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1.  CSAR 2014: A Benchmark Exercise Using Unpublished Data from Pharma 
The 2014 CSAR Benchmark Exercise was the last community-wide exercise that was conducted by the group at the University of Michigan, Ann Arbor. For this event, GlaxoSmithKline (GSK) donated unpublished crystal structures and affinity data from in-house projects. Three targets were used: tRNA (m1G37) methyltransferase (TrmD), Spleen Tyrosine Kinase (SYK), and Factor Xa (FXa). A particularly strong feature of the GSK data is its large size, which lends greater statistical significance to comparisons between different methods. In Phase 1 of the CSAR 2014 Exercise, participants were given several protein-ligand complexes and asked to identify the one near-native pose from among 200 decoys provided by CSAR. Though decoys were requested by the community, we found that they complicated our analysis. We could not discern whether poor predictions were failures of the chosen method or an incompatibility between the participant’s method and the setup protocol we used. This problem is inherent to decoys and we strongly advise against their use. In Phase 2, participants had to dock and rank/score a set of small molecules given only the SMILES strings of the ligands and a protein structure with a different ligand bound. Overall, docking was a success for most participants, much better in Phase 2 than in Phase 1. However, scoring was a greater challenge. No particular approach to docking and scoring had an edge, and successful methods included empirical, knowledge-based, machine-learning, shape-fitting, and even those with solvation and entropy terms. Several groups were successful in ranking TrmD and/or SYK, but ranking FXa ligands was intractable for all participants. Methods that were able to dock well across all submitted systems include MDock1, Glide-XP2, PLANTS3, Wilma4, Gold5, SMINA6, Glide-XP2/PELE7, FlexX8, and MedusaDock9. In fact, the submission based on Glide-XP2/PELE7 cross-docked all ligands to many crystal structures, and it was particularly impressive to see success across an ensemble of protein structures for multiple targets. For scoring/ranking, submissions that showed statistically significant achievement include MDock1 using ITScore1,10 with a flexible-ligand term11, SMINA6 using Autodock-Vina12,13, FlexX8 using HYDE14, and Glide-XP2 using XP DockScore2 with and without ROCS15 shape similarity16. Of course, these results are for only three protein targets, and many more systems need to be investigated to truly identify which approaches are more successful than others. Furthermore, our exercise is not a competition.
Graphical abstract
doi:10.1021/acs.jcim.5b00523
PMCID: PMC5228621  PMID: 27149958
2.  Early sex work initiation and condom use among alcohol-using female sex workers in Mombasa, Kenya: a cross-sectional analysis 
Sexually transmitted infections  2016;92(8):593-598.
Objectives
Early initiation of sex work is prevalent among female sex workers (FSWs) worldwide. The objectives of this study were to investigate if early initiation of sex work was associated with: (1) consistent condom use, (2) condom negotiation self-efficacy or (3) condom use norms among alcohol-using FSWs in Mombasa, Kenya.
Methods
In-person interviews were conducted with 816 FSWs in Mombasa, Kenya. Sample participants were: recruited from HIV prevention drop-in centres, 18 years or older and moderate risk drinkers. Early initiation was defined as first engaging in sex work at 17 years or younger. Logistic regression modelled outcomes as a function of early initiation, adjusting for drop-in centre, years in sex work, supporting others and HIV status.
Results
FSWs who initiated sex work early were significantly less likely to report consistent condom use with paying sex partners compared with those who initiated sex work in adulthood. There was no significant difference between groups in consistent condom use with non-paying sex partners. FSWs who initiated sex work early endorsed less condom negotiation self-efficacy with paying sex partners compared with FSWs who did not initiate sex work early.
Conclusions
Findings highlight a need for early intervention for at-risk youth and adolescent FSWs, particularly in relation to HIV sexual risk behaviours. Evidence-based interventions for adolescent FSWs or adult FSWs who began sex work in adolescence should be developed, implemented and evaluated.
doi:10.1136/sextrans-2016-052549
PMCID: PMC5215884  PMID: 27217378
3.  Pre-Clinical Study of Panobinostat in Xenograft and Genetically Engineered Murine Diffuse Intrinsic Pontine Glioma Models 
PLoS ONE  2017;12(1):e0169485.
Background
Diffuse intrinsic pontine glioma (DIPG), or high-grade brainstem glioma (BSG), is one of the major causes of brain tumor-related deaths in children. Its prognosis has remained poor despite numerous efforts to improve survival. Panobinostat, a histone deacetylase inhibitor, is a targeted agent that has recently shown pre-clinical efficacy and entered a phase I clinical trial for the treatment of children with recurrent or progressive DIPG.
Methods
A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo.
Results
In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice.
Conclusion
Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.
doi:10.1371/journal.pone.0169485
PMCID: PMC5215670  PMID: 28052119
4.  Evolution and Escalation of an Emergency Department Routine, Opt-out HIV Screening and Linkage-to-Care Program 
Public Health Reports  2016;131(Suppl 1):96-106.
Objective
The Centers for Disease Control and Prevention has recommended emergency department (ED) opt-out HIV screening since 2006. Routine screening can prove challenging due to the ED's complexity and competing priorities. This study examined the implementation and evolution of a routine, integrated, opt-out HIV screening program at an urban academic ED in Alabama since August 2011.
Methods
ED routine, opt-out HIV screening was implemented as a standard of care in September 2011. To describe the outcomes and escalation of the screening program, data analyses were performed from three separate data queries: (1) encounter-level HIV screening questionnaire and test results from September 21, 2011, through December 31, 2013; (2) test-level, fourth-generation HIV results from July 9 through December 31, 2013; and (3) daily HIV testing rates and trends from September 9, 2011, through June 30, 2014.
Results
Of the 46,385 HIV screening tests performed, 252 (0.5%) were confirmed to be positive. Acute HIV infection accounted for 11.8% of all HIV patients identified using the fourth-generation HIV screening assay. Seventy-six percent of confirmed HIV-positive patients had successful linkage to care. Implementation of fourth-generation HIV instrument-based testing resulted in a 15.0% decline in weekly HIV testing rates. Displacement of nursing provider HIV test offers from triage to the bedside resulted in a 31.6% decline in weekly HIV testing rates.
Conclusion
This program demonstrated the capacity for high-volume, routine, opt-out HIV screening. Evolving ED challenges require program monitoring and adaptation to sustain scalable HIV screening in EDs.
PMCID: PMC4720611  PMID: 26862235
5.  Influence of resveratrol release on the tissue response to mechanically adaptive cortical implants 
Acta biomaterialia  2015;29:81-93.
The stability and longevity of recordings obtained from intracortical microelectrodes continues to remain an area of concern for neural interfacing applications. The limited longevity of microelectrode performance has been associated with the integrity of the blood brain barrier (BBB) and the neuroinflammatory response to the microelectrode. Here, we report the investigation of an additive approach that targets both mechanical and chemical factors believed to contribute to chronic BBB instability and the neuroinflammatory response associated with implanted intracortical microelectrodes. The implants investigated were based on a mechanically adaptive, compliant nanocomposite (NC), which reduces the tissue response and tissue strain. This material was doped with various concentrations of the antioxidant resveratrol with the objective of local and rapid delivery. In vitro analysis of resveratrol release, antioxidant activity, and cytotoxicity suggested that a resveratrol content of 0.01% was optimal for in vivo assessment. Thus, probes made from the neat NC reference and probes containing resveratrol (NC Res) were implanted into the cortical tissue of rats for up to sixteen weeks. Histochemical analysis suggested that at three days post-implantation, neither materials nor therapeutic approaches (independently or in combination) could alter the initial wound healing response. However, at two weeks post-implantation, the NC Res implant showed a reduction in activated microglia/macrophages and improvement in neuron density at the tissue-implant interface when compared to the neat NC reference. However, sixteen weeks post-implantation, when the antioxidant was exhausted, NC Res and the neat NC reference exhibited similar tissue responses. The data show that NC Res provides short-term, short-lived benefits due to the antioxidant release, and a long-term reduction in neuroinflammation on account of is mechanical adaptive, compliant nature. Together, these results demonstrate that local delivery of resveratrol can provide an additive advantage by providing a consistent reduction in the tissue response.
doi:10.1016/j.actbio.2015.11.001
PMCID: PMC4727752  PMID: 26553391
Resveratrol; Mechanically adaptive nanocomposite; Intracortical microelectrodes; Neuroinflammation
6.  Current Concepts in Hip Preservation Surgery 
Sports Health  2016;8(1):57-64.
Context:
Successful treatment of nonarthritic hip pain in young athletic individuals remains a challenge. A growing fund of clinical knowledge has paralleled technical innovations that have enabled hip preservation surgeons to address a multitude of structural variations of the proximal femur and acetabulum and concomitant intra-articular joint pathology. Often, a combination of open and arthroscopic techniques are necessary to treat more complex pathomorphologies. Peri- and postoperative recovery after such procedures can pose a substantial challenge to the patient, and a dedicated, thoughtful approach may reduce setbacks, limit morbidity, and help optimize functional outcomes.
Evidence Acquisition:
PubMed and CINAHL databases were searched to identify relevant scientific and review articles through December 2014 using the search terms hip preservation, labrum, surgical dislocation, femoroacetabular impingement, postoperative rehabilitation, peri-acetabular osteotomy, and rotational osteotomy. Reference lists of included articles were reviewed to locate additional references of interest.
Study Design:
Clinical review.
Level of Evidence:
Level 4.
Results:
Hip preservation procedures and appropriate rehabilitation have allowed individuals to return to a physically active lifestyle.
Conclusion:
Effective postoperative rehabilitation must consider modifications and precautions specific to the particular surgical techniques used. Proper postoperative rehabilitation after hip preservation surgery may help optimize functional recovery and maximize clinical success and patient satisfaction.
doi:10.1177/1941738115577621
PMCID: PMC4702152  PMID: 26733593
hip preservation; periacetabular osteotomy; surgical dislocation; labrum; rehabilitation
7.  Assessing the Everyday Discrimination Scale Among American Indians and Alaska Natives 
Psychological assessment  2015;28(1):51-58.
The Everyday Discrimination Scale (EDS) has been used widely as a measure of subjective experiences of discrimination. The usefulness of this measure for assessments of perceived experiences of discrimination by American Indian and Alaska Native (AI/AN) peoples has not been explored. Data derived from the Special Diabetes Program for Indians – Healthy Heart Demonstration Project (SDPI-HH), a large-scale initiative to reduce cardiovascular risk among AI/ANs with Type 2 diabetes. Participants (N=3,039) completed a self-report survey that included the EDS and measures of convergent and divergent validity. Missing data were estimated by multiple imputation techniques. Reliability estimates for the EDS were calculated, yielding a single factor with high internal consistency (α=0.92). Younger, more educated respondents reported greater perceived discrimination; retired or widowed respondents reported less. Convergent validity was evidenced by levels of distress, anger, and hostility, which increased as the level of perceived discrimination increased (all p<0.001). Divergent validity was evidenced by the absence of an association between EDS and resilient coping. Resilient coping and insulin-specific diabetes knowledge were not significantly associated with perceived discrimination (p=0.61 and 0.16, respectively). However, general diabetes-related health knowledge was significantly associated with perceived discrimination (p=0.02). The EDS is a promising measure for assessing perceived experiences of discrimination among those AI/ANs who participated in the SDPI-HH.
doi:10.1037/a0039337
PMCID: PMC4703564  PMID: 26146948
perceived discrimination; American Indian; Alaska Native; Everyday Discrimination Scale; validity; diabetes
8.  An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis 
Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a Kb of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3–20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30–240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists.
doi:10.1124/jpet.116.236372
PMCID: PMC5193077  PMID: 27811173
9.  Genetic and environmental influences on adult human height across birth cohorts from 1886 to 1994 
Jelenkovic, Aline | Hur, Yoon-Mi | Sund, Reijo | Yokoyama, Yoshie | Siribaddana, Sisira H | Hotopf, Matthew | Sumathipala, Athula | Rijsdijk, Fruhling | Tan, Qihua | Zhang, Dongfeng | Pang, Zengchang | Aaltonen, Sari | Heikkilä, Kauko | Öncel, Sevgi Y | Aliev, Fazil | Rebato, Esther | Tarnoki, Adam D | Tarnoki, David L | Christensen, Kaare | Skytthe, Axel | Kyvik, Kirsten O | Silberg, Judy L | Eaves, Lindon J | Maes, Hermine H | Cutler, Tessa L | Hopper, John L | Ordoñana, Juan R | Sánchez-Romera, Juan F | Colodro-Conde, Lucia | Cozen, Wendy | Hwang, Amie E | Mack, Thomas M | Sung, Joohon | Song, Yun-Mi | Yang, Sarah | Lee, Kayoung | Franz, Carol E | Kremen, William S | Lyons, Michael J | Busjahn, Andreas | Nelson, Tracy L | Whitfield, Keith E | Kandler, Christian | Jang, Kerry L | Gatz, Margaret | Butler, David A | Stazi, Maria A | Fagnani, Corrado | D'Ippolito, Cristina | Duncan, Glen E | Buchwald, Dedra | Derom, Catherine A | Vlietinck, Robert F | Loos, Ruth JF | Martin, Nicholas G | Medland, Sarah E | Montgomery, Grant W | Jeong, Hoe-Uk | Swan, Gary E | Krasnow, Ruth | Magnusson, Patrik KE | Pedersen, Nancy L | Dahl-Aslan, Anna K | McAdams, Tom A | Eley, Thalia C | Gregory, Alice M | Tynelius, Per | Baker, Laura A | Tuvblad, Catherine | Bayasgalan, Gombojav | Narandalai, Danshiitsoodol | Lichtenstein, Paul | Spector, Timothy D | Mangino, Massimo | Lachance, Genevieve | Bartels, Meike | van Beijsterveldt, Toos CEM | Willemsen, Gonneke | Burt, S Alexandra | Klump, Kelly L | Harris, Jennifer R | Brandt, Ingunn | Nilsen, Thomas Sevenius | Krueger, Robert F | McGue, Matt | Pahlen, Shandell | Corley, Robin P | Hjelmborg, Jacob v B | Goldberg, Jack H | Iwatani, Yoshinori | Watanabe, Mikio | Honda, Chika | Inui, Fujio | Rasmussen, Finn | Huibregtse, Brooke M | Boomsma, Dorret I | Sørensen, Thorkild I A | Kaprio, Jaakko | Silventoinen, Karri
eLife  null;5:e20320.
Human height variation is determined by genetic and environmental factors, but it remains unclear whether their influences differ across birth-year cohorts. We conducted an individual-based pooled analysis of 40 twin cohorts including 143,390 complete twin pairs born 1886–1994. Although genetic variance showed a generally increasing trend across the birth-year cohorts, heritability estimates (0.69-0.84 in men and 0.53-0.78 in women) did not present any clear pattern of secular changes. Comparing geographic-cultural regions (Europe, North America and Australia, and East Asia), total height variance was greatest in North America and Australia and lowest in East Asia, but no clear pattern in the heritability estimates across the birth-year cohorts emerged. Our findings do not support the hypothesis that heritability of height is lower in populations with low living standards than in affluent populations, nor that heritability of height will increase within a population as living standards improve.
DOI: http://dx.doi.org/10.7554/eLife.20320.001
doi:10.7554/eLife.20320
PMCID: PMC5156525  PMID: 27964777
height; twins; heritability; birth cohorts; CODATwins project; Human
10.  Human Stem Cell-like Memory T Cells Are Maintained in a State of Dynamic Flux 
Cell Reports  2016;17(11):2811-2818.
Summary
Adaptive immunity requires the generation of memory T cells from naive precursors selected in the thymus. The key intermediaries in this process are stem cell-like memory T (TSCM) cells, multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. In theory, antigen specificity within the TSCM pool may be imprinted statically as a function of largely dormant cells and/or retained dynamically by more transitory subpopulations. To explore the origins of immunological memory, we measured the turnover of TSCM cells in vivo using stable isotope labeling with heavy water. The data indicate that TSCM cells in both young and elderly subjects are maintained by ongoing proliferation. In line with this finding, TSCM cells displayed limited telomere length erosion coupled with high expression levels of active telomerase and Ki67. Collectively, these observations show that TSCM cells exist in a state of perpetual flux throughout the human lifespan.
Graphical Abstract
Highlights
•Human stem cell-like memory T (TSCM) cells proliferate extensively in vivo•Human TSCM cells express high levels of Ki67•Human TSCM cells have long telomeres•Human TSCM cells display high levels of telomerase activity
Stem cell-like memory T (TSCM) cells are multipotent progenitors that can both self-renew and replenish more differentiated subsets of memory T cells. Ahmed et al. find that human TSCM cells are maintained by ongoing proliferation and display limited telomere length erosion coupled with high expression levels of active telomerase and Ki67.
doi:10.1016/j.celrep.2016.11.037
PMCID: PMC5186732  PMID: 27974195
adaptive immunity; memory T cells; stem cell-like memory T cells; CD4+ T cells; CD8+ T cells; in vivo heavy water labeling; proliferation; telomere length; telomerase activity; memory T cell maintenance
11.  Tennessee’s 3-Star Report: Using Available Data Systems to Reduce Missed Opportunities to Vaccinate Preteens 
Biomedical Informatics Insights  2016;8(Suppl 2):15-21.
All preteens should receive tetanus–diphtheria–pertussis vaccine (Tdap), quadrivalent meningococcal vaccine (Men-ACWY), and the human papillomavirus (HPV) cancer vaccine series. In Tennessee, HPV vaccination rates have stagnated at low levels for a decade. Three fundamental strategies to reduce missed opportunities for immunization include administering all recommended vaccines at the same visit, making strong recommendations for vaccines, and auditing and feedback. In Tennessee, during each summer, a surge of preteens visit local health departments (LHDs) to receive a required Tdap vaccine before entering seventh grade, presenting an opportunity to administer Men-ACWY and HPV. The Tennessee Immunization Program (TIP) coined the term “3-Star visit” for such encounters and developed a monthly report to track them using data from the Patient Tracking Billing Management Information System (PTBMIS) used by LHDs across Tennessee. Implementation of this quality improvement report has correlated with a substantial increase in 3-Star visits from 2013 to 2016, particularly during the summer months.
doi:10.4137/BII.S40207
PMCID: PMC5138065  PMID: 27980415
adolescent immunization; HPV vaccine; public health; information systems; quality improvement
12.  Interaction between Nitrogen and Phosphate Stress Responses in Sinorhizobium meliloti 
Bacteria have developed various stress response pathways to improve their assimilation and allocation of limited nutrients, such as nitrogen and phosphate. While both the nitrogen stress response (NSR) and phosphate stress response (PSR) have been studied individually, there are few experiments reported that characterize effects of multiple stresses on one or more pathways in Sinorhizobium meliloti, a facultatively symbiotic, nitrogen-fixing bacteria. The PII proteins, GlnB and GlnK, regulate the NSR activity, but analysis of global transcription changes in a PII deficient mutant suggest that the S. meliloti PII proteins may also regulate the PSR. PII double deletion mutants grow very slowly and pseudoreversion of the slow growth phenotype is common. To understand this phenomenon better, transposon mutants were isolated that had a faster growing phenotype. One mutation was in phoB, the response regulator for a two component regulatory system that is important in the PSR. phoB::Tn5 mutants had different phenotypes in the wild type compared to a PII deficient background. This led to the hypothesis that phosphate stress affects the NSR and conversely, that nitrogen stress affects the PSR. Our results show that phosphate availability affects glutamine synthetase activity and expression, which are often used as indicators of NSR activity, but that nitrogen availability did not affect alkaline phosphatase activity and expression, which are indicators of PSR activity. We conclude that the NSR is co-regulated by nitrogen and phosphate, whereas the PSR does not appear to be co-regulated by nitrogen in addition to its known phosphate regulation.
doi:10.3389/fmicb.2016.01928
PMCID: PMC5127829  PMID: 27965651
nitrogen stress; phosphate stress; glutamine synthetase; alkaline phosphatase; PII nitrogen regulatory proteins; Phob
13.  Evaluation of a Teaching Assistant Program for Third-Year Pharmacy Students 
Objectives. To determine if a teaching assistant (TA) program for third-year pharmacy students (PY3s) improves confidence in teaching abilities. Additionally, 3 assessment methods (faculty, student, and TA self-evaluations) were compared for similarities and correlations.
