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1.  Hair regrowth in alopecia areata patients following Stem Cell Educator therapy 
BMC Medicine  2015;13:87.
Background
Alopecia areata (AA) is one of the most common autoimmune diseases and targets the hair follicles, with high impact on the quality of life and self-esteem of patients due to hair loss. Clinical management and outcomes are challenged by current limited immunosuppressive and immunomodulating regimens.
Methods
We have developed a Stem Cell Educator therapy in which a patient’s blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, allows the cells to briefly interact with adherent human cord blood-derived multipotent stem cells (CB-SC), and returns the “educated” autologous cells to the patient’s circulation. In an open-label, phase 1/phase 2 study, patients (N = 9) with severe AA received one treatment with the Stem Cell Educator therapy. The median age was 20 years (median alopecic duration, 5 years).
Results
Clinical data demonstrated that patients with severe AA achieved improved hair regrowth and quality of life after receiving Stem Cell Educator therapy. Flow cytometry revealed the up-regulation of Th2 cytokines and restoration of balancing Th1/Th2/Th3 cytokine production in the peripheral blood of AA subjects. Immunohistochemistry indicated the formation of a “ring of transforming growth factor beta 1 (TGF-β1)” around the hair follicles, leading to the restoration of immune privilege of hair follicles and the protection of newly generated hair follicles against autoimmune destruction. Mechanistic studies revealed that co-culture with CB-SC may up-regulate the expression of coinhibitory molecules B and T lymphocyte attenuator (BTLA) and programmed death-1 receptor (PD-1) on CD8β+NKG2D+ effector T cells and suppress their proliferation via herpesvirus entry mediator (HVEM) ligands and programmed death-1 ligand (PD-L1) on CB-SCs.
Conclusions
Current clinical data demonstrated the safety and efficacy of the Stem Cell Educator therapy for the treatment of AA. This innovative approach produced lasting improvement in hair regrowth in subjects with moderate or severe AA.
Trial registration
ClinicalTrials.gov, NCT01673789, 21 August 2012
doi:10.1186/s12916-015-0331-6
PMCID: PMC4417286  PMID: 25896390
Alopecia areata; Autoimmune; Stem Cell Educator; Immune modulation; Hair regrowth
2.  The rising tide of polypharmacy and drug-drug interactions: population database analysis 1995–2010 
BMC Medicine  2015;13:74.
Background
The escalating use of prescribed drugs has increasingly raised concerns about polypharmacy. This study aims to examine changes in rates of polypharmacy and potentially serious drug-drug interactions in a stable geographical population between 1995 and 2010.
Methods
This is a repeated cross-sectional analysis of community-dispensed prescribing data for all 310,000 adults resident in the Tayside region of Scotland in 1995 and 2010. The number of drug classes dispensed and the number of potentially serious drug-drug interactions (DDIs) in the previous 84 days were calculated, and age-sex standardised rates in 1995 and 2010 compared. Patient characteristics associated with receipt of ≥10 drugs and with the presence of one or more DDIs were examined using multilevel logistic regression to account for clustering of patients within primary care practices.
Results
Between 1995 and 2010, the proportion of adults dispensed ≥5 drugs doubled to 20.8%, and the proportion dispensed ≥10 tripled to 5.8%. Receipt of ≥10 drugs was strongly associated with increasing age (20–29 years, 0.3%; ≥80 years, 24.0%; adjusted OR, 118.3; 95% CI, 99.5–140.7) but was also independently more common in people living in more deprived areas (adjusted OR most vs. least deprived quintile, 2.36; 95% CI, 2.22–2.51), and in people resident in a care home (adjusted OR, 2.88; 95% CI, 2.65–3.13). The proportion with potentially serious drug-drug interactions more than doubled to 13% of adults in 2010, and the number of drugs dispensed was the characteristic most strongly associated with this (10.9% if dispensed 2–4 drugs vs. 80.8% if dispensed ≥15 drugs; adjusted OR, 26.8; 95% CI 24.5–29.3).
