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1.  Antidiabetic Properties of Germinated Brown Rice: A Systematic Review 
Diet is an important variable in the course of type 2 diabetes, which has generated interest in dietary options like germinated brown rice (GBR) for effective management of the disease among rice-consuming populations. In vitro data and animal experiments show that GBR has potentials as a functional diet for managing this disease, and short-term clinical studies indicate encouraging results. Mechanisms for antidiabetic effects of GBR due to bioactive compounds like γ-aminobutyric acid (GABA), γ-oryzanol, dietary fibre, phenolics, vitamins, acylated steryl β-glucoside, and minerals include antihyperglycemia, low insulin index, antioxidative effect, antithrombosis, antihypertensive effect, hypocholesterolemia, and neuroprotective effects. The evidence so far suggests that there may be enormous benefits for diabetics in rice-consuming populations if white rice is replaced with GBR. However, long-term clinical studies are still needed to verify these findings on antidiabetic effects of GBR. Thus, we present a review on the antidiabetic properties of GBR from relevant preclinical and clinical studies, in order to provide detailed information on this subject for researchers to review the potential of GBR in combating this disease.
doi:10.1155/2012/816501
PMCID: PMC3529503  PMID: 23304216
3.  Statistical Methods Used to Test for Agreement of Medical Instruments Measuring Continuous Variables in Method Comparison Studies: A Systematic Review 
PLoS ONE  2012;7(5):e37908.
Background
Accurate values are a must in medicine. An important parameter in determining the quality of a medical instrument is agreement with a gold standard. Various statistical methods have been used to test for agreement. Some of these methods have been shown to be inappropriate. This can result in misleading conclusions about the validity of an instrument. The Bland-Altman method is the most popular method judging by the many citations of the article proposing this method. However, the number of citations does not necessarily mean that this method has been applied in agreement research. No previous study has been conducted to look into this. This is the first systematic review to identify statistical methods used to test for agreement of medical instruments. The proportion of various statistical methods found in this review will also reflect the proportion of medical instruments that have been validated using those particular methods in current clinical practice.
Methodology/Findings
Five electronic databases were searched between 2007 and 2009 to look for agreement studies. A total of 3,260 titles were initially identified. Only 412 titles were potentially related, and finally 210 fitted the inclusion criteria. The Bland-Altman method is the most popular method with 178 (85%) studies having used this method, followed by the correlation coefficient (27%) and means comparison (18%). Some of the inappropriate methods highlighted by Altman and Bland since the 1980s are still in use.
Conclusions
This study finds that the Bland-Altman method is the most popular method used in agreement research. There are still inappropriate applications of statistical methods in some studies. It is important for a clinician or medical researcher to be aware of this issue because misleading conclusions from inappropriate analyses will jeopardize the quality of the evidence, which in turn will influence quality of care given to patients in the future.
doi:10.1371/journal.pone.0037908
PMCID: PMC3360667  PMID: 22662248
4.  CBX4-mediated SUMO modification regulates BMI1 recruitment at sites of DNA damage 
Nucleic Acids Research  2012;40(12):5497-5510.
Polycomb group (PcG) proteins are involved in epigenetic silencing where they function as major determinants of cell identity, stem cell pluripotency and the epigenetic gene silencing involved in cancer development. Recently numerous PcG proteins, including CBX4, have been shown to accumulate at sites of DNA damage. However, it remains unclear whether or not CBX4 or its E3 sumo ligase activity is directly involved in the DNA damage response (DDR). Here we define a novel role for CBX4 as an early DDR protein that mediates SUMO conjugation at sites of DNA lesions. DNA damage stimulates sumoylation of BMI1 by CBX4 at lysine 88, which is required for the accumulation of BMI1 at DNA damage sites. Moreover, we establish that CBX4 recruitment to the sites of laser micro-irradiation-induced DNA damage requires PARP activity but does not require H2AX, RNF8, BMI1 nor PI-3-related kinases. The importance of CBX4 in the DDR was confirmed by the depletion of CBX4, which resulted in decreased cellular resistance to ionizing radiation. Our results reveal a direct role for CBX4 in the DDR pathway.