Methods. An application and interview process was used to select 21 pharmacy students to serve as TAs for the Pharmaceutical Care Laboratory course for 2 semesters. Participants’ self-perceived confidence in teaching abilities was assessed at the start, midpoint, and conclusion of the program. The relationships between the scores were analyzed using 3 assessment methods.
Results. All 21 TAs agreed to participate in the study and completed the 2 teaching semesters. The TAs confidence in overall teaching abilities increased significantly (80.7 vs 91.4, p<0.001). There was a significant difference between the three assessment scores in the fall (p=0.027) and spring (p<0.001) semesters. However, no correlation was found among the assessment scores.
Conclusions. The TA program was effective in improving confidence in teaching abilities. The lack of correlation among the assessment methods highlights the importance of various forms of feedback.
doi:10.5688/ajpe809149
PMCID: PMC5222740  PMID: 28090098
teaching assistants; teaching evaluations; skills lab; pharmacy education
14.  Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages 
Scientific Reports  2016;6:36928.
The extracellular matrix glycosaminoglycan, hyaluronan, has been described as a regulator of tissue inflammation, with hyaluronan fragments reported to stimulate innate immune cells. High molecular mass hyaluronan is normally present in tissues, but upon inflammation lower molecular mass fragments are generated. It is unclear if these hyaluronan fragments induce an inflammatory response or are a consequence of inflammation. In this study, mouse bone marrow derived macrophages and dendritic cells (DCs) were stimulated with various sizes of hyaluronan from different sources, fragmented hyaluronan, hyaluronidases and heavy chain modified-hyaluronan (HA-HC). Key pro-inflammatory molecules, tumour necrosis factor alpha, interleukin-1 beta, interleukin-12, CCL3, and the co-stimulatory molecules, CD40 and CD86 were measured. Only human umbilical cord hyaluronan, bovine testes and Streptomyces hyaluronlyticus hyaluronidase stimulated macrophages and DCs, however, these reagents were found to be contaminated with endotoxin, which was not fully removed by polymyxin B treatment. In contrast, pharmaceutical grade hyaluronan and hyaluronan fragments failed to stimulate in vitro-derived or ex vivo macrophages and DCs, and did not induce leukocyte recruitment after intratracheal instillation into mouse lungs. Hence, endotoxin-free pharmaceutical grade hyaluronan does not stimulate macrophages and DCs in our inflammatory models. These results emphasize the importance of ensuring hyaluronan preparations are endotoxin free.
doi:10.1038/srep36928
PMCID: PMC5116629  PMID: 27869206
15.  Caspase-Dependent Degradation of MDMx/MDM4 Cell Cycle Regulatory Protein in Amyloid β-induced Neuronal Damage 
Neuroscience letters  2015;609:182-188.
MDMx/MDM4 is a negative regulator of the p53 tumor suppressor protein and is necessary for survival in dividing cells. MDMx is also expressed in postmitotic neurons, with prosurvival roles that are independent of its extensively described roles in carcinogenesis. We and others have shown a role for MDMx loss in neuronal death in vitro and in vivo in several neurodegenerative diseases. Further, we have recently shown that MDMx is targeted for proteolytic degradation by calcium-dependent proteases, calpains, in neurons in vitro, and that MDMx overexpression provided partial neuroprotection in a model of HIV-associated neurodegeneration. Here, we assessed whether amyloid β (Aβ)-induced MDMx degradation occurred in Alzheimer’s Disease (AD) models. Our data shows an age-dependent reduction in MDMx levels in cholinergic neurons within the cortex of adult mice expressing the swedish mutant of the amyloid precursor protein, APP in the Tg2576 murine model of AD. In vitro, Aβ treatment of primary cortical neurons led to the caspase-dependent MDMx degradation. Our findings suggest that MDMx degradation associated with neuronal death occurs via caspase activation in neurons, and that the progressive loss of MDMx protein represents a potential mechanism of Aβ-induced neuronal death during disease progression in AD.
doi:10.1016/j.neulet.2015.10.031
PMCID: PMC4679561  PMID: 26477779
MDMx; MDM4; Alzheimer’s Disease; amyloid β; caspase
16.  NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice 
Cell reports  2016;16(7):1851-1860.
SUMMARY
Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle, and adipose tissue dysfunction, manifested by increased plasma free fatty acids concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. Remarkably, these deleterious alterations were normalized by administering rosiglitazone or a key NAD+ intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance.
doi:10.1016/j.celrep.2016.07.027
PMCID: PMC5094180  PMID: 27498863
Adipocyte; NAMPT; NAD+; insulin resistance; obesity; PPARγ
17.  Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Anti-Retrovirals in HIV-Associated Neurocognitive Disorders 
Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals suffer from HIV-Associated Neurocognitive Disorders (HAND). Studies of antiretroviral treated patients have revealed persistent white matter pathologies including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction as the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance. We hypothesized that myelin changes in HAND are partly due to effects of antiretroviral drugs on oligodendrocyte survival and/or maturation. We showed that primary mouse oligodendrocyte precursor cell cultures treated with therapeutic concentrations of HIV protease inhibitors Ritonavir or Lopinavir displayed dose-dependent decreases in oligodendrocyte maturation; however, this effect was rapidly reversed following drug removal. Conversely, nucleoside reverse transcriptase inhibitor Zidovudine had no effect. Furthermore, in vivo Ritonavir administration to adult mice reduced frontal cortex myelin protein levels. Finally, prefrontal cortex tissue from HIV-positive individuals with HAND on cART showed a significant decrease in myelin basic protein compared with untreated HIV-positive individuals with HAND or HIV-negative controls. These findings demonstrate that antiretrovirals can impact myelin integrity, and have implications for myelination in juvenile HIV patients, and myelin maintenance in adults on lifelong therapy.
doi:10.1097/NEN.0000000000000255
PMCID: PMC4608376  PMID: 26469251
Antiretroviral; oligodendrocyte; myelin; HIV; HIV-Associated Neurocognitive Disorders; pediatric AIDS; Protease Inhibitor
18.  Current Concepts in Hip Preservation Surgery 
Sports Health  2015;7(6):518-526.
Context:
An evolution in conceptual understanding, coupled with technical innovations, has enabled hip preservation surgeons to address complex pathomorphologies about the hip joint to reduce pain, optimize function, and potentially increase the longevity of the native hip joint. Technical aspects of hip preservation surgeries are diverse and range from isolated arthroscopic or open procedures to hybrid procedures that combine the advantages of arthroscopy with open surgical dislocation, pelvic and/or proximal femoral osteotomy, and biologic treatments for cartilage restoration.
Evidence Acquisition:
PubMed and CINAHL databases were searched to identify relevant scientific and review articles from January 1920 to January 2015 using the search terms hip preservation, labrum, surgical dislocation, femoroacetabular impingement, peri-acetabular osteotomy, and rotational osteotomy. Reference lists of included articles were reviewed to locate additional references of interest.
Study Design:
Clinical review.
Level of Evidence:
Level 4.
Results:
Thoughtful individualized surgical procedures are available to optimize the femoroacetabular joint in the presence of hip dysfunction.
Conclusion:
A comprehensive understanding of the relationship between femoral and pelvic orientation, morphology, and the development of intra-articular abnormalities is necessary to formulate a patient-specific approach to treatment with potential for a successful long-term result.
doi:10.1177/1941738115587270
PMCID: PMC4622374  PMID: 26502445
hip preservation; peri-acetabular osteotomy; surgical dislocation; labrum; arthroscopy
19.  Changes in Genetic Risk for Emotional Eating across the Menstrual Cycle: A Longitudinal Study 
Psychological medicine  2015;45(15):3227-3237.
Background
Previous studies show significant within-person changes in binge eating and emotional eating across the menstrual cycle, with substantial increases in both phenotypes during post-ovulation. Increases in both estradiol and progesterone levels appear to account for these changes in phenotypic risk, possibly via increases in genetic effects. However, to date, no study has examined changes in genetic risk for binge phenotypes (or any other phenotype) across the menstrual cycle. The goal of the present study was to examine within-person changes in genetic risk for emotional eating scores across the menstrual cycle.
Methods
Participants were 230 female twin pairs (460 twins) from the Michigan State University Twin Registry (MSUTR) who completed daily measures of emotional eating for 45 consecutive days. Menstrual cycle phase was coded based on dates of menstrual bleeding and daily ovarian hormone levels.
Results
Findings revealed important shifts in genetic and environmental influences, where estimates of genetic influences were two times higher in post- as compared to pre-ovulation. Surprisingly, pre-ovulation was marked by a predominance of environmental influences, including shared environmental effects which have not been previously detected for binge eating phenotypes in adulthood.
Conclusions
Our study was the first to examine within-person shifts in genetic and environmental influences on a behavioral phenotype across the menstrual cycle. Results highlight a potentially critical role for these shifts in risk for emotional eating across the menstrual cycle and underscore the need for additional, large-scale studies to identify the genetic and environmental factors contributing to menstrual cycle effects.
doi:10.1017/S0033291715001221
PMCID: PMC4631616  PMID: 26174083
Emotional eating; genetic; environmental; menstrual cycle; ovarian hormones
20.  Item Banks for Substance Use from the Patient-Reported Outcomes Measurement Information System (PROMIS®): Severity of Use and Positive Appeal of Use* 
Drug and alcohol dependence  2015;156:184-192.
Background
Two item banks for substance use were developed as part of the Patient-Reported Outcomes Measurement Information System (PROMIS®): severity of substance use and positive appeal of substance use.
Methods
Qualitative item analysis (including focus groups, cognitive interviewing, expert review, and item revision) reduced an initial pool of more than 5,300 items for substance use to 119 items included in field testing. Items were written in a first-person, past-tense format, with 5 response options reflecting frequency or severity. Both 30-day and 3-month time frames were tested. The calibration sample of 1,336 respondents included 875 individuals from the general population (ascertained through an internet panel) and 461patients from addiction treatment centers participating in the National Drug Abuse Treatment Clinical Trials Network.