Conclusions
Drug regimens are increasingly complex and potentially harmful, and people with polypharmacy need regular review and prescribing optimisation. Research is needed to better understand the impact of multiple interacting drugs as used in real-world practice and to evaluate the effect of medicine optimisation interventions on quality of life and mortality.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0322-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0322-7
PMCID: PMC4417329  PMID: 25889849
Drug interactions; Family practice; Physician; Polypharmacy; Prescribing patterns; Primary care
3.  Ablation of Osteopontin Improves the Skeletal Phenotype of Phospho1−/− Mice 
PHOSPHO1 and tissue-nonspecific alkaline phosphatase (TNAP) have nonredundant functions during skeletal mineralization. Although TNAP deficiency (Alpl−/− mice) leads to hypophosphatasia, caused by accumulation of the mineralization inhibitor inorganic pyrophosphate (PPi), comparably elevated levels of PPi in Phospho1−/− mice do not explain their stunted growth, spontaneous fractures, bowed long bones, osteomalacia, and scoliosis. We have previously shown that elevated PPi in Alpl−/− mice is accompanied by elevated osteopontin (OPN), another potent mineralization inhibitor, and that the amount of OPN correlates with the severity of hypophosphatasia in mice. Here we demonstrate that plasma OPN is elevated and OPN expression is upregulated in the skeleton, particularly in the vertebrae, of Phospho1−/− mice. Liquid chromatography/tandem mass spectrometry showed an increased proportion of phosphorylated OPN (p-OPN) peptides in Phospho1−/− mice, suggesting that accumulation of p-OPN causes the skeletal abnormalities in Phospho1−/− mice. We also show that ablation of the OPN gene, Spp1, leads to improvements in the skeletal phenotype in Phospho1−/− as they age. In particular, their scoliosis is ameliorated at 1 month of age and is completely rescued at 3 months of age. There is also improvement in the long bone defects characteristic of Phospho1−/− mice at 3 months of age. Mineralization assays comparing [Phospho1−/−; Spp1−/−], Phospho1−/−, and Spp1−/− chondrocytes display corrected mineralization by the double knockout cells. Expression of chondrocyte differentiation markers was also normalized in the [Phospho1−/−; Spp1−/−] mice. Thus, although Alpl and Phospho1 deficiencies lead to similar skeletal phenotypes and comparable changes in the expression levels of PPi and OPN, there is a clear dissociation in the hierarchical roles of these potent inhibitors of mineralization, with elevated PPi and elevated p-OPN levels causing the respective skeletal phenotypes in Alpl−/− and Phospho1−/− mice.
doi:10.1002/jbmr.2281
PMCID: PMC5247257  PMID: 24825455
4.  Mitochondrial dysfunction induces SESN2 gene expression through Activating Transcription Factor 4 
Cell Cycle  2016;15(1):64-71.
ABSTRACT
We found that inhibitors of mitochondrial respiratory chain complexes III (myxothiazol) and I (piericidin A) in some epithelial carcinoma cell lines induce transcription of the p53-responsive SESN2 gene that plays an important role in stress response and homeostatic regulation. However, the effect did not depend on p53 because i) there was no induction of p53 after the treatment with piericidin A; ii) after the treatment with myxothiazol the peak of SESN2 gene upregulation occurred as early as 5h, before the onset of p53 activation (13h); iii) a supplementation with uridine that abolishes the p53 activation in response to myxothiazol did not abrogate the induction of SESN2 transcripts; iv) in the p53 negative HCT116 p53 -/- cells SESN2 transcription could be also induced by myxothiazol. In response to the respiratory chain inhibitors we observed an induction of ATF4, the key transcription factor of the integrated stress response (ISR). We found that the induction of SESN2 transcripts could be prevented by the ISR inhibitory small molecule ISRIB. Also, by inhibiting or overexpressing ATF4 with specific shRNA or ATF4-expressing constructs, respectively, we have confirmed the role of ATF4 in the SESN2 gene upregulation induced by mitochondrial dysfunction. At a distance of 228 bp upstream from the SESN2 transcription start site we found a candidate sequence for the ATF4 binding site and confirmed its requirement for the induction of SESN2 in luciferase reporter experiments. We suggest that the upregulation of SESN2 by mitochondrial dysfunction provides a homeostatic feedback that attenuates biosynthetic processes during temporal losses of energy supply from mitochondria thereby assisting better adaptation and viability of cells in hostile environments.
doi:10.1080/15384101.2015.1120929
PMCID: PMC4825760  PMID: 26771712
ATF4-binding site; integrated stress response; ISRIB; mitochondrial respiratory chain complex III; SESN2 promoter; Sestrin 2; transcription factor ATF4; tumor suppressor p53
5.  Catalytic Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones: Efficient Access to Chiral β-Fluoroamines 
Herein, we report a Zn-Prophenol catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of β–fluoroamine motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram-scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed. Together, these reactions provide a new approach for the preparation of pharmaceutically relevant products possessing tetrasubstituted C–F centers.