doi:10.1093/nar/gks222
PMCID: PMC3384338  PMID: 22402492
6.  Neuroprotective Effects of Germinated Brown Rice against Hydrogen Peroxide Induced Cell Death in Human SH-SY5Y Cells 
The neuroprotective and antioxidative effects of germinated brown rice (GBR), brown rice (BR) and commercially available γ-aminobutyric acid (GABA) against cell death induced by hydrogen peroxide (H2O2) in human neuroblastoma SH-SY5Y cells have been investigated. Results show that GBR suppressed H2O2-mediated cytotoxicity and induced G0/G1 phase cell cycle arrest in SH-SY5Y cells. Moreover, GBR reduced mitochondrial membrane potential (MMP) and prevented phosphatidylserine (PS) translocation in SH-SY5Y cells, key features of apoptosis, and subsequent cell death. GBR exhibited better neuroprotective and antioxidative activities as compared to BR and GABA. These results indicate that GBR possesses high antioxidative activities and suppressed cell death in SH-SY5Y cells by blocking the cell cycle re-entry and apoptotic mechanisms. Therefore, GBR could be developed as a value added functional food to prevent neurodegenerative diseases caused by oxidative stress and apoptosis.
doi:10.3390/ijms13089692
PMCID: PMC3431823  PMID: 22949825
germinated brown rice; γ-aminobutyric acid; hydrogen peroxide; neuroprotective; SH-SY5Y cell death
7.  Effect of structural modulation of polyphenolic compounds on the inhibition of Escherichia coli ATP synthase 
In this paper we present the inhibitory effect of a variety of structurally modulated/modified polyphenolic compounds on purified F1 or membrane bound F1Fo E. coli ATP synthase. Structural modulation of polyphenols with two phenolic rings inhibited ATP synthase essentially completely; one or three ringed polyphenols individually or fused together inhibited partially. We found that the position of hydroxyl and nitro groups play critical role in the degree of binding and inhibition of ATPase activity. The extended positioning of hydroxyl groups on imino diphenolic compounds diminished the inhibition and abridged position enhanced the inhibition potency. This was contrary to the effect by simple single ringed phenolic compounds where extended positioning of hydroxyl group was found to be effective for inhibition. Also, introduction of nitro group augmented the inhibition on molar scale in comparison to the inhibition by resveratrol but addition of phosphate group did not. Similarly, aromatic diol or triol with rigid or planar ring structure and no free rotation poorly inhibited the ATPase activity. The inhibition was identical in both F1Fo membrane preparations as well as in isolated purified F1 and was reversible in all cases. Growth assays suggested that modulated compounds used in this study inhibited F1-ATPase as well as ATP synthesis nearly equally.
doi:10.1016/j.ijbiomac.2012.01.019
PMCID: PMC4303583  PMID: 22285988
F1Fo ATP synthase; E. coli ATP synthase; ATPase; Polyphenolic compounds; Enzyme inhibition; ATP synthase inhibition
8.  Administration of general anaesthesia to a paediatric patient with osteopetrosis 
BMJ Case Reports  2012;2012:bcr2012006901.
Osteopetrosis is a rare clinical syndrome characterised by the failure of bone resorption and remodelling, which causes multiple anatomical and physiological impairments. Pathological fractures can occur, in addition to, haemathological and metabolic impairments. Our patient was a 9-year-old girl diagnosed with osteopetrosis in the neonatal period. She had severe anaemia, thrombocytopaenia, hypocalcaemia, as well as growth and development delays. In this case report, the administration of general anaesthesia to the patient for a biopsy of the scalp and skull and a partial maxillectomy is presented.
doi:10.1136/bcr-2012-006901
PMCID: PMC4312795  PMID: 23188843
9.  Angiopoietin-1 and Vascular Endothelial Growth Factor Regulation of Leukocyte Adhesion to Endothelial Cells: Role of Nuclear Receptor-77 
Objective
Vascular endothelial growth factor (VEGF) promotes leukocyte adhesion to endothelial cells (ECs). Angiopoietin-1 (Ang-1) inhibits this response. Nuclear receptor-77 (Nur77) is a proangiogenic nuclear receptor. In the present study, we assessed the influence of Ang-1 and VEGF on Nur77 expression in ECs, and evaluated its role in Ang-1/VEGF-mediated leukocyte adhesion.
