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1.  Higher Educational Attainment but not Higher Income is Protective for Cardiovascular Risk in Deaf American Sign Language (ASL) Users 
Disability and health journal  2013;7(1):49-55.
Higher educational attainment and income provide cardiovascular protection in the general population. It is unknown if the same effect is seen among Deaf American Sign Language (ASL) users who face communication barriers in healthcare settings.
We sought to examine whether educational attainment and/or annual household income were inversely associated with cardiovascular risk in a sample of Deaf ASL users.
This cross-sectional study included 302 Deaf respondents aged 18-88 years from the Deaf Health Survey (2008), an adapted and translated Behavioral Risk Factor Surveillance System (BRFSS) administered in sign language. Associations between the self-reported cardiovascular disease equivalents (CVDE; any of the following: diabetes, myocardial infarction (MI), cerebral vascular attack (CVA), and angina) with educational attainment (≤high school [low education], some college, and ≥4 year college degree [referent]), and annual household income (<$25,000, $25,000-<$50,000, or ≥$50,000 [referent]) were assessed using a multivariate logistic regression adjusting for age, sex, race/ethnicity, and smoking history.
Deaf respondents who reported ≤high school education were more likely to report the presence of a CVDE (OR 5.92; 95% CI 2.12-16.57) compared to Deaf respondents who reported having ≥4 year college degree after adjustment. However, low-income Deaf individuals (i.e. household incomes <$25,000) were not more likely to report the presence of a CVDE (OR=2.24; 95% CI 0.76-6.68) compared to high-income Deaf respondents after adjustment.
Low educational attainment was associated with higher likelihood of reported cardiovascular equivalents among Deaf individuals. Higher income did not appear to provide a cardiovascular protective effect for Deaf respondents.
PMCID: PMC3893794  PMID: 24411507
Deaf; cardiovascular health; education; income; health disparities
4.  A Cell Culture Substrate with Biologically Relevant Size-Scale Topography and Compliance of the Basement Membrane 
Langmuir  2014;30(8):2101-2108.
A growing body of literature broadly documents that a wide array of fundamental cell behaviors are modulated by the physical attributes of the cellular microenvironment, yet in vitro assays are typically carried out using tissue culture plastic or glass substrates that lack the 3-dimensional topography present in vivo and have stiffness values that far exceed that of cellular and stromal microenvironments. This work presents a method for the fabrication of thin hydrogel films that can replicate arbitrary topographies with a resolution of 400 nm that possess an elastic modulus of approximately 250 kPa. Material characterization including swelling behavior and mechanics were performed and reported. Cells cultured on these surfaces patterned with anisotropic ridges and grooves react to the biophysical cues present and show an alignment response.
PMCID: PMC3983385  PMID: 24524303
5.  Antibodies VRC01 and 10E8 neutralize HIV-1 with high breadth and potency even with immunoglobulin-framework regions substantially reverted to germline 
Antibodies capable of effectively neutralizing HIV-1 generally exhibit very high levels of somatic hypermutation, both in their complementarity-determining and framework-variable regions. In many cases, full reversion of the antibody framework mutations back to germline has been shown to result in substantial to complete loss of HIV-1 neutralizing activity. However, it is currently not known whether all or most of the observed framework mutations are necessary, or whether a small subset of these mutations may be sufficient for broad and potent neutralization. To address this issue and to explore the dependence of neutralization activity on the level of somatic hypermutation in antibody framework, we applied a computationally guided framework reversion procedure to two broadly neutralizing anti-HIV-1 antibodies, VRC01 and 10E8, which target two different HIV-1 sites of vulnerability. Antibody variants in which up to 78% (38 out of 49 for VRC01) and 89% (31 out of 35 for 10E8) of framework mutations were reverted to germline retained breadth and potency within 3-fold of the mature antibodies when evaluated on a panel of 21-diverse viral strains. Further, a VRC01 variant with a ~50% framework-reverted light chain showed a 2-fold improvement in potency over the mature antibody. Our results indicate that only a small number of antibody-framework mutations may be sufficient for high breadth and potency of HIV-1 neutralization by antibodies VRC01 and 10E8. Partial framework revertants of HIV-1 broadly neutralizing antibodies may present advantages over their highly mutated counterparts as antibody therapeutics and as targets for immunogen design.