Graphical abstract
A Zn-Prophenol catalysed direct Mannich reaction using α-fluoroketones allows the efficient construction of β–fluoroamine motifs with high enantio- and diastereoselectivities (up to 99% ee, >20:1 d.r.). A stereocomplementary aldol reaction is also described.
doi:10.1002/anie.201509719
PMCID: PMC4837127  PMID: 26609784
β–fluoroamines; asymmetric catalysis; Mannich reaction; Zn-Prophenol; tetrasubstituted C–F centers
6.  Genome Editing in Human Pluripotent Stem Cells: Approaches, Pitfalls, and Solutions 
Cell stem cell  2016;18(1):53-65.
Human pluripotent stem cells (hPSCs) with knockout or mutant alleles can be generated using custom-engineered nucleases. Transcription Activator-Like Effector Nucleases (TALENs) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 - nucleases are the most commonly employed technologies for editing hPSC genomes. In this Protocol Review we provide a brief overview of custom-engineered nucleases in the context of gene editing in hPSCs with a focus on the application of TALENs and CRISPR/Cas9. We will highlight the advantages and disadvantages of each method and discuss theoretical and technical considerations for experimental design.
doi:10.1016/j.stem.2015.12.002
PMCID: PMC4709030  PMID: 26748756
7.  Natural and Sun-Induced Aging of Human Skin 
With worldwide expansion of the aging population, research on age-related pathologies is receiving growing interest. In this review, we discuss current knowledge regarding the decline of skin structure and function induced by the passage of time (chronological aging) and chronic exposure to solar UV irradiation (photoaging). Nearly every aspect of skin biology is affected by aging. The self-renewing capability of the epidermis, which provides vital barrier function, is diminished with age. Vital thermoregulation function of eccrine sweat glands is also altered with age. The dermal collagenous extracellular matrix, which comprises the bulk of skin and confers strength and resiliency, undergoes gradual fragmentation, which deleteriously impacts skin mechanical properties and dermal cell functions. Aging also affects wound repair, pigmentation, innervation, immunity, vasculature, and subcutaneous fat homeostasis. Altogether, age-related alterations of skin lead to age-related skin fragility and diseases.
Chronologically aged and photoaged skin are clinically distinct (e.g., thin vs. leathery), but they share similar biochemical and cellular features (e.g., cumulative damage to collagen fibers).
doi:10.1101/cshperspect.a015370
PMCID: PMC4292080  PMID: 25561721
8.  DNA Strand Exchange and RecA Homologs in Meiosis 
Homology search and DNA strand–exchange reactions are central to homologous recombination in meiosis. During meiosis, these processes are regulated such that the probability of choosing a homolog chromatid as recombination partner is enhanced relative to that of choosing a sister chromatid. This regulatory process occurs as homologous chromosomes pair in preparation for assembly of the synaptonemal complex. Two strand–exchange proteins, Rad51 and Dmc1, cooperate in regulated homology search and strand exchange in most organisms. Here, we summarize studies on the properties of these two proteins and their accessory factors. In addition, we review current models for the assembly of meiotic strand–exchange complexes and the possible mechanisms through which the interhomolog bias of recombination partner choice is achieved.
In most eukaryotes, Rad51 and Dmc1 carry out the search for a recombination partner and perform strand exchange during meiosis. These proteins and their accessory factors promote pairing with a homologous chromatid, rather than the sister.
doi:10.1101/cshperspect.a016659
PMCID: PMC4292170  PMID: 25475089
9.  Mitochondrial Calpain-1 Disrupts ATP Synthase and Induces Superoxide Generation in Type 1 Diabetic Hearts: A Novel Mechanism Contributing to Diabetic Cardiomyopathy 
Diabetes  2015;65(1):255-268.