Methods and Results
Expression of Nur77 was evaluated with real-time polymerase chain reaction and immunoblotting. Adhesion of leukocytes to ECs was monitored with inverted microscopy. Nur77 expression or activity was inhibited using adenoviruses expressing dominant-negative form of Nur77, retroviruses expressing Nur77 in the antisense direction, and small interfering RNA oligos. Both Ang-1 and VEGF induce Nur77 expression, by >5- and 30-fold, respectively. When combined, Ang-1 potentiates VEGF-induced Nur77 expression. Ang-1 induces Nur77 through the phosphoinositide 3-kinase and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces Nur77 expression through the protein kinase D/histone deacetylase 7/myocyte enhancer factor 2 and extracellular signal-regulated protein kinase 1/2 pathways. VEGF induces nuclear factor-kappaB transcription factor, vascular cell adhesion molecule-1, and E-selectin expressions, and promotes leukocyte adhesion to ECs. Ang-1 inhibits these responses. This inhibitory effect of Ang-1 disappears when Nur77 expression is disrupted, restoring the inductive effects of VEGF on adhesion molecule expression, and increased leukocyte adhesion to ECs.
Conclusion
Nur77 promotes anti-inflammatory effects of Ang-1, and functions as a negative feedback inhibitor of VEGF-induced EC activation.
doi:10.1161/ATVBAHA.112.251546
PMCID: PMC4183139  PMID: 22628435
angiopoietin-1; endothelial cells; inflammation; leukocyte adhesion; nuclear receptor-77; vascular endothelial growth factor
10.  A pubertal immune challenge alters the antidepressant-like effects of chronic estradiol treatment in inbred and outbred adult female mice 
Neuroscience  2012;249:43-52.
Puberty is a period characterized by brain reorganization that contributes to the development of neural and behavioral responses to gonadal steroids. A single injection of the bacterial endotoxin, lipopolysaccharide (LPS), during the pubertal period decreases sexual receptivity in response to ovarian hormones in adulthood. Because chronic estradiol treatment alleviates depression-like symptoms in ovariectomized adult mice, we investigated the effect of pubertal LPS treatment on estradiol’s antidepressant effects. We hypothesized that pubertal LPS treatment would decrease the antidepressant-like effect of estradiol in adult ovariectomized female mice, as it decreases other behavioral responses to ovarian hormones. As expected, chronic estradiol treatment decreased depression-like behavior, as measured by the duration of immobility, in saline-treated mice from two different strains, as well as in mice treated with LPS in adulthood. In contrast, in mice treated pubertally with LPS, estradiol strikingly increased the duration of immobility. No difference in body weight and in locomotion was found among the groups, suggesting that the differences in depression-like behavior were not due to differences in body weight or locomotor activity between LPS-treated and control mice. These results suggest that exposure to an immune challenge during the pubertal period alters the responsiveness of depression-like behavior to estradiol.
doi:10.1016/j.neuroscience.2012.09.047
PMCID: PMC3567249  PMID: 23036617
Lipopolysaccharide; Depression; Estradiol; Puberty; Females; Forced Swim test; Tail Suspension test; Stress; Immune Challenge
11.  Intestinal necrosis in young patient due to arterial tumour embolism 
BMJ Case Reports  2012;2012:bcr0120125558.
A patient in the thirties, currently undergoing chemotherapy for metastatic osteosarcoma diagnosed 3 years earlier, was admitted with in the emergency department with abdominal pain. Laparoscopic surgery revealed severe inflammation and an abscess. 18 cm of small intestine was removed because of intestinal necrosis. Histological examination showed several arterial tumour emboli, morphologically similar to the primary sarcoma. The patient died 1 year after successful surgery. Because of the improved survival of patients with osteosarcoma, acute mesenteric ischaemia should be considered in acute abdomen in these patients.
doi:10.1136/bcr.01.2012.5558
PMCID: PMC3448735  PMID: 22983997
12.  Isomeric differentiation of polycyclic aromatic hydrocarbons using silver nitrate reactive desorption electrospray ionization mass spectrometry 
RATIONALE
Polycyclic aromatic hydrocarbons (PAHs) are nonpolar and difficult to detect by desorption electrospray ionization. We present a new detection method based on cationization with silver ions, which has the added advantage of being able to differentiate PAHs with the same mass but different structure.
METHODS
9,10-Diphenylanthracene and triptycene, in addition to four different groups of PAH isomers: (1) anthracene and phenanthrene, (2) pyrene and fluoranthene, (3) benz[a]anthracene, benz[b]anthracene (tetracene), and chrysene (4) benzo[a]pyrene and benzo[k]fluoranthene, were deposited on a paper surface and bombarded with methanol droplets containing silver nitrate. The resulting microdroplets entered a quadruple mass spectrometer for mass analysis.
