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1.  CD4 T Cells Promote Rather than Control Tuberculosis in the Absence of PD-1–Mediated Inhibition 
Although CD4 T cells are required for host resistance to Mycobacterium tuberculosis, they may also contribute to pathology. In this study, we examine the role of the inhibitory receptor PD-1 and its ligand PD-L1 during M. tuberculosis infection. After aerosol exposure, PD-1 knockout (KO) mice develop high numbers of M. tuberculosis-specific CD4 T cells but display markedly increased susceptibility to infection. Importantly, we show that CD4 T cells themselves drive the increased bacterial loads and pathology seen in infected PD-1 KO mice, and PD-1 deficiency in CD4 T cells is sufficient to trigger early mortality. PD-L1 KO mice also display enhanced albeit less severe susceptibility, indicating that T cells are regulated by multiple PD ligands during M. tuberculosis infection. M. tuberculosis-specific CD8 T cell responses were normal in PD-1 KO mice, and CD8 T cells only had a minor contribution to the exacerbated disease in the M. tuberculosis-infected PD-1 KO and PD-L1 KO mice. Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection.
doi:10.4049/jimmunol.1003304
PMCID: PMC4059388  PMID: 21172867
2.  Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through Mincle/CARD9 signaling and the inflammasome 
Although adjuvants are critical vaccine components, their modes of action are poorly understood. Here, we investigated the mechanisms by which the heat-killed mycobacteria in complete Freund’s adjuvant (CFA) promote T helper 17 (Th17) CD4+ T cell responses. We found that IL-17 secretion by CD4+ T cells following CFA immunization requires MyD88 and IL-1β/IL-1 receptor (IL-1R) signaling. Through measurement of antigen-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase 1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule CARD9 plays a major role in triggering pro-IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase 1-and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators.
doi:10.4049/jimmunol.1203343
PMCID: PMC3719989  PMID: 23630357
3.  Plasma Heme Oxygenase-1 Levels Distinguish Latent or Successfully Treated Human Tuberculosis from Active Disease 
PLoS ONE  2013;8(5):e62618.
Background
Tuberculosis (TB) is associated with oxidative stress and the induction of host anti-oxidants to counteract this response. Heme oxygenase-1 (HO-1) is a critical promoter of cytoprotection in diverse disease models including mycobacterial infection. Nevertheless, the pattern of expression of HO-1 in human tuberculosis has not been studied. Here, we examine expression of HO-1 in M. tuberculosis-exposed and -infected individuals and test its ability to distinguish active from latent and successfully treated TB cases. In addition, we assess correlations between plasma levels of HO-1 and cytokines closely associated with the immunopathogenesis of TB.
Methods
Cross-sectional and longitudinal analyses of levels of HO-1, acute phase proteins and pro-inflammatory cytokines were performed in plasma samples from individuals with active pulmonary, extra-pulmonary or latent TB infection and healthy controls as part of a prospective cohort study in South India.
Results
Systemic levels of HO-1 were dramatically increased in individuals with active pulmonary and extra-pulmonary tuberculosis and particularly those with bilateral lung lesions and elevated bacillary loads in sputum. HO-1 levels effectively discriminated active from latent tuberculosis with higher predictive values than either C-reactive protein or serum amyloid protein. Moreover, there was a marked reduction in HO-1 levels in active TB cases following anti-tuberculous therapy but not in those who failed treatment. Pulmonary TB patients displaying the highest concentrations of HO-1 in plasma exhibited significantly elevated plasma levels of interleukin (IL)-10, interferon (IFN)-γ and IL-17 and diminished levels of tumor necrosis factor (TNF)-α.
Conclusion
These findings establish HO-1 levels as a potentially useful parameter for distinguishing active from latent or treated pulmonary tuberculosis, that is superior in this respect to the measurement of other acute inflammatory proteins.
doi:10.1371/journal.pone.0062618
PMCID: PMC3646008  PMID: 23671613
4.  Innate and adaptive interferons suppress IL-1α and IL-1β production by distinct pulmonary myeloid subsets during Mycobacterium tuberculosis infection 
Immunity  2011;35(6):1023-1034.
SUMMARY
Interleukin-1 (IL-1) receptor signaling is required for control of Mycobacterium tuberculosis (Mtb) infection, yet the role of its two ligands, IL-1α and IL-1β, and the regulation of their expression in vivo are poorly understood. Here we show that in addition to IL-1β, IL-1α was independently required for host resistance. We identified two multifunctional inflammatory monocyte-macrophage and DC populations that co-expressed both IL-1 species at the single cell level in lungs of Mtb infected mice. Moreover, we demonstrated that interferons (IFNs) played important roles in fine-tuning IL-1 production by these cell populations in vivo. Type I IFNs inhibited IL-1 production by both subsets while CD4+ T cell derived IFNγ suppressed IL-1 expression selectively in inflammatory monocytes. These data provide a cellular basis for the anti-inflammatory effects of IFNs as well as pro-bacterial functions of type I IFNs during Mtb infection and reveal differential regulation of IL-1 induction by specialized cellular sources as an additional layer of complexity in the activity of IL-1 in vivo.
doi:10.1016/j.immuni.2011.12.002
PMCID: PMC3246221  PMID: 22195750
5.  Cutting Edge: Caspase-1 Independent IL-1β Production Is Critical for Host Resistance to Mycobacterium tuberculosis and Does Not Require TLR Signaling In Vivo 
To investigate the respective contributions of TLR versus IL-1R mediated signals in MyD88 dependent control of Mycobacterium tuberculosis, we compared the outcome of M. tuberculosis infection in MyD88, TRIF/MyD88, IL-1R1, and IL-1β-deficient mice. All four strains displayed acute mortality with highly increased pulmonary bacterial burden suggesting a major role for IL-1β signaling in determining the MyD88 dependent phenotype. Unexpectedly, the infected MyD88 and TRIF/MyD88-deficient mice, rather than being defective in IL-1β expression, displayed increased cytokine levels relative to wild-type animals. Similarly, infected mice deficient in caspase-1 and ASC, which have critical functions in inflammasome-mediated IL-1β maturation, showed unimpaired IL-1β production and importantly, were considerably less susceptible to infection than IL-1β deficient mice. Together our findings reveal a major role for IL-1β in host resistance to M. tuberculosis and indicate that during this infection the cytokine can be generated by a mechanism that does not require TLR signaling or caspase-1. The Journal of Immunology, 2010, 184: 3326–3330.
doi:10.4049/jimmunol.0904189
PMCID: PMC3420351  PMID: 20200276
6.  An in vitro screening cascade to identify neuroprotective antioxidants in ALS 
Free Radical Biology & Medicine  2009;46(8):1127-1138.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease, characterized by progressive dysfunction and death of motor neurons. Although evidence for oxidative stress in ALS pathogenesis is well described, antioxidants have generally shown poor efficacy in animal models and human clinical trials. We have developed an in vitro screening cascade to identify antioxidant molecules capable of rescuing NSC34 motor neuron cells expressing an ALS-associated mutation of superoxide dismutase 1. We have tested known antioxidants and screened a library of 2000 small molecules. The library screen identified 164 antioxidant molecules, which were refined to the 9 most promising molecules in subsequent experiments. Analysis of the in silico properties of hit compounds and a review of published literature on their in vivo effectiveness have enabled us to systematically identify molecules with antioxidant activity combined with chemical properties necessary to penetrate the central nervous system. The top-performing molecules identified include caffeic acid phenethyl ester, esculetin, and resveratrol. These compounds were tested for their ability to rescue primary motor neuron cultures after trophic factor withdrawal, and the mechanisms of action of their antioxidant effects were investigated. Subsequent in vivo studies can be targeted using molecules with the greatest probability of success.
doi:10.1016/j.freeradbiomed.2009.01.019
PMCID: PMC2742740  PMID: 19439221
5-LOX, 5-lipoxygenase; AAPH, 2,2′-azobis(2-methylpropionamidine) dihydrochloride; ALS, amyotrophic lateral sclerosis; ARE, antioxidant response element; BBB, blood–brain barrier; CAPE, caffeic acid phenethyl ester; CNS, central nervous system; DCF, dichlorofluorescein; DMSO, dimethyl sulfoxide; Esc, esculetin; EthD1, ethidium homodimer-1; EGFP, enhanced green fluorescent protein; LTB4, leukotriene B4; MN, motor neuron; MTT, methylthiazolyldiphenyl tