in cortical and subcortical GM volume over two years. In conclusion, MIC-1/GDF15 serum levels were inversely associated with GM volumes both cross-sectionally and longitudinally.
doi:10.1371/journal.pone.0123399
PMCID: PMC4395016  PMID: 25867953
18.  Stabilization of Resveratrol in Blood Circulation by Conjugation to mPEG and mPEG-PLA Polymers: Investigation of Conjugate Linker and Polymer Composition on Stability, Metabolism, Antioxidant Activity and Pharmacokinetic Profile 
PLoS ONE  2015;10(3):e0118824.
Resveratrol is naturally occurring phytochemical with diverse biological activities such as chemoprevention, anti-inflammatory, anti-cancer, anti-oxidant. But undergoes rapid metabolism in the body (half life 0.13h). Hence Polymer conjugation utilizing different chemical linkers and polymer compositions was investigated for enhanced pharmacokinetic profile of resveratrol. Ester conjugates such as α-methoxy-ω-carboxylic acid poly(ethylene glycol) succinylamide resveratrol (MeO-PEGN-Succ-RSV) (2 and 20 kDa); MeO-PEG succinyl ester resveratrol (MeO-PEGO-Succ-RSV) (2 kDa); α-methoxy poly(ethylene glycol)-co-polylactide succinyl ester resveratrol (MeO-PEG-PLAO-Succ-RSV) (2 and 6.6kDa) were prepared by carbodiimide coupling reactions. Resveratrol-PEG ethers (2 and 5 kDa) were synthesized by alkali-mediated etherification. All polymer conjugates were fully characterized in vitro and the pharmacokinetic profile of selected conjugates was characterized in rats. Buffer and plasma stability of conjugates was dependent on polymer hydrophobicity, aggregation behavior and PEG corona, with MeO-PEG-PLAO-Succ-RSV (2 kDa) showing a 3h half-life in rat plasma in vitro. Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro. MeO-PEG-PLAO-Succ-RSV (2 kDa), Resveratrol-PEG ether (2 and 5 kDa) displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resveratrol.
doi:10.1371/journal.pone.0118824
PMCID: PMC4370505  PMID: 25799413
19.  Prostate Cancer Targeting Motifs: Expression of ανβ3, Neurotensin Receptor 1, Prostate Specific Membrane Antigen, and Prostate Stem Cell Antigen in Human Prostate Cancer Cell Lines and Xenografts 
The Prostate  2011;72(5):523-532.
Background
Membrane receptors are frequent targets of cancer therapeutic and imaging agents. However, promising in vitro results often do not translate to in vivo clinical applications. To better understand this obstacle, we measured the expression differences in receptor signatures among several human prostate cancer cell lines and xenografts as a function of tumorigenicity.
Methods
Messenger RNA and protein expression levels for integrin ανβ3, neurotensin receptor 1 (NTSR1), prostate specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA) were measured in LNCaP, C4-2, and PC-3 human prostate cancer cell lines and in murine xenografts using quantitative reverse transcriptase polymerase chain reaction, flow cytometry, and immunohistochemistry.
Results
Stable expression patterns were observed for integrin αν and PSMA in all cells and corresponding xenografts. Integrin β3 mRNA expression was greatly reduced in C4-2 xenografts and greatly elevated in PC-3 xenografts compared with the corresponding cultured cells. NTSR1 mRNA expression was greatly elevated in LNCaP and PC-3 xenografts. PSCA mRNA expression was elevated in C4-2 xenografts when compared with C4-2 cells cultured in vitro. Furthermore, at the protein level, PSCA was re-expressed in all xenografts compared with cells in culture.
Conclusions
The regulation of mRNA and protein expression of the cell-surface target proteins ανβ3, NTSR1, PSMA, and PSCA, in prostate cancer cells with different tumorigenic potential, was influenced by factors of the microenvironment, differing between cell cultures and murine xenotransplants. Integrin ανβ3, NTRS1 and PSCA mRNA expression increased with tumorigenic potential, but mRNA expression levels for these proteins do not translate directly to equivalent expression levels of membrane bound protein.
doi:10.1002/pros.21454
PMCID: PMC4366051  PMID: 21748756
ανβ3; NTSR1; PSCA; PSMA; tumorigenic potential; cells versus xenografts; membrane proteins
20.  Characteristics of horizontal force generation for individuals post-stroke walking against progressive resistive forces 
Background
Walking, while experiencing horizontal resistive forces, can allow researchers to assess characteristics of force generation in a task specific manner for individuals post-stroke.
Methods
Ten neurologically nonimpaired individuals (mean age 52 years) and fourteen chronic stroke survivors (mean age 54 years) with hemiparesis walked in the treadmill-based KineAssist Walking and Balance System, while experiencing twelve progressive horizontal resistive forces at their comfortable walking speed. Slope coefficients of the observed force–velocity relationship were quantified and submitted to an iterative k-means cluster analysis to test for subgroups within the post-stroke sample. Extrapolated force values for individuals were quantified by extrapolating the line of best fit of the force–velocity relationship to the x-intercept.
Findings
Within the post-stroke group, six individuals were clustered into a high sensitivity group, i.e., large reduction in speed with resistance, and eight were clustered into a low sensitive group, i.e., small reduction in speed with resistance. The low sensitivity group was similar to non-impaired individual. The extrapolated force was significantly higher for non-impaired individuals compared to individuals post-stroke in either the high or low sensitivity group. The differences between low and high sensitivity group suggest that high sensitivity of walking speed to applied resistive force is indicative of overall weakness.