RESULTS
The mass spectrum shows [PAH]+, [Ag + OH + PAH]+, and [Ag(PAH)n]+ n (n = 1, 2) (and [PAH + O2]+ in the case of benz[b]anthracene) ions. PAHs having a bay structure, such as phenanthrene, showed a different tendency to interact with silver ions from those PAHs having a linear arrangement of the fused benzene rings, such as anthracene. The ratios of the [PAH]+ peak intensity to that of [Ag–PAH]+, [Ag + OH + PAH]+, [Ag(PAH)2]+, and [PAH + O2]+ were used to differentiate the PAH isomers sharing the same molecular formula with different structures. For isomeric mixtures the [PAH]+ to [Ag + OH + PAH]+ ratio was found to be the most useful parameter. The uncertainty in the mole fraction of an isomeric mixture was ±0.09, 0.13, ±0.25, and ±0.1 for phenanthrene-anthracene, fl benz[a] anthracene-chrysene, and benzo[a]pyrene-benzo[k]fluoranthene, respectively.
CONCLUSIONS
A simple method has been developed for the detection of PAHs in desorption electrospray ionization mass spectrometry based on Ag(I) cationization. The method showed a capability to differentiate PAHs isomers (having the same molecular mass) in isomeric mixture with an uncertainty in the mole fraction of about 0.1. At high inlet temperature and voltage, this method showed better sensitivity but less ability to differentiate between ± isomeric species.
doi:10.1002/rcm.6309
PMCID: PMC4145873  PMID: 22847697
13.  Angiopoietin-2 is a potential mediator of endothelial barrier dysfunction following cardiopulmonary bypass 
Cytokine  2012;60(2):352-359.
Introduction
Endothelial activation leading to vascular barrier dysfunction and organ failure is a well-recognized complication of cardiovascular surgery with cardiopulmonary bypass (CPB). The endothelial-specific angiopoietin–Tie2 ligand–receptor system has been identified as a non-redundant regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to the Tie2 receptor antagonizes Tie2 signaling and renders the endothelial barrier responsive to pro-inflammatory cytokines. We aimed to study the time course and potential triggering factors of Ang-2 release after CPB, as well as the association of Ang-2 changes with surrogates of increased vascular permeability, organ dysfunction, and outcome.
Methods
Serum levels of Ang-2 from 25 adult patients (140 screened) were measured before and at 0, 12, and 24 h following CPB procedure by in-house immuno-luminometric assay (ILMA), and compared with indices of organ dysfunction, duration of mechanical ventilation (MV), length of stay (LOS) in the intensive care unit (ICU), and hospital mortality. The effect of Ang-2 was studied in vitro by incubating high Ang-2 patient serum with endothelial cells (EC).
Results
Ang-2 levels steadily increased from 2.6 ± 2.4 ng/mL at 0 h up to 7.3 ± 4.6 ng/mL at 24 h following CPB (P < 0.001). The release of Ang-2 correlated with the duration of CPB, aortic cross-clamp time, and post-CPB lactate levels. Changes in Ang-2 during follow-up correlated with partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) ratio, alveolar–arterial oxygen tension difference (AaDO2), hemodynamics, fluid balance, and disease severity measures. Ang-2 levels at 12 h predicted the duration of MV, ICU-LOS, and hospital mortality. High Ang-2 patient sera disrupted EC architecture in vitro, an effect reversed by treatment with the competitive Tie2 ligand angiopoietin-1 (Ang-1).
Conclusions
Collectively, our results suggest that Ang-2 is a putative mediator of endothelial barrier dysfunction after CPB. These findings suggest that targeting the Ang/Tie2 pathway may mitigate organ dysfunction and improve outcome in patients undergoing CPB.
doi:10.1016/j.cyto.2012.04.002
PMCID: PMC4127984  PMID: 22770562
Cardiopulmonary bypass; Endothelium; Endothelial activation; Angiopoietin-2; Tie2
14.  Pubertal immune challenge blocks the ability of estradiol to enhance performance on cognitive tasks in adult female mice 
Psychoneuroendocrinology  2012;38(7):1170-1177.
Summary
Puberty is a period characterized by brain reorganization that contributes to the development of neural and behavioral responses to gonadal steroids. Previously, we have shown that a single injection of the bacterial endotoxin, lipopolysaccharide (LPS; 1.5mg/kg IP), during the pubertal period (around 6 weeks old) in mice decreases sexual receptivity in response to estradiol and progesterone in adulthood. These findings suggest that pubertal immune challenge has an enduring effect of decreasing the behavioral responsiveness to gonadal steroid hormones. Since estradiol improves cognitive function in certain tasks in mice, we investigated the effect of pubertal immune challenge on the ability of estradiol to enhance cognitive function. We hypothesized that estradiol would be less effective at enhancing performance on particular cognitive tasks in female mice treated with LPS during puberty. Six-week old (pubertal) and ten-week old (adult) female CD1 mice were injected with either saline or LPS. Five weeks later, they were ovariectomized and implanted subcutaneously with either an estradiol- or oil-filled Silastic© capsule followed one week later with testing for cognitive function. The duration of juvenile investigation during social discrimination and recognition tests was used as a measure of social memory, and the duration of object investigation during object recognition and placement tests was used as a measure of object memory. Chronic estradiol treatment enhanced social and object memory in saline-treated females and in females treated with LPS in adulthood. In contrast, in females treated with LPS at 6 weeks old, estradiol failed to improve social and object memories. These results support the hypothesis that exposure to an immune challenge during puberty reduces at least some of the cognitive effects of estradiol. Moreover, these results support the idea that pubertal immune challenge compromises a wide variety of behavioral influences of ovarian hormones.
doi:10.1016/j.psyneuen.2012.11.003
PMCID: PMC3604046  PMID: 23218519
Estradiol; hippocampus-dependent tasks; immune challenge; puberty
15.  Neurobehavioral performance among agricultural workers and pesticide applicators: a meta-analytic study 
Chronic low level exposure of agricultural workers and applicators to pesticides has been found to be associated with different degrees of decrement in cognitive and psychomotor functions. The goal of this study was to use meta-analysis to (1) identify and quantify neurobehavioral deficits among agricultural workers and pesticide applicators, and (2) analyse the potential confounders or moderators of these neurobehavioral deficits. Seventeen studies, reporting on 21 independent cohort groups, were included in the meta-analysis. These studies involved 16 neuropsychological tests providing 23 different performance measures that constitute the neurobehavioral constructs. All tests and measures of the neurobehavioral functions of attention, visuomotor integration, verbal abstraction and perception constructs showed significant decrements for exposed participants. One out of three tests of memory, two of five tests of sustained attention, and four of eight tests of motor speed constructs also showed significant decrements. Nine out of these 15 effect size distributions demonstrated significant heterogeneity across cohorts. A search for cohort-level variables (eg, agricultural workers vs applicators, duration of exposure, age and percentage of male participants) to explain this heterogeneity was largely unsuccessful. However, for one test, Block Design, the duration of exposure was positively associated with performance decrements. Furthermore, it was also found that performance decrements on this test were smaller for older participants. Increasing the number of studies and using more consistent methodologies in field studies are needed.
doi:10.1136/oemed-2011-100204
PMCID: PMC3969985  PMID: 22267395
16.  Force Sensing Micro-Forceps for Robot Assisted Retinal Surgery 
Membrane peeling is a standard vitreoretinal procedure, where the surgeon delaminates a very thin membrane from retina surface using surgical picks and forceps. This requires extremely delicate manipulation of the retinal tissue. Applying excessive forces during the surgery can cause serious complications leading to vision loss. For successful membrane peeling, most of the applied forces need to be very small, well below the human tactile sensation threshold. In this paper, we present a robotic system that combines a force sensing forceps tool and a cooperatively-controlled surgical robot. This combination allows us to measure the forces directly at the tool tip and use this information for limiting the applied forces on the retina. This may prevent many iatrogenic injuries and allow safer maneuvers during vitreoretinal procedures. We show that our system can successfully eliminate hand-tremor and excessive forces in membrane peeling experiments on the inner shell membrane of a chicken embryo.
doi:10.1109/EMBC.2012.6346201
PMCID: PMC3957212  PMID: 23366162
17.  A neonatal case of congenital coronary artery fistula 
BMJ Case Reports  2012;2012:bcr0920114773.
Coronary artery fistulae (CAF) are rare forms of congenital heart disease with an incidence of one in 50 000 live births. The authors present the case of an asymptomatic neonate with a precordial murmur. Pre and postductal saturations, blood pressure and ECG were normal. Echocardiography revealed a large right coronary artery fistula to the right ventricle (4.5 mm). At 11 months, transcatheter occlusion of the fistula with a vascular plug was performed. A year on, the child was thriving, ECG and echocardiogram remained normal. CAF complications and symptoms (including aneurysm, myocardial ischaemia, angina, heart failure and dyspnoea) are commoner in older patients, so traditionally we intervene early. With increasing case reports of spontaneous closure of even large and symptomatic fistulae, management of especially asymptomatic children is unclear. Long-term complications of intervention also remain largely unknown. As such more information is required on the conditions natural history to better manage patients and counsel parents.
doi:10.1136/bcr.09.2011.4773
PMCID: PMC3279660  PMID: 22665398
18.  Aptamer Conjugated Multifunctional Nanoflowers as a Platform for Targeting, Capture and Detection in Laser Desorption Ionization Mass Spectrometry 
ACS nano  2012;7(1):417-427.