Calpain plays a critical role in cardiomyopathic changes in type 1 diabetes (T1D). This study investigated how calpain regulates mitochondrial reactive oxygen species (ROS) generation in the development of diabetic cardiomyopathy. T1D was induced in transgenic mice overexpressing calpastatin, in mice with cardiomyocyte-specific capn4 deletion, or in their wild-type littermates by injection of streptozotocin. Calpain-1 protein and activity in mitochondria were elevated in diabetic mouse hearts. The increased mitochondrial calpain-1 was associated with an increase in mitochondrial ROS generation and oxidative damage and a reduction in ATP synthase-α (ATP5A1) protein and ATP synthase activity. Genetic inhibition of calpain or upregulation of ATP5A1 increased ATP5A1 and ATP synthase activity, prevented mitochondrial ROS generation and oxidative damage, and reduced cardiomyopathic changes in diabetic mice. High glucose concentration induced ATP synthase disruption, mitochondrial superoxide generation, and cell death in cardiomyocytes, all of which were prevented by overexpression of mitochondria-targeted calpastatin or ATP5A1. Moreover, upregulation of calpain-1 specifically in mitochondria induced the cleavage of ATP5A1, superoxide generation, and apoptosis in cardiomyocytes. In summary, calpain-1 accumulation in mitochondria disrupts ATP synthase and induces ROS generation, which promotes diabetic cardiomyopathy. These findings suggest a novel mechanism for and may have significant implications in diabetic cardiac complications.
doi:10.2337/db15-0963
PMCID: PMC4686953  PMID: 26470784
10.  Human Milk Components Modulate Toll-Like Receptor–Mediated Inflammation12 
Advances in Nutrition  2016;7(1):102-111.
Toll-like receptor (TLR) signaling is central to innate immunity. Aberrant expression of TLRs is found in neonatal inflammatory diseases. Several bioactive components of human milk modulate TLR expression and signaling pathways, including soluble toll-like receptors (sTLRs), soluble cluster of differentiation (sCD) 14, glycoproteins, small peptides, and oligosaccharides. Some milk components, such as sialyl (α2,3) lactose and lacto-N-fucopentaose III, are reported to increase TLR signaling; under some circumstances this might contribute toward immunologic balance. Human milk on the whole is strongly anti-inflammatory, and contains abundant components that depress TLR signaling pathways: sTLR2 and sCD14 inhibit TLR2 signaling; sCD14, lactadherin, lactoferrin, and 2′-fucosyllactose attenuate TLR4 signaling; 3′-galactosyllactose inhibits TLR3 signaling, and β-defensin 2 inhibits TLR7 signaling. Feeding human milk to neonates decreases their risk of sepsis and necrotizing enterocolitis. Thus, the TLR regulatory components found in human milk hold promise as benign oral prophylactic and therapeutic treatments for the many gastrointestinal inflammatory disorders mediated by abnormal TLR signaling.
doi:10.3945/an.115.010090
PMCID: PMC4717889  PMID: 26773018
immune function; toll like receptors; inflammation; human milk; glycans
11.  Feshbach enhanced s-wave scattering of fermions: direct observation with optimized absorption imaging 
New journal of physics  2015;18:013001.
We directly measured the normalized s-wave scattering cross-section of ultracold 40K atoms across a magnetic-field Feshbach resonance by colliding pairs of degenerate Fermi gases (DFGs) and imaging the scattered atoms. We extracted the scattered fraction for a range of bias magnetic fields, and measured the resonance location to be B0 = 20.206(15) mT with width Δ = 1.0(5) mT. To optimize the signal-to-noise ratio of atom number in scattering images, we developed techniques to interpret absorption images in a regime where recoil induced detuning corrections are significant. These imaging techniques are generally applicable to experiments with lighter alkalis that would benefit from maximizing signal-to-noise ratio on atom number counting at the expense of spatial imaging resolution.
doi:10.1088/1367-2630/18/1/013001
PMCID: PMC4759653  PMID: 26903778
Quantum gases; Atomic physics
12.  Epigenetics of the myotonic dystrophy-associated DMPK gene neighborhood 
Epigenomics  2016;8(1):13-31.
Aim:
Identify epigenetic marks in the vicinity of DMPK (linked to myotonic dystrophy, DM1) that help explain tissue-specific differences in its expression.
Materials & methods:
At DMPK and its flanking genes (DMWD, SIX5, BHMG1 and RSPH6A), we analyzed many epigenetic and transcription profiles from myoblasts, myotubes, skeletal muscle, heart and 30 nonmuscle samples.
Results:
In the DMPK gene neighborhood, muscle-associated DNA hypermethylation and hypomethylation, enhancer chromatin, and CTCF binding were seen. Myogenic DMPK hypermethylation correlated with high expression and decreased alternative promoter usage. Testis/sperm hypomethylation of BHMG1 and RSPH6A was associated with testis-specific expression. G-quadruplex (G4) motifs and sperm-specific hypomethylation were found near the DM1-linked CTG repeats within DMPK.
Conclusion:
Tissue-specific epigenetic features in DMPK and neighboring genes help regulate its expression. G4 motifs in DMPK DNA and RNA might contribute to DM1 pathology.
doi:10.2217/epi.15.104
PMCID: PMC4863877  PMID: 26756355
alternative promoters; CTCF; DNA methylation; enhancers; G-quadruplex; histone modification; muscle; myotonic dystrophy; sperm DNA; testis
13.  Fabric Force Sensors for the Clinical Breast Examination Simulator 
Sensor enabled simulators may help in training and assessing clinical skill. Their are imitations on the locations current sensors can be placed without interfering with the clinical examination. In this study novel fabric force sensors were developed and tested. These sensors are soft and flexible and undetectable when placed in different locations in the simulator. Five sensors were added to our current sensor enabled breast simulator. Eight participants performed the clinical breast examination on the simulator and documented their findings. There was a significant relationship for both clinical breast examination time (r(6) = 0.99, p < 0.001 ) and average force (r(6) = 0.92, p < 0.005) between our current sensors and the new fabric sensors. In addition the senors were not noticed by the participants. These new sensors provide new methods to measure and assess clinical skill and performance.
PMCID: PMC4924804  PMID: 27046577
Clinical breast examination; Medical simulators; Force Sensors
14.  Exogenous glucagon-like peptide-1 acts in sites supplied by the cranial mesenteric artery to reduce meal size and prolong the intermeal interval in rats 
Appetite  2015;96:254-259.
Three experiments were done to better assess the gastrointestinal (GI) site(s) of action of GLP-1 on food intake in rats. First, near-spontaneous nocturnal chow meal size (MS), intermeal intervals (IMI) length and satiety ratios (SR = MS/IMI) were measured after infusion of saline, 0.025 or 0.5 nmol/kg GLP-1 into the celiac artery (CA, supplying the stomach and upper duodenum), cranial mesenteric artery (CMA, supplying small and all of the large intestine except the rectum), femoral artery (FA, control) or portal vein (PV, control). Second, infusion of 0.5 nmol/kg GLP-1 was tested after pretreatment with the GLP-1 receptor (GLP-1R) antagonist exendin-4(3–39) via the same routes. Third, the regional distribution of GLP-1R in the rat GI tract was determined using rtPCR. CA, CMA and FA GLP-1 reduced first MS relative to saline, with the CMA route more effective than the others. Only CMA GLP-1 prolonged the IMI. None of the infusions affected second MS or later eating. CA and CMA GLP-1 increased the SR, with the CMA route more effective than the CA route. CMA exendin-4 (3–39) infusion reduced the effect of CMA GLP-1. Finally GLP-1R expression was found throughout the GI tract. The results suggest that exogenous GLP-1 acts in multiple GI sites to reduce feeding under our conditions and that GLP-1R in the area supplied by the CMA, i.e., the small and part of the large intestine, plays the leading role.
doi:10.1016/j.appet.2015.09.030
PMCID: PMC4993531  PMID: 26431682
GLP-1; Intermeal Interval; Satiety Ratio; Celiac Artery; Portal Vein
15.  Intravitreal Bevacizumab Versus Ranibizumab for Treatment of Neovascular Age-Related Macular Degeneration: Findings from a Cochrane Systematic Review 
Ophthalmology  2015;123(1):70-77.e1.
Topic
To summarize the relative effects of bevacizumab (Avastin®, Genentech, Inc.) and ranibizumab (Lucentis®, Genentech, Inc.), using findings from a Cochrane Eyes and Vision Group systematic review .
Clinical relevance
Neovascular age-related macular degeneration (NVAMD) is the most common cause of uncorrectable vision loss in the elderly in developed countries. Bevacizumab and ranibizumab are the most frequently-used anti-VEGF agents injected intravitreally to treat NVAMD
Methods
We included only randomized controlled trials (RCTs) in which the two anti-VEGF agents had been compared directly. The primary outcome was 1-year gain in best-corrected visual acuity (BCVA) of 15 or more logMAR letters. We followed Cochrane methods for trial selection, data extraction, and data analyses. Relative effects of bevacizumab versus ranibizumab are presented as estimated risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs).
Results
We identified 6 eligible RCTs with 2809 participants. The proportion of eyes that gained 15 or more letters of BCVA by 1 year was similar for the two agents when the same regimens were compared: RR=0.90, 95% CI: 0.73 to 1.11. The mean change in BCVA from baseline also was similar: MD=−0.5 letter; 95% CI: −1.6 to +0.6. Other BCVA and quality-of-life outcomes were similar for the two agents. One-year treatment cost with ranibizumab was 5.1 and 25.5 times the cost for bevacizumab in the two largest trials. Ocular adverse events were uncommon (<1%); rates were similar for the two agents.
Conclusions
We found no important difference in effectiveness or safety between bevacizumab and ranibizumab for NVAMD treatment but a large cost difference.
doi:10.1016/j.ophtha.2015.09.002
PMCID: PMC4695272  PMID: 26477843
16.  Molecular basis for antibody-mediated neutralization of New World hemorrhagic fever mammarenaviruses 
Cell host & microbe  2015;18(6):705-713.
SUMMARY
In the Western hemisphere, at least five mammarenaviruses cause human viral hemorrhagic fevers with high case fatality rates. Junín virus (JUNV) is the only hemorrhagic fever virus for which transfusion of survivor immune plasma that contains neutralizing antibodies (‘passive immunity’) is an established treatment. Here, we report the structure of the JUNV surface glycoprotein receptor-binding subunit (GP1) bound to a neutralizing monoclonal antibody. The antibody engages the GP1 site that binds transferrin receptor 1 (TfR1) – the host cell surface receptor for all New World hemorrhagic fever mammarenaviruses - and mimics an important receptor contact. We show that survivor immune plasma contains antibodies that bind the same epitope. We propose that viral receptor-binding site accessibility explains the success of passive immunity against JUNV and that this functionally conserved epitope is a potential target for therapeutics and vaccines to limit infection by all New World hemorrhagic fever mammarenaviruses.
doi:10.1016/j.chom.2015.11.005
PMCID: PMC4685251  PMID: 26651946
18.  Inflammatory mediator-induced modulation of GABAA currents in human sensory neurons 
Neuroscience  2015;310:401-409.
The purpose of the present study was to characterize the properties of GABAA receptor currents in human sensory neurons. Neurons were obtained from adult organ donors. GABAA currents were recorded in isolated neurons. Both large inactivating low affinity currents and smaller persistent high affinity currents were present in all of the 129 neurons studied from 15 donors. The kinetics of human GABAA currents were slower than those in rat sensory neurons. GABA currents were completely blocked by bicuculline (10 µM), and persistent currents were activated by the δ-subunit preferring agonist, THIP. The GABA current equilibrium potential was ~20 mV more hyperpolarized than in rat neurons. Both low and high affinity currents were increased by inflammatory mediators but via different second messenger pathways. These results highlight potentially important species differences in the properties of ion channels present in their native environment and suggest the use of human sensory neurons may be a valuable tool to test compounds prior to use in humans.
doi:10.1016/j.neuroscience.2015.09.048
PMCID: PMC4633346  PMID: 26415765
dorsal root ganglion; intracellular Cl- concentration; patch clamp; protein kinase A; protein kinase C; tyrosine kinase
19.  Progression of micronutrient alteration and hepatotoxicity following acute PCB126 exposure 
Toxicology  2015;338:1-7.
Polychlorinated Biphenyls (PCBs) are industrial chemicals that have become a persistent threat to human health due to ongoing exposure. A subset of PCBs, known as dioxin-like PCBs, pose a special threat given their potent hepatic effects. Micronutrients, especially Cu, Zn and Se, homeostatic dysfunction is commonly seen after exposure to dioxin-like PCBs. This study investigates whether micronutrient alteration is the byproduct of the ongoing hepatotoxicity, marked by lipid accumulation, or a concurrent, yet independent event of hepatic damage. A time course study was carried out using male Sprague-Dawley rats with treatments of PCB126, the prototypical dioxin-like PCB, resulting in 6 different time points. Animals were fed a purified diet, based on AIN-93G, for three weeks to ensure micronutrient equilibration. A single IP injection of either tocopherol-stripped soy oil vehicle (5 mL/kg) or 5 umol/kg PCB126 dose in vehicle was given at various time points resulting in exposures of 9 hr, 18 hr, 36 hr, 3 days, 6 days, and 12 days. Mild hepatic vacuolar change was seen as early as 36 hours with drastic changes at the later time points, 6 and 12 days. Micronutrient alterations, specifically Cu, Zn, and Se, were not seen until after day 3 and only observed in the liver. No alterations were seen in the duodenum, suggesting that absorption and excretion may not be involved. Micronutrient alterations occur with ROS formation, lipid accumulation, and hepatomegaly. To probe the mechanistic underpinnings, alteration of gene expression of several copper chaperones was investigated; only metallothionein appeared elevated. These data suggest that the disruption in micronutrient status is a result of the hepatic injury elicited by PCB126 and is mediated in part by metallothionein.
Graphical Abstract
doi:10.1016/j.tox.2015.09.004
PMCID: PMC4658301  PMID: 26410179
Micronutrients; Metals; Homeostasis; PCB126; Time Course; AhR
20.  Motion Plan Changes Predictably in Dyadic Reaching 
PLoS ONE  2016;11(12):e0167314.
Parents can effortlessly assist their child to walk, but the mechanism behind such physical coordination is still unknown. Studies have suggested that physical coordination is achieved by interacting humans who update their movement or motion plan in response to the partner’s behaviour. Here, we tested rigidly coupled pairs in a joint reaching task to observe such changes in the partners’ motion plans. However, the joint reaching movements were surprisingly consistent across different trials. A computational model that we developed demonstrated that the two partners had a distinct motion plan, which did not change with time. These results suggest that rigidly coupled pairs accomplish joint reaching movements by relying on a pre-programmed motion plan that is independent of the partner’s behaviour.
doi:10.1371/journal.pone.0167314
PMCID: PMC5135107  PMID: 27911938
21.  Neuropsychopharmacology: Reflections on 40 Volumes 
Neuropsychopharmacology  2015;40(13):2853-2855.
doi:10.1038/npp.2015.290
PMCID: PMC4864642  PMID: 26548764
22.  Communal visual histories to detect environmental change in northern areas: Examples of emerging North American and Eurasian practices 
Ambio  2015;44(8):766-777.
This article explores the pioneering potential of communal visual-optic histories which are recorded, painted, documented, or otherwise expressed. These materials provide collective meanings of an image or visual material within a specific cultural group. They potentially provide a new method for monitoring and documenting changes to ecosystem health and species distribution, which can effectively inform society and decision makers of Arctic change. These visual histories can be positioned in a continuum that extends from rock art to digital photography. They find their expressions in forms ranging from images to the oral recording of knowledge and operate on a given cultural context. For monitoring efforts in the changing boreal zone and Arctic, a respectful engagement with visual histories can reveal emerging aspects of change. The examples from North America and case studies from Eurasia in this article include Inuit sea ice observations, Yu’pik visual traditions of masks, fish die-offs in a sub-boreal catchment area, permafrost melt in the Siberian tundra and early, first detection of a scarabaeid beetle outbreak, a Southern species in the Skolt Sámi area. The pros and cons of using these histories and their reliability are reviewed.