PMCID: PMC4140862  PMID: 24391217
6.  Classification of Bartonella Strains Associated with Straw-Colored Fruit Bats (Eidolon helvum) across Africa Using a Multi-locus Sequence Typing Platform 
PLoS Neglected Tropical Diseases  2015;9(1):e0003478.
Bartonellae are facultative intracellular bacteria and are highly adapted to their mammalian host cell niches. Straw-colored fruit bats (Eidolon helvum) are commonly infected with several bartonella strains. To elucidate the genetic diversity of these bartonella strains, we analyzed 79 bartonella isolates from straw-colored fruit bats in seven countries across Africa (Cameroon, Annobon island of Equatorial Guinea, Ghana, Kenya, Nigeria, Tanzania, and Uganda) using a multi-locus sequencing typing (MLST) approach based on nucleotide sequences of eight loci (ftsZ, gltA, nuoG, ribC, rpoB, ssrA, ITS, and 16S rRNA). The analysis of each locus but ribC demonstrated clustering of the isolates into six genogroups (E1 – E5 and Ew), while ribC was absent in the isolates belonging to the genogroup Ew. In general, grouping of all isolates by each locus was mutually supportive; however, nuoG, gltA, and rpoB showed some incongruity with other loci in several strains, suggesting a possibility of recombination events, which were confirmed by network analyses and recombination/mutation rate ratio (r/m) estimations. The MLST scheme revealed 45 unique sequence types (ST1 – 45) among the analyzed bartonella isolates. Phylogenetic analysis of concatenated sequences supported the discrimination of six phylogenetic lineages (E1 – E5 and Ew) corresponding to separate and unique Bartonella species. One of the defined lineages, Ew, consisted of only two STs (ST1 and ST2), and comprised more than one-quarter of the analyzed isolates, while other lineages contained higher numbers of STs with a smaller number of isolates belonging to each lineage. The low number of allelic polymorphisms of isolates belonging to Ew suggests a more recent origin for this species. Our findings suggest that at least six Bartonella species are associated with straw-colored fruit bats, and that distinct STs can be found across the distribution of this bat species, including in populations of bats which are genetically distinct.
Author Summary
Bats, with over 1000 recognized species, represent about 20% of all classified mammalian species worldwide. These mammals have a wide range of ecologies and life-history traits, and are now widely recognized as important reservoirs of many pathogens. Bartonella species have been found distributed in a wide range of mammalian species, including bats. About half of recognized Bartonella species, including one bat-associated species, have been associated with human illness. Previous studies have shown that Bartonella species are extremely diverse, with or without evident specificity to their mammalian hosts. Possessing many unique aspects, bartonellae can serve as a useful biological marker to study how microorganisms have evolved and diversified along with their animal hosts in evolutionary history. In this study, we applied multi-locus sequence typing, or MLST, to study the genetic differences of straw-colored fruit bat (Eidolon helvum)-associated Bartonella species. Our studies suggest Bartonella species have both exchanged genetic materials among species through recombination events and lost genes that are perhaps superfluous to their life cycles, which includes an intracellular stage in mammals.
PMCID: PMC4311972  PMID: 25635826
7.  Suppression of Tumor Growth in Mice by Rationally Designed Pseudopeptide Inhibitors of Fibroblast Activation Protein and Prolyl Oligopeptidase1 
Neoplasia (New York, N.Y.)  2015;17(1):43-54.
Tumor microenvironments (TMEs) are composed of cancer cells, fibroblasts, extracellular matrix, microvessels, and endothelial cells. Two prolyl endopeptidases, fibroblast activation protein (FAP) and prolyl oligopeptidase (POP), are commonly overexpressed by epithelial-derived malignancies, with the specificity of FAP expression by cancer stromal fibroblasts suggesting FAP as a possible therapeutic target. Despite overexpression in most cancers and having a role in angiogenesis, inhibition of POP activity has received little attention as an approach to quench tumor growth. We developed two specific and highly effective pseudopeptide inhibitors, M83, which inhibits FAP and POP proteinase activities, and J94, which inhibits only POP. Both suppressed human colon cancer xenograft growth > 90% in mice. By immunohistochemical stains, M83- and J94-treated tumors had fewer microvessels, and apoptotic areas were apparent in both. In response to M83, but not J94, disordered collagen accumulations were observed. Neither M83- nor J94-treated mice manifested changes in behavior, weight, or gastrointestinal function. Tumor growth suppression was more extensive than noted with recently reported efforts by others to inhibit FAP proteinase function or reduce FAP expression. Diminished angiogenesis and the accompanying profound reduction in tumor growth suggest that inhibition of either FAP or POP may offer new therapeutic approaches that directly target TMEs.
PMCID: PMC4309729  PMID: 25622898
FAP, fibroblast activation protein; POP, prolyl oligopeptidase; TME, tumor microenvironment; DPPIV, dipeptidyl peptidase IV; ECM, extracellular matrix; IHC, immunohistochemistry; CAFs, cancer-associated fibroblasts; MMPs, matrix metalloproteinases
8.  Chronic traumatic encephalopathy: a spectrum of neuropathological changes following repetitive brain trauma in athletes and military personnel 
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that occurs in association with repetitive traumatic brain injury experienced in sport and military service. In most instances, the clinical symptoms of the disease begin after a long period of latency ranging from several years to several decades. The initial symptoms are typically insidious, consisting of irritability, impulsivity, aggression, depression, short-term memory loss and heightened suicidality. The symptoms progress slowly over decades to include cognitive deficits and dementia. The pathology of CTE is characterized by the accumulation of phosphorylated tau protein in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer’s disease. The hyperphosphorylated tau abnormalities begin focally, as perivascular neurofibrillary tangles and neurites at the depths of the cerebral sulci, and then spread to involve superficial layers of adjacent cortex before becoming a widespread degeneration affecting medial temporal lobe structures, diencephalon and brainstem. Most instances of CTE (>85% of cases) show abnormal accumulations of phosphorylated 43 kDa TAR DNA binding protein that are partially colocalized with phosphorylated tau protein. As CTE is characterized pathologically by frontal and temporal lobe atrophy, by abnormal deposits of phosphorylated tau and by 43 kDa TAR DNA binding protein and is associated clinically with behavioral and personality changes, as well as cognitive impairments, CTE is increasingly categorized as an acquired frontotemporal lobar degeneration. Currently, some of the greatest challenges are that CTE cannot be diagnosed during life and the incidence and prevalence of the disorder remain uncertain. Furthermore, the contribution of age, gender, genetics, stress, alcohol and substance abuse to the development of CTE remains to be determined.
PMCID: PMC3979082  PMID: 24423082
9.  Assessing the physical environment of older people’s residential care facilities: development of the Swedish version of the Sheffield Care Environment Assessment Matrix (S-SCEAM) 
BMC Geriatrics  2015;15:3.
There is emerging evidence that the physical environment is important for health, quality of life and care, but there is a lack of valid instruments to assess health care environments. The Sheffield Care Environment Assessment Matrix (SCEAM), developed in the United Kingdom, provides a comprehensive assessment of the physical environment of residential care facilities for older people. This paper reports on the translation and adaptation of SCEAM for use in Swedish residential care facilities for older people, including information on its validity and reliability.
SCEAM was translated into Swedish and back-translated into English, and assessed for its relevance by experts using content validity index (CVI) together with qualitative data. After modification, the validity assessments were repeated and followed by test-retest and inter-rater reliability tests in six units within a Swedish residential care facility that varied in terms of their environmental characteristics.
Translation and back translation identified linguistic and semantic related issues. The results of the first content validity analysis showed that more than one third of the items had item-CVI (I-CVI) values less than the critical value of 0.78. After modifying the instrument, the second content validation analysis resulted in I-CVI scores above 0.78, the suggested criteria for excellent content validity. Test-retest reliability showed high stability (96% and 95% for two independent raters respectively), and inter-rater reliability demonstrated high levels of agreement (95% and 94% on two separate rating occasions). Kappa values were very good for test-retest (κ = 0.903 and 0.869) and inter-rater reliability (κ = 0.851 and 0.832).
Adapting an instrument to a domestic context is a complex and time-consuming process, requiring an understanding of the culture where the instrument was developed and where it is to be used. A team, including the instrument’s developers, translators, and researchers is necessary to ensure a valid translation and adaption. This study showed preliminary validity and reliability evidence for the Swedish version (S-SCEAM) when used in a Swedish context. Further, we believe that the S-SCEAM has improved compared to the original instrument and suggest that it can be used as a foundation for future developments of the SCEAM model.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2318-15-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4323237  PMID: 25563507
Questionnaire; Translation; Validity; Reliability; Health care environment; Residential care facility; Elderly care
10.  A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes 
Nature  2014;506(7489):498-502.