Although many different nanomaterials have been tested as substrates for laser desorption and ionization mass spectrometry (LDI-MS), this emerging field still requires more efficient multifuncional nanomaterials for targeting, enrichment and detection. Here, we report the use of gold-manganese oxide (Au@MnO) hybrid nanoflowers as an efficient matrix for LDI–MS. The nanoflowers were also functionalized with two different aptamers to target cancer cells and capture adenosine triphosphate (ATP), respectively. These nanoflowers were successfully used for metabolite extraction from cancer cell lysates. Thus, in one system, our multifunctional nanoflowers can 1) act as an ionization substrate for mass spectrometry, 2) target cancer cells, and 3) detect and analyze metabolites from cancer cells.
doi:10.1021/nn304458m
PMCID: PMC3568519  PMID: 23211039
hybrid nanoparticles; nanoflower; aptamer; ATP; cancer cell; mass spectrometry
19.  Insulin-Producing Cells From Adult Human Bone Marrow Mesenchymal Stem Cells Control Streptozotocin-Induced Diabetes In Nude Mice 
Cell transplantation  2012;22(1):133-145.
Harvesting, expansion and directed differentiation of human bone marrow-derived mesenchymal stem cells (BM-MSCs) could provide an autologous source of surrogate β-cells that would alleviate the limitations of availability and/or allogenic rejection following pancreatic or islet transplantation. Bone marrow cells were obtained from three adult type 2 diabetic volunteers and 3 non-diabetic donors. After 3 days in culture, adherent MSCs were expanded for 2 passages. At passage 3, differentiation was carried out in a 3-staged procedure. Cells were cultured in a glucose-rich medium containing several activation and growth factors. Cells were evaluated in-vitro by flow cytometry, immunolabelling, Rt-PCR and human insulin and c-peptide release in responses to increasing glucose concentrations. One thousand cell-clusters were inserted under the renal capsule of diabetic nude mice followed by monitoring of their diabetic status. At the end of differentiation, ~5–10% of cells were immunofluorescent for insulin, c-peptide or glucagon; insulin and c-peptide were co-expressed. Nanogold immunolabelling for electron microscopy demonstrated the presence of c-peptide in the rough endoplasmic reticulum. Insulin-producing cells (IPCs) expressed transcription factors and genes of pancreatic hormones similar to those expressed by pancreatic islets. There was a stepwise increase in human insulin and c-peptide release by IPCs in response to increasing glucose concentrations. Transplantation of IPCs into nude diabetic mice resulted in control of their diabetic status for 3 months. The sera of IPC-transplanted mice contained human insulin and c-peptide but negligible levels of mouse insulin. When the IPCs-bearing kidneys were removed, rapid return of diabetic state was noted. BM-MSCs from diabetic and non-diabetic human subjects could be differentiated without genetic manipulation to form IPCs which, when transplanted, could maintain euglycaemia in diabetic mice for 3 months. Optimization of the culture conditions are required to improve the yield of IPCs and their functional performance.
doi:10.3727/096368912X647162
PMCID: PMC3893040  PMID: 22710060
Human bone marrow mesenchymal stem cells; differentiation insulin; soluble factors; diabetes
20.  Effects of captopril on factors affecting gastric mucosal integrity in aspirin-induced gastric lesions in Sprague-Dawley rats 
Archives of Medical Science : AMS  2012;9(6):1132-1137.
Introduction
Captopril is an angiotensin-converting enzyme inhibitor, which is used as an antihypertensive agent and has shown antioxidant properties. This study aims at determining the effects of captopril on factors affecting gastric mucosal integrity in aspirin-induced gastric lesions.
Material and methods
Eighteen male Sprague-Dawley (200-250 g) rats that were given aspirin (40 mg/100 g body weight) were divided into three groups: the control, captopril (1 mg/100 g body weight daily) and ranitidine (2.5 mg/100 g body weight twice daily) groups. Ranitidine and captopril were given orally for 28 days. Rats in all groups were sacrificed and the parameters measured.
Results
Captopril reduced gastric acidity, and increased gastric glutathione (GSH) and prostaglandin E2 (PGE2) significantly in comparison to the control group. Captopril also reduced malondialdehyde (MDA) and gastric lesions insignificantly compared to the control group. Ranitidine healed the lesions significantly compared to the control group. There was no difference between ranitidine and captopril on the severity of lesions, gastric acidity, MDA and GSH. Captopril increased PGE2 compared to ranitidine (p < 0.05).
Conclusions
Captopril has desirable effects on the factors affecting gastric mucosal integrity (acidity, PGE2 and GSH) and is comparable to ranitidine in ulcer healing.
doi:10.5114/aoms.2012.31252
PMCID: PMC3902702  PMID: 24482662
captopril; ranitidine; aspirin; gastric lesions
21.  Aptamer-Nanoparticle Assembly for Logic-Based Detection 
ACS applied materials & interfaces  2012;4(6):3007-3011.
In this work, gold nanoparticles perform Boolean logic operations in response to two proangiogenic targets important in cancer diagnosis and treatment: PDGF and VEGF. In the absence of protein target, gold nanoparticles are initially dispersed as a red solution, addition of target proteins causes nanoparticle aggregation, turning the solution blue, as well as the release of dye-labelled aptamer probes which causes an increase of fluorescence. These outputs constitute an AND or OR gate for simultaneous protein detection. We believe this logic-gate-based detection system will become the basis for novel rapid, cheap, and reliable sensors for diagnostic applications.
doi:10.1021/am300374q
PMCID: PMC3483412  PMID: 22650355
Boolean Logic-based detection; Aptamer; Gold Nanoparticle; Nanoparticle; PDGF; VEGF
22.  Heterocyclic Dications as a New Class of Telomeric G-Quadruplex Targeting Agents 
Current pharmaceutical design  2012;18(14):1934-1947.
Small molecules that can induce and stabilize G-quadruplex DNA structures represent a novel approach for anti-cancer and anti-parasitic therapy and extensive efforts have been directed towards discovering lead compounds that are capable of stabilizing quadruplexes. The purpose of this study is to explore conformational modifications in a series of heterocyclic dications to discover structural motifs that can selectively bind and stabilize specific G-quadruplexes, such as those present in the human telomere. The G-quadruplex has various potential recognition sites for small molecules; however, the primary interaction site of most of these ligands is the terminal tetrads. Similar to duplex-DNA groove recognition, quadruplex groove recognition by small molecules offers the potential for enhanced selectivity that can be developed into a viable therapeutic strategy. The compounds investigated were selected based on preliminary studies with DB832, a bifuryl-phenyl diamidine with a unique telomere interaction. This compound provides a paradigm that can help in understanding the optimum compound-DNA interactions that lead to quadruplex groove recognition. DNA recognition by the DB832 derivatives was investigated by biophysical experiments such as thermal melting, circular dichroism, mass spectrometry and NMR. Biological studies were also performed to complement the biophysical data. The results suggest a complex binding mechanism which involves the recognition of grooves for some ligands as well as stacking at the terminal tetrads of the human telomeric G-quadruplex for most of the ligands. These molecules represent an excellent starting point for further SAR analysis for diverse modes of quadruplex recognition and subsequent structure optimization for drug development.
PMCID: PMC3865530  PMID: 22380518
Heterocyclic dications; Telomere; Telomerase; G-quadruplex; Circular dichroism; Nuclear magnetic resonance; Groove binding; Dimer
23.  Activation of the Inflammasome and Enhanced Migration of Microparticle-Stimulated Dendritic Cells to the Draining Lymph Node 
Molecular pharmaceutics  2012;9(7):2049-2062.
Porous silicon microparticles presenting pathogen-associated molecular patterns mimic pathogens, enhancing internalization of the microparticles and activation of antigen presenting dendritic cells. We demonstrate abundant uptake of microparticles bound by the TLR-4 ligands LPS and MPL by murine bone marrow-derived dendritic cells (BMDC). Labeled microparticles induce concentration-dependent production of IL-1β, with inhibition by the caspase inhibitor Z-VAD-FMK supporting activation of the NLRP3-dependent inflammasome. Inoculation of BALB/c mice with ligand-bound microparticles induces a significant increase in circulating levels of IL-1β, TNF-α, and IL-6. Stimulation of BMDC with ligand-bound microparticles increases surface expression of co-stimulatory and MHC molecules, and enhances migration of BMDC to the draining lymph node. LPS-microparticles stimulate in vivo C57BL/6 BMDC and OT-1 transgenic T cell interactions in the presence of OVA SIINFEKL peptide in lymph nodes, with intact nodes imaged using two-photon microscopy. Formation of in vivo and in vitro immunological synapses between BMDC, loaded with OVA peptide and LPS-microparticles, and OT-1 T cells are presented, as well as elevated intracellular interferon gamma levels in CD8+ T cells stimulated by BMDC carrying peptide-loaded microparticles. In short, ligand-bound microparticles enhance 1) phagocytosis of microparticles; 2) BMDC inflammasome activation and up-regulation of co-stimulatory and MHC molecules; 3) cellular migration of BMDC to lymphatic tissue; and 4) cellular interactions leading to T cell activation in the presence of antigen.