doi:10.1007/s13280-015-0671-7
PMCID: PMC4646853  PMID: 26008615
Visual observation; Optic history; Traditional knowledge; Photography; Rock art
23.  Panax notoginseng saponins ameliorates coxsackievirus B3-induced myocarditis by activating the cystathionine-γ-lyase/hydrogen sulfide pathway 
This study is to determine the therapeutic effects of Panax notoginseng saponins (PNS) on coxsackievirus B3 (CVB3)-induced myocarditis, and whether cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) pathway is involved. Mouse model of myocarditis was induced by CVB3 infection and the mice were subjected to vehicle (saline) or drug treatments (sodium bisulfide (NaHS), propargylglycine (PAG) or PNS). The results showed that there were inflammatory cell infiltrations, interstitial edemas, as well as elevated inflammatory cytokines, in CVB3-induced myocarditis. PAG administration increased, whereas NaHS treatment decreased the severity of the myocarditis. PNS treatment dramatically alleviated these myocardial injuries and decreased the viral mRNA expression by the enhanced expression of CSE/H2S pathway. Moreover, the therapeutic effects of PNS on myocarditis were stronger than NaHS. Finally, the effect of PNS on CSE/H2S pathway and cardiac cell protection were verified in cultured cardiac cells. PNS may be a promising medication for viral myocarditis therapy.
doi:10.1007/s12265-015-9659-8
PMCID: PMC4674358  PMID: 26525047
Myocarditis; Panax notoginseng saponins; hydrogen sulfide; cystathionine-γ-lyase
24.  Simvastatin and Vitamin D for Migraine Prevention: A Randomized Controlled Trial 
Annals of neurology  2015;78(6):970-981.
Objective
To assess efficacy and tolerability of simvastatin plus vitamin D for migraine prevention in adults with episodic migraine.
Methods
We performed a randomized, double-blind, placebo-controlled trial with a 12-week baseline period and 24-week intervention period in 57 adults with episodic migraine. Participants were randomly assigned to simvastatin 20 mg tablets twice daily plus vitamin D3 1000 international units capsules twice daily or matching placebo tablets and capsules.
Results
Compared to placebo, participants using simvastatin plus vitamin D3 demonstrated a greater decrease in number of migraine days from the baseline period to intervention weeks 1-12: a change of -8.0 (IQR: -15.0 to -2.0) days in the active treatment group versus +1.0 (IQR: 1.0 to +6.0) days in the placebo group, P<0.001; and to intervention weeks 13-24: a change of -9.0 (IQR: -13 to -5) days in the active group versus +3.0 (IQR: -1.0 to +5.0) days in the placebo group, P<0.001. In the active treatment group, 8 patients (25%) experienced 50% reduction in the number of migraine days at 12 weeks and 9 (29%) at 24 weeks post randomization. In comparison, only 1 patient (3%) in the placebo group (p=0.03) experienced such reduction. Adverse events were similar in both active treatment and placebo groups.
Interpretation
The results demonstrate that simvastatin plus vitamin D is effective for prevention of headache in adults with episodic migraine. Given statins ability to repair endothelial dysfunction, this economical approach may also reduce the increased risk for vascular diseases among migraineurs.
doi:10.1002/ana.24534
PMCID: PMC4715556  PMID: 26418341
25.  Effects of a selected exercise programon executive function of children with attention deficit hyperactivity disorder  
Journal of Medicine and Life  2016;9(4):373-379.
Introduction. The aim of this study was to examine the effectiveness of a Selected exercise program on the executive function of children with ADHD.
Method. The participants were 40 male students, aged 7-11 years. The participants were randomly assigned into two groups (experimental and control). The experimental group participated in an exercise program for 24 sessions, 90 minutes per session. The control group did not receive any intervention. Before and after the exercise period, all the participants were assessed with Stroop and Go-No-Go tests, and the resulting data were analyzed by using MANCOVA.
Result. The results showed that the cognitive inhibition of the children in the experimental group was significantly different compared with the control group (p < 0.05). Additionally, there was a significant difference between the experimental and control groups in the behavioral inhibition (p < 0.05).
Conclusion. An organized physical activity helps to improve the executive function in children with ADHD.
PMCID: PMC5141397  PMID: 27928441
Attention Deficit Hyperactivity Disorder (ADHD); Selective exercise program; Executive Function

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