Results
Final banks of 37 and 18 items were calibrated for severity of substance use and positive appeal of substance use, respectively, using the two-parameter graded response model from item response theory (IRT). Initial calibrations were similar for the 30-day and 3-month time frames, and final calibrations used data combined across the time frames, making the items applicable with either interval. Seven-item static short forms were also developed from each item bank.
Conclusions
Test information curves showed that the PROMIS item banks provided substantial information in a broad range of severity, making them suitable for treatment, observational, and epidemiological research in both clinical and community settings.
doi:10.1016/j.drugalcdep.2015.09.008
PMCID: PMC4633351  PMID: 26423364
substance use; drug use; item response theory; measurement
21.  Intramuscular Heating Characteristics of Multihour Low-Intensity Therapeutic Ultrasound 
Journal of Athletic Training  2015;50(11):1158-1164.
Context
The heating characteristics of a stationary device delivering sustained acoustic medicine with low-intensity therapeutic ultrasound (LITUS) are unknown.
Objective
To measure intramuscular (IM) heating produced by a LITUS device developed for long-duration treatment of musculoskeletal injuries.
Design
Controlled laboratory study.
Setting
University research laboratory.
Patients or Other Participants
A total of 26 healthy volunteers (16 men, 10 women; age = 23.0 ± 2.1 years, height = 1.74 ± 0.09 m, mass = 73.48 ± 14.65 kg).
Intervention(s)
Participants were assigned randomly to receive active (n = 20) or placebo (n = 6) LITUS at a frequency of 3 MHz and an energy intensity of 0.132 W/cm2 continuously for 3 hours with a single transducer or dual transducers on the triceps surae muscle. We measured IM temperature using thermocouples inserted at 1.5- and 3-cm depths into muscle. Temperatures were recorded throughout treatment and 30 minutes posttreatment.
Main Outcome Measure(s)
We used 2-sample t tests to determine the heating curve of the LITUS treatment and differences in final temperatures between depth and number of transducers.
Results
A mild IM temperature increase of 1°C was reached 10 ± 5 minutes into the treatment, and a more vigorous temperature increase of 4°C was reached 80 ± 10 minutes into the treatment. The maximal steady-state IM temperatures produced during the final 60 minutes of treatment at the 1.5-cm depth were 4.42°C ± 0.08°C and 3.92°C ± 0.06°C using 1 and 2 transducers, respectively. At the 3.0-cm depth, the maximal steady-state IM temperatures during the final 60 minutes of treatment were 3.05°C ± 0.09°C and 3.17°C ± 0.05°C using 1 and 2 transducers, respectively. We observed a difference between the temperatures measured at each depth (t78 = −2.45, P = .02), but the number of transducers used to generate heating was not different (t78 = 1.79, P = .08).
Conclusions
The LITUS device elicited tissue heating equivalent to traditional ultrasound but could be sustained for multiple hours. It is a safe and effective alternative tool for delivering therapeutic ultrasound and exploring dosimetry for desired physiologic responses.
doi:10.4085/1062-6050-50.11.03
PMCID: PMC4732395  PMID: 26509683
therapeutic modalities; tissue temperature; rehabilitation
22.  Wolbachia endosymbionts induce neutrophil extracellular trap formation in human onchocerciasis 
Scientific Reports  2016;6:35559.
The endosymbiotic bacteria, Wolbachia, induce neutrophilic responses to the human helminth pathogen Onchocerca volvulus. The formation of Neutrophil Extracellular Traps (NETs), has been implicated in anti-microbial defence, but has not been identified in human helminth infection. Here, we demonstrate NETs formation in human onchocerciasis. Extracellular NETs and neutrophils were visualised around O. volvulus in nodules excised from untreated patients but not in nodules from patients treated with the anti-Wolbachia drug, doxycycline. Whole Wolbachia or microspheres coated with a synthetic Wolbachia lipopeptide (WoLP) of the major nematode Wolbachia TLR2/6 ligand, peptidoglycan associated lipoprotein, induced NETosis in human neutrophils in vitro. TLR6 dependency of Wolbachia and WoLP NETosis was demonstrated using purified neutrophils from TLR6 deficient mice. Thus, we demonstrate for the first time that NETosis occurs during natural human helminth infection and demonstrate a mechanism of NETosis induction via Wolbachia endobacteria and direct ligation of Wolbachia lipoprotein by neutrophil TLR2/6.