doi:10.1021/mp3001292
PMCID: PMC3524399  PMID: 22680980
microparticle; vaccine; dendritic cell; migration; phagocytosis; atomic force microscopy; LPS; monophosphoryl lipid A
24.  Incidence of symptomatic brain metastasis following radical radiotherapy for non-small cell lung cancer: is there a role for prophylactic cranial irradiation? 
The British Journal of Radiology  2012;85(1020):1546-1550.
Objective
Brain metastases following radical radiotherapy for non-small cell lung cancer (NSCLC) are a recognised phenomenon; however, the incidence of symptomatic brain metastasis is currently unknown. The aim of the study was to identify the number of patients, staged in accordance with National Institute for Health and Clinical Excellence (NICE) guidance, who developed symptomatic brain metastasis following radical radiotherapy. There are two aims: to evaluate NICE guidance; and to provide vital information on the likely benefit of prophylactic cranial irradiation (PCI) in reducing neurological symptoms from brain metastasis.
Methods
A retrospective review of 455 patients with NSCLC who had undergone radical radiotherapy in 2009 and 2010 was performed. Computer-based systems were used to identify patient and tumour demographics, the staging procedures performed and whether brain imaging had identified brain metastasis in the follow-up period.
Results
The total number of patients with brain metastasis within 6 months was 3.7%. The proportion of brain metastasis within 6 months in Stage I, II and III NSCLC throughout both years was 2.8%, 1.0% and 5.7%, respectively. Within the follow-up period (median 16 months, range 6–30 months), the total number of patients who developed symptomatic brain metastasis was 7.9%.
Conclusion
Patients staged in accordance with NICE guidance, of whom only 7.7% underwent brain staging, have a minimal incidence of brain metastasis following radical radiotherapy. The number of patients developing symptoms from brain metastasis following radical radiotherapy may be less than the morbidity caused by PCI.
Advances in knowledge
This finding supports the NICE guidance and brings into question the potential benefit of PCI.
doi:10.1259/bjr/23314501
PMCID: PMC3611712  PMID: 22993386
25.  Vanillin Differentially Affects Azoxymethane-Injected Rat Colon Carcinogenesis and Gene Expression 
Journal of Medicinal Food  2012;15(12):1096-1102.
Abstract
Vanillin is the substance responsible for the flavor and smell of vanilla, a widely used flavoring agent. Previous studies reported that vanillin is a good antimutagen and anticarcinogen. However, there are also some contradicting findings showing that vanillin was a comutagen and cocarcinogen. This study investigated whether vanillin is an anticarcinogen or a cocarcinogen in rats induced with azoxymethane (AOM). Rats induced with AOM will develop aberrant crypt foci (ACF). AOM-challenged rats were treated with vanillin orally and intraperitoneally at low and high concentrations and ACF density, multiplicity, and distribution were observed. The gene expression of 14 colorectal cancer-related genes was also studied. Results showed that vanillin consumed orally had no effect on ACF. However, high concentrations (300 mg/kg body weight) of vanillin administered through intraperitoneal injection could increase ACF density and ACF multiplicity. ACF were mainly found in the distal colon rather than in the mid-section and proximal colon. The expression of colorectal cancer biomarkers, protooncogenes, recombinational repair, mismatch repair, and cell cycle arrest, and tumor suppressor gene expression were also affected by vanillin. Vanillin was not cocarcinogenic when consumed orally. However, it was cocarcinogenic when being administered intraperitoneally at high concentration. Hence, the use of vanillin in food should be safe but might have cocarcinogenic potential when it is used in high concentration for therapeutic purposes.
doi:10.1089/jmf.2012.2245
PMCID: PMC3523249  PMID: 23216109
apoptosis; cell cycle; DNA repair; protooncogene; tumor suppressor gene; vanillin

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