A well-balanced human diet includes a significant intake of non-starch polysaccharides, collectively termed “dietary fibre,” from the cell walls of diverse fruits and vegetables.1 Due to a paucity of alimentary enzymes encoded by the human genome,2 our ability to derive energy from dietary fibre depends on saccharification and fermentation of complex carbohydrates by the massive microbial community residing in our distal gut.3,4 The xyloglucans (XyGs), in particular, are a ubiquitous family of highly branched plant cell wall polysaccharides5,6 whose mechanism(s) of degradation in the human gut and consequent importance in nutrition was heretofore unknown.1,7,8 Here, we demonstrate that a single, complex gene locus in Bacteroides ovatus confers xyloglucan catabolism in this common colonic symbiont. Through targeted gene disruption, biochemical analysis of all predicted glycoside hydrolases and carbohydrate-binding proteins, and three-dimensional structural determination of the vanguard endo-xyloglucanase, we reveal the molecular mechanisms through which XyGs are hydrolysed to component monosaccharides for further metabolism. We also observe that orthologous xyloglucan utilization loci (XyGULs) serve as genetic markers of xyloglucan catabolism in Bacteroidetes, that XyGULs are restricted to a limited number of phylogenetically diverse strains, and that XyGULs are ubiquitous in surveyed human metagenomes. Our findings reveal that the metabolism of even highly abundant components of dietary fibre may be mediated by niche species, which has immediate fundamental and practical implications for gut symbiont population ecology in the context of human diet, nutrition and health.9–12
PMCID: PMC4282169  PMID: 24463512
11.  GP commissioning and the NHS reforms: what lies behind the hard sell? 
PMCID: PMC3265229  PMID: 22275493
Cigarette taxation has been recognized as one of the most significant policy instruments to reduce smoking. Smoking and drinking are highly comorbid behaviors, and the public health benefits of cigarette taxation may extend beyond smoking-related outcomes to impact alcohol consumption. The current study is the first to test whether increases in cigarette taxes are associated with reductions in alcohol consumption among smokers using a large, prospective U.S. sample.
Our sample included 21,473 alcohol consumers from the National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Multiple linear regression analyses were conducted to evaluate whether increases in cigarette taxes between Waves I (2001–2002) and II (2004–2005) were associated with reductions in quantity and frequency of alcohol consumption, adjusting for demographics, baseline alcohol consumption, and alcohol price. Stratified analyses were conducted by sex, hazardous drinking status, and age and income group.
Increases in cigarette taxes were associated with modest reductions in typical quantity of alcohol consumption and frequency of binge drinking among smokers. Cigarette taxation was not associated with changes in alcohol consumption among non-smokers. In analyses stratified by sex, the inverse associations of cigarette taxes with typical quantity and binge drinking frequency were found only for male smokers. Further, the inverse association of cigarette taxation and alcohol consumption was stronger among hazardous drinkers (translating into approximately 1/2 a drink less alcohol consumption per episode), young adult smokers, and smokers in the lowest income category.
Findings from this longitudinal, epidemiological study suggest increases in cigarette taxes are associated with modest to moderate reductions in alcohol consumption among vulnerable groups. Additional research is needed to further quantify the public health benefits of cigarette taxation on alcohol consumption and to evaluate the potential broader crossover effects of cigarette taxation on other health behaviors.
PMCID: PMC3830619  PMID: 23930623
cigarette tax; alcohol; longitudinal; smokers; hazardous drinking; sex
13.  Rat Silicone Hydrogel Contact Lens Model: Effects of High vs. Low Dk Lens Wear 
Eye & contact lens  2008;34(6):306-311.
This study used a rat contact lens (CL) model to test if high vs. low Dk lens wear caused changes in: 1) conjunctival Langerhans cell (LC) number or location; 2) Bcl-2 expression; and 3) infection risk.
Female, Lewis rats wore a high or low Dk CL continuously for 2 weeks. Afterward, corneas were harvested and processed for ADPase activity to identify Langerhans cells (LC), for immunostaining and for real time RT-PCR. CL wearing rats also were challenged with Pseudomonas aeruginosa by placing a bacterial-soaked CL on the eye followed by topical delivery of bacteria. After 48 hours, slit lamp examination and real time RT-PCR were used to evaluate the corneal response.
Conjunctival LC were significantly increased after low vs. high Dk CL wear (p<0.0001). In contrast, conjunctival LC in non-lens wearing rats was not significantly different from the high Dk lens wearing group. Bcl-2 mRNA levels were significantly decreased in low vs. high Dk Cl wearing rats, while Bax, FasL, caspase 3 and caspase 9 levels were unchanged. Immunostaining for Bcl-2 showed fewer positively stained epithelial cells in the low vs. high Dk lens wearing group. After bacterial challenge, 30% of low vs. none of the high Dk CL wearing corneas became infected and showed increased mRNA levels for several pro-inflammatory cytokines/chemokines, inducible nitric oxide synthase (iNOS) and matrix metalloproteinase (MMP)-9.
Low vs. high Dk and/or no CL wear led to an increased number of conjunctival LC, decreased Bcl-2 levels, and increased the risk of bacterial infection.
PMCID: PMC4274951  PMID: 18997538
rat; contact lens; Langerhans cells; conjunctiva; P. aeruginosa
14.  Retaining Critical Therapeutic Elements of Behavioral Interventions Translated For Delivery via the Internet: Recommendations and an Example Using Pain Coping Skills Training 
Evidence supporting the efficacy of behavioral interventions based on principles of cognitive behavioral therapies has spurred interest in translating these interventions for delivery via the Internet. However, the benefits of this dissemination method cannot be realized unless the translated interventions are as effective as possible. We describe a challenge that must be overcome to ensure this occurs—Internet interventions must retain therapeutic components and processes underlying the success of face-to-face interventions on which they are based. These components and processes vary in the ease with which they can be translated to the online environment. Moreover, some are subtle and may be overlooked, despite being recognized as essential to the success of face-to-face interventions. We provide preliminary guidance for retaining critical therapeutic components and processes in the translation process, using Pain Coping Skills Training for osteoarthritis pain to illustrate methods. Directions for future research are also discussed.
PMCID: PMC4285744  PMID: 25532216
psychotherapeutic processes; cognitive behavioral therapy; Internet; eHealth; intervention; treatment efficacy; musculoskeletal pain; osteoarthritis
15.  Using Structured Observation and Content Analysis to Explore the Presence of Older People in Public Fora in Developing Countries 
Journal of Aging Research  2014;2014:860612.
There is a lack of research on the everyday lives of older people in developing countries. This exploratory study used structured observation and content analysis to examine the presence of older people in public fora and considered the methods' potential for understanding older people's social integration and inclusion. Structured observation occurred of public social spaces in six cities each located in a different developing country and in one city in the United Kingdom, together with content analysis of the presence of people in newspaper pictures and on television in the selected countries. Results indicated that across all fieldwork sites and data sources, there was a low presence of older people, with women considerably less present than men in developing countries. There was variation across fieldwork sites in older people's presence by place and time of day and in their accompanied status. The presence of older people in images drawn from newspapers was associated with the news/non-news nature of the source. The utility of the study's methodological approach is considered, as is the degree to which the presence of older people in public fora might relate to social integration and inclusion in different cultural contexts.
PMCID: PMC4273510  PMID: 25548675
16.  R-flurbiprofen improves tau, but not Aß pathology in a triple transgenic model of Alzheimer's disease 
Brain research  2013;1541:10.1016/j.brainres.2013.10.025.
We have previously reported that chronic ibuprofen treatment improves cognition and decreases intracellular Aß and phosphorylated-tau levels in 3xTg-AD mice. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) that independently of its anti-inflammatory effects has anti-amyloidogenic activity as a gamma-secretase modulator (GSM) and both activities have the potential to decrease Aß pathology. To further understand the effects of NSAIDs in 3xTg-AD mice, we treated 3xTg-AD mice with R-flurbiprofen, an enantiomer of the NSAID flurbiprofen that maintains the GSM activity but has greatly reduced anti-inflammatory activity, and analyzed its effect on cognition, Aß, tau, and the neurochemical profile of the hippocampus. Treatment with R-flurbiprofen from 5 to 7 months of age resulted in improved cognition on the radial arm water maze (RAWM) test and decreased the level of hyperphosphorylated tau immunostained with AT8 and PHF-1 antibodies. No significant changes in the level of Aß (using 6E10 and NU-1 antibodies) were detected. Using magnetic resonance spectroscopy (MRS) we found that R-flurbiprofen treatment decreased the elevated level of glutamine in 3xTg-AD mice down to the level detected in non-transgenic mice. Glutamine levels correlated with PHF-1 immunostained hyperphosphorylated tau. We also found an inverse correlation between the concentration of glutamate and learning across all the mice in the study. Glutamine and glutamate, neurochemicals that shuttles between neurons and astrocytes to maintain glutamate homeostasis in the synapses, deserve further attention as MR markers of cognitive function.
PMCID: PMC3863610  PMID: 24161403
R-flurbiprofen; hyperphosphorylated tau; Aß; 3xTg-AD mice; magnetic resonance spectroscopy
17.  Military-related traumatic brain injury and neurodegeneration 
Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with postconcussion syndrome and posttraumatic stress disorder, suggesting that the three disorders might share some biological underpinnings.
PMCID: PMC4255273  PMID: 24924675
Chronic traumatic encephalopathy; Veterans; Neurodegeneration; Traumatic brain injury; Tauopathy; TDP-43; Alzheimer's disease
18.  The neuropathology of sport 
Acta neuropathologica  2013;127(1):29-51.
The benefits of regular exercise, physical fitness and sports participation on cardiovascular and brain health are undeniable. Physical activity reduces the risk for cardiovascular disease, type 2 diabetes, hypertension, obesity, and stroke, and produces beneficial effects on cholesterol levels, antioxidant systems, inflammation, and vascular function. Exercise also enhances psychological health, reduces age-related loss of brain volume, improves cognition, reduces the risk of developing dementia, and impedes neurodegeneration. Nonetheless, the play of sports is associated with risks, including a risk for mild TBI (mTBI) and, rarely, catastrophic traumatic injury and death. There is also growing awareness that repetitive mTBIs, such as concussion and subconcussion, can occasionally produce persistent cognitive, behavioral, and psychiatric problems as well as lead to the development of a neurodegeneration, chronic traumatic encephalopathy (CTE). In this review, we summarize the beneficial aspects of sports participation on psychological, emotional, physical and cognitive health, and specifically analyze some of the less common adverse neuropathological outcomes, including concussion, second-impact syndrome, juvenile head trauma syndrome, catastrophic sudden death, and CTE. CTE is a latent neurodegeneration clinically associated with behavioral changes, executive dysfunction and cognitive impairments, and pathologically characterized by frontal and temporal lobe atrophy, neuronal and axonal loss, and abnormal deposits of paired helical filament (PHF)-tau and 43 kDa TAR deoxyribonucleic acid (DNA)-binding protein (TDP-43). CTE often occurs as a sole diagnosis, but may be associated with other neurodegenerative disorders, including motor neuron disease (CTE-MND). Although the incidence and prevalence of CTE are not known, CTE has been reported most frequently in American football players and boxers. Other sports associated with CTE include ice hockey, professional wrestling, soccer, rugby, and baseball.
PMCID: PMC4255282  PMID: 24366527
19.  Current Understanding of Chronic Traumatic Encephalopathy 
PMCID: PMC4255271  PMID: 25023937
Chronic traumatic encephalopathy (CTE); Concussion; Brain trauma; Traumatic brain injury (TBI); APOE; Biomarker; Tau; Football
20.  Is There a Statistical Relationship between Economic Crises and Changes in Government Health Expenditure Growth? An Analysis of Twenty-Four European Countries 
Health Services Research  2012;47(6):2204-2224.
To identify whether, by what means, and the extent to which historically, government health care expenditure growth in Europe has changed following economic crises.
Data Sources
Organization for Economic Cooperation and Development Health Data 2011.
Study Design
Cross-country fixed effects multiple regression analysis is used to determine whether statutory health care expenditure growth in the year after economic crises differs from that which would otherwise be predicted by general economic trends. Better understanding of the mechanisms involved is achieved by distinguishing between policy responses which lead to cost-shifting and all others.
In the year after an economic downturn, public health care expenditure grows more slowly than would have been expected given the longer term economic climate. Cost-shifting and other policy responses are both associated with these slowdowns. However, while changes in tax-derived expenditure are associated with both cost-shifting and other policy responses following a crisis, changes in expenditure derived from social insurance have been associated only with changes in cost-shifting.
Disproportionate cuts to the health sector, as well as reliance on cost-shifting to slow growth in health care expenditure, serve as a warning in terms of potentially negative effects on equity, efficiency, and quality of health services and, potentially, health outcomes following economic crises.
PMCID: PMC3523372  PMID: 22670771
Health economics; health care financing/insurance/premiums; comparative health systems/international health; health care organizations and systems
21.  Effect of Chitosan Incorporation and Scaffold Geometry on Chondrocyte Function in Dense Collagen Type I Hydrogels 
Tissue Engineering. Part A  2013;19(23-24):2553-2564.
Tissue engineering approaches for articular cartilage (AC) repair using collagen type I (Coll)-based hydrogels are limited by their low collagen fibril density (CFD; <0.5 wt%) and their poor capacity to support chondrocyte differentiation. Chitosan (CTS) is a well-characterized polysaccharide that mimics the glycosaminoglycans (GAGs) present in native AC extracellular matrix and exhibits chondroprotective properties. Here dense Coll/CTS hydrogel discs (16 mm diameter, 140–250 μm thickness) with CFD (∼6 wt%) approaching that of AC were developed to investigate the effect of CTS content on the growth and differentiation of three-dimensionally seeded RCJ3.1C5.18 chondroprogenitor cells. Compared to dense Coll alone, cells seeded within Coll/CTS showed increased viability and metabolic activity, as well as a decrease in cell-mediated gel contraction. Immunohistochemistry for collagen type II, in combination with Safranin O staining and GAG quantification, indicated greater chondroprogenitor differentiation within Coll/CTS, compared to cells seeded within Coll alone. The complex interplay between scaffold geometry, microstructure, composition, mechanical properties and cell function was further evaluated by rolling dense planar sheets to prepare cylindrically shaped constructs having clinically relevant diameters (3–5 mm diameter, 9 mm height). The compressive modulus of the cylindrically shaped constructs decreased significantly after 7 days in culture, and remained unchanged up to 21 days for each scaffold composition. Unlike Coll, cells seeded within Coll/CTS showed greater viability along the entire radial extent of the cylindrical rolls and increased GAG production at each time point. While GAG content decreased over time and reduced cell viability was observed within the core region of all cylindrical rolls, the incorporation of CTS diminished both these effects. In summary, these findings provide insight into the challenges involved when scaling up scaffolds designed and optimised in vitro for tissue repair.
PMCID: PMC3856934  PMID: 23859275
22.  T Cell Recognition of Beryllium 
Current opinion in immunology  2013;25(6):10.1016/j.coi.2013.07.012.
Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by a hypersensitivity to beryllium and characterized by the accumulation of beryllium-specific CD4+ T cells in the lung. Genetic susceptibility to beryllium-induced disease is strongly associated with HLA-DP alleles possessing a glutamic acid at the 69th position of the β-chain (βGlu69). The structure of HLA-DP2, the most prevalent βGlu69-containing molecule, revealed a unique solvent-exposed acidic pocket that includes βGlu69 and represents the putative beryllium binding site. The delineation of mimotopes and endogenous self-peptides that complete the αβTCR ligand for beryllium-specific CD4+ T cells suggests a unique role of these peptides in metal ion coordination and the generation of altered self-peptides, blurring the distinction between hypersensitivity and autoimmunity.
PMCID: PMC3883670  PMID: 23978481
23.  Family Group Cognitive-Behavioral Preventive Intervention for Families of Depressed Parents: 18- and 24-month Outcomes 
In a long-term follow-up of a randomized controlled trial (Compas et al., 2009), to examine the effects at 18- and 24-month follow-ups of a Family Group Cognitive Behavioral (FGCB) preventive intervention for mental health outcomes for children and parents from families (N = 111) of parents with a history of major depressive disorder (MDD).
Parents with a history of MDD and their 9 to 15-year-old children were randomly assigned to a FGCB intervention or a Written Information (WI) comparison condition. Children’s internalizing, externalizing, anxiety/depression, and depressive symptoms, episodes of MDD and other psychiatric diagnoses, and parents’ depressive symptoms and episodes of MDD were assessed at 18- and 24-months after randomization.
Children in the FGCB condition were significantly lower in self-reports of anxiety/depression and internalizing symptoms at 18-months and significantly lower in externalizing symptoms at 18- and 24-months. Rates of MDD were significantly lower for children in the FGCB intervention over the 24-month follow-up (odds ratio = 2.91). No significant effects were found for parents’ symptoms of depression or episodes of MDD.
Support was found for a FGCB preventive intervention for children of parents with a history of MDD significantly reducing children’s episodes of MDD over a period of 2 years. Significant effects for the FGCB intervention were also found on internalizing and externalizing symptoms, with stronger effects at 18- than at 24-month follow-up.
PMCID: PMC4249929  PMID: 21707137
parental depression; children; prevention; family; cognitive-behavioral
24.  Observed Parental Responsiveness/Warmth and Children’s Coping: Cross-Sectional and Prospective Relations in a Family Depression Preventive Intervention 
The current study examined concurrent and prospective relations between observed parenting behaviors and children’s coping strategies in the context of a preventive intervention designed to change both parenting and children’s use of secondary control coping. Questionnaires and direct observations were obtained from parents with a history of depression (N = 180) and their children (ages 9–15 years) at baseline, 6-month (after completion of the intervention), and 18-month follow-up assessments. Cross-sectional analyses indicate that baseline observed parental responsiveness/warmth was significantly associated with composite parent/child reports of children’s baseline primary control, secondary control, and disengagement coping. Using a mixed effects model, prospective mediational analyses indicate that intervention-driven improvements in observed parental responsiveness/warmth from baseline to 6-months significantly accounted for increases in children’s use of secondary control coping strategies from baseline to the 18-month follow-up assessment. No significant mediation effects emerged for primary control coping or disengagement coping. The present findings suggest that it may be possible to improve children’s coping strategies not only through targeted interventions, but also indirectly by improving responsive and warm parenting behaviors. Limitations and strengths are noted and implications for future research are outlined.
PMCID: PMC4249931  PMID: 24773219
coping; parental responsiveness; parental warmth; cognitive-behavioral intervention; parental depression
25.  Prevalence of alcohol-related pathologies at autopsy: Estonian Forensic Study of Alcohol and Premature Death 
Addiction (Abingdon, England)  2014;109(12):2018-2026.
Alcohol can induce diverse serious pathologies, yet this complexity may be obscured when alcohol-related deaths are classified according to a single underlying cause. We sought to quantify this issue and its implications for analysing mortality data.
Design, Setting and Participants
Cross-sectional study included 554 men aged 25–54 in Estonia undergoing forensic autopsy in 2008–09.
Potentially alcohol-related pathologies were identified following macroscopic and histological examination. Alcohol biomarkers levels were determined. For a subset (26%), drinking behaviour was provided by next-of-kin. The Estonian Statistics Office provided underlying cause of death.
Most deaths (75%) showed evidence of potentially alcohol-related pathologies, and 32% had pathologies in two or more organs. The liver was most commonly affected [60.5%, 95% confidence interval (CI) = 56.3–64.6] followed by the lungs (18.6%, 95% CI = 15.4–22.1), stomach (17.5%, 95% CI = 14.4–20.9), pancreas (14.1%, 95% CI = 11.3–17.3), heart (4.9%, 95% CI = 3.2–7.0) and oesophagus (1.4%, 95% CI = 0.6–2.8). Only a minority with liver pathology had a second pathology. The number of pathologies correlated with alcohol biomarkers (phosphatidylethanol, gamma-glytamyl transpeptidase in blood, ethylglucuronide, ethylsulphate in urine). Despite the high prevalence of liver pathology, few deaths had alcoholic liver disease specified as the underlying cause.
The majority of 554 men aged 25–54 undergoing forensic autopsy in Estonia in 2008–09 showed evidence of alcohol-related pathology. However, the recording of deaths by underlying cause failed to capture the scale and nature of alcohol-induced pathologies found.
PMCID: PMC4241049  PMID: 25066373
Alcohol drinking; alcohol-related pathologies; epidemiology; Estonia/forensic autopsy; ICD codes; post-mortem alcohol biomarkers.

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