doi:10.1038/srep35559
PMCID: PMC5067710  PMID: 27752109
23.  Autosomal Dominant Hypocalcemia (Hypoparathyroidism) Types 1 and 2 
Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR), expressed on the surface of parathyroid cells. In response to low ionized calcium, the parathyroids increase secretion of parathyroid hormone (PTH) which increases serum calcium. The CASR is also highly expressed in the kidneys, where it regulates the reabsorption of calcium from the primary filtrate. Autosomal dominant hypocalcemia (ADH) type 1 is caused by heterozygous activating mutations in the CASR which increase the sensitivity of the CASR to extracellular ionized calcium. Consequently, PTH synthesis and secretion are suppressed at normal ionized calcium concentrations. Patients present with hypocalcemia, hyperphosphatemia, low magnesium levels, and low or low-normal levels of PTH. Urinary calcium excretion is typically increased due to the decrease in circulating PTH concentrations and by the activation of the renal tubular CASR. Therapeutic attempts using CASR antagonists (calcilytics) to treat ADH are currently under investigation. Recently, heterozygous mutations in the alpha subunit of the G protein G11 (Gα11) have been identified in patients with ADH, and this has been classified as ADH type 2. ADH2 mutations lead to a gain-of-function of Gα11, a key mediator of CASR signaling. Therefore, the mechanism of hypocalcemia appears similar to that of activating mutations in the CASR, namely an increase in the sensitivity of parathyroid cells to extracellular ionized calcium. Studies of activating mutations in the CASR and gain-of-function mutations in Gα11 can help define new drug targets and improve medical management of patients with ADH types 1 and 2.
doi:10.3389/fphys.2016.00458
PMCID: PMC5067375  PMID: 27803672
autosomal-dominant hypocalcemia; CASR; calcium metabolism; GNA11; G11; calcilytics; YM254890; hypocalcemia
24.  Near Point of Convergence After a Sport-Related Concussion 
Background
Convergence insufficiency (CI) is a common binocular vision deficit after a sport-related concussion (SRC). CI may result in visual discomfort and vision-mediated functional difficulties such as slowed reading and compromised attention, leading to impaired academic, work, and sport performance.
Purpose
To test the reliability of repeated near point of convergence (NPC) measurements in a sample of athletes after an SRC; compare the symptoms and cognitive impairment of athletes with normal NPC to those with CI after an SRC; and explore the relationship among age, sex, learning disability, migraine history, and CI.
Study Design
Cross-sectional study; Level of evidence, 3.
Methods
A total of 78 athletes (mean age, 14.31 ± 2.77 years) who were seen a mean 5.79 ± 5.63 days after an SRC were administered 3 trials of an NPC assessment, along with neurocognitive (Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT]) and symptom assessments. Patients were divided into normal NPC (NPC ≤5 cm; n = 45) and CI (NPC >5 cm; n = 33) groups. Intraclass correlation coefficients (ICCs) and repeated-measures analyses of variance (ANOVAs) assessed the consistency of NPC across the 3 trials. The ANOVAs were employed to examine differences on neurocognitive composites and symptoms between the normal NPC and CI groups. Stepwise regressions (controlling for age and symptom scores on the Post-Concussion Symptom Scale [PCSS]) were conducted to evaluate the predictive utility of the NPC distance for neurocognitive impairment.
Results
Groups did not differ on demographic or injury characteristics. NPC differed between trial 1 and trials 2 (P = .02) and 3 (P = .01) for the CI group but not the normal NPC group. Internal consistency was high across NPC measurements (ICC range, 0.95–0.98). Patients with CI performed worse on verbal memory (P = .02), visual motor speed (P = .02), and reaction time (P = .001, η2 = .13) and had greater total symptom scores (P = .02) after the injury. Results of hierarchical regression revealed that the NPC distance contributed significantly to the model for reaction time (P < .001).
Conclusion
CI was common (~42%) in athletes evaluated within 1 month after an SRC. Athletes with CI had worse neurocognitive impairment and higher symptom scores than did those with normal NPC. Clinicians should consider routinely screening for NPC as part of a comprehensive concussion evaluation to help inform treatment recommendations, academic accommodations, and referrals for vision therapy.
doi:10.1177/0363546515606430
PMCID: PMC5067104  PMID: 26453625
concussion; eye injuries; convergence insufficiency; neurocognitive impairment
25.  Coexistent Pseudogout and Mycobacterium avium-intracellulare Septic Arthritis in a Patient with HIV and ESRD 
Case Reports in Rheumatology  2016;2016:5495928.
Pseudogout is a crystal-induced arthropathy characterized by the deposition of calcium pyrophosphate dihydrate (CPPD) crystals in synovial fluid, menisci, or articular cartilage. Although not very common, this entity can be seen in patients with chronic kidney disease (CKD). Septic arthritis due to Mycobacterium avium-intracellulare (MAI) is a rare entity that can affect immunocompromised patients such as those with acquired immunodeficiency syndrome (AIDS) or those who are on immunosuppressive drugs. Here, we describe a 51-year-old female who presented with fever, right knee pain, swelling, warmth, and decreased range of motion for several days. The initial assessment was consistent with pseudogout, with negative bacterial and fungal cultures. However, due to high white blood cell (WBC) count in the synovial fluid analysis, she was empirically started on intravenous (IV) vancomycin and piperacillin-tazobactam and discharged on IV vancomycin and cefepime, while acid-fast bacilli (AFB) culture was still in process. Seventeen days later, AFB culture grew Mycobacterium avium-intracellulare (MAI), and she was readmitted for relevant management. This case illustrates that septic arthritis due to MAI should be considered in the differential diagnosis of septic arthritis in immunocompromised patients.
doi:10.1155/2016/5495928
PMCID: PMC5075596  PMID: 27803833

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