Interpretation
Individuals with high sensitivity to horizontal resistive force may be walking at or near their maximum force generating capacity when at comfortable walking speed, while low sensitivity individuals may have greater reserve force generating capacity when walking at a particular comfortable walking speed.
doi:10.1016/j.clinbiomech.2014.11.006
PMCID: PMC4362732  PMID: 25481856
Post-stroke hemiparesis; Force generation; Walking speed; Locomotion
21.  Results from a survey of national immunization programmes on home-based vaccination record practices in 2013 
International Health  2015;7(4):247-255.
Background
Data on home-based records (HBRs) practices within national immunization programmes are non-existent, making it difficult to determine whether current efforts of immunization programmes related to basic recording of immunization services are appropriately focused.
Methods
During January 2014, WHO and the United Nations Children's Fund sent a one-page questionnaire to 195 countries to obtain information on HBRs including type of record used, number of records printed, whether records were provided free-of-charge or required by schools, whether there was a stock-out and the duration of any stock-outs that occurred, as well as the total expenditure for printing HBRs during 2013.
Results
A total of 140 countries returned a completed HBR questionnaire. Two countries were excluded from analysis because they did not use a HBR during 2013. HBR types varied across countries (vaccination only cards, 32/138 [23.1%]; vaccination plus growth monitoring records, 31/138 [22.4%]; child health books, 48/138 [34.7%]; combination of these, 27/138 [19.5%] countries). HBRs were provided free-of-charge in 124/138 (89.8%) respondent countries. HBRs were required for school entry in 62/138 (44.9%) countries. Nearly a quarter of countries reported HBR stock-outs during 2013. Computed printing cost per record was
Conclusions
These results provide a basis for national immunization programmes to develop, implement and monitor corrective activities to improve the availability and utilization of HBRs. Much work remains to improve forecasting where appropriate, to prevent HBR stock-outs, to identify and improve sustainable financing options and to explore viable market shaping opportunities.
doi:10.1093/inthealth/ihv014
PMCID: PMC4492340  PMID: 25733540
Health records; Immunization; Immunization systems; Medical records; Vaccination; Vaccination card
PLoS ONE  2015;10(2):e0115189.
The divergent TGF-β superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-). On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+). Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1) had metastases than TRAMPMIC+/+ mice (p<0.0001). We conclude that germ line gene deletion of MIC-1/GDF15 leads to increased local tumor growth resulting in decreased survival consistent with an overall protective role for MIC-1/GDF15 in early primary tumor development. However, in advancing disease, as we have previously noted, MIC-1/GDF15 overexpression may promote local invasion and metastatic spread.
doi:10.1371/journal.pone.0115189
PMCID: PMC4335046  PMID: 25695521
Background
Individuals post-stroke select slow comfortable walking speeds (CWS) and the major factors used to select their CWS is unknown.
Objective
To determine the extent to which slow CWS post-stroke is achieved through matching a relative force output or targeting a particular walking speed.
Methods
Ten neurologically nonimpaired individuals and fourteen chronic stroke survivors with hemiplegia were recruited. Participants were instructed to “walk at the speed that feels most comfortable” on a treadmill against 12 progressively increasing horizontal resistive force levels applied at the pelvis using a robotic system that allowed participant to self-select their walking speed. We compared slope coefficients of the simple linear regressions between the observed normalized force vs. normalized speed relationship in each group to a slope of -1.0 (i.e. ideal slope for a constant relative force output) and 0.0 (i.e. ideal slope for a constant relative speed). We also compared slope coefficients between groups.
Results
The slope coefficients were significantly greater than -1.0 (p < 0.001 for both) and significantly less than 0 (p < 0.001 for both). However, compared with nonimpaired individuals, people post-stroke were less able to maintain their walking speed (p = 0.003).
Conclusions
The results of this study provide evidence for a complex interaction between the regulation of relative force output and intention to move at a particular speed in the selection of the CWS for individuals post-stroke. This would suggest that therapeutic interventions should not only focus on task specific lower-limb strengthening exercises (e.g. walking against resistance), but should also focus on increasing the range of speeds at which people can safely walk.
doi:10.1186/s12984-015-0007-7
PMCID: PMC4329221  PMID: 25884953
Locomotion; Post-stroke; Force generation; Comfortable walking speed
Eplasty  2015;15:ic10.
PMCID: PMC4329948  PMID: 25834691
Klippel-Feil; phrenic nerve; nerve transfer; cervical; spinal cord
Scientific Reports  2015;5:8168.
We studied links between human malnutrition and wild meat availability within the Rainforest Biotic Zone in central Africa. We distinguished two distinct hunted mammalian diversity distributions, one in the rainforest areas (Deep Rainforest Diversity, DRD) containing taxa of lower hunting sustainability, the other in the northern rainforest-savanna mosaic, with species of greater hunting potential (Marginal Rainforest Diversity, MRD). Wild meat availability, assessed by standing crop mammalian biomass, was greater in MRD than in DRD areas. Predicted bushmeat extraction was also higher in MRD areas. Despite this, stunting of children, a measure of human malnutrition, was greater in MRD areas. Structural equation modeling identified that, in MRD areas, mammal diversity fell away from urban areas, but proximity to these positively influenced higher stunting incidence. In DRD areas, remoteness and distance from dense human settlements and infrastructures explained lower stunting levels. Moreover, stunting was higher away from protected areas. Our results suggest that in MRD areas, forest wildlife rational use for better human nutrition is possible. By contrast, the relatively low human populations in DRD areas currently offer abundant opportunities for the continued protection of more vulnerable mammals and allow dietary needs of local populations to be met.
doi:10.1038/srep08168
PMCID: PMC4313087  PMID: 25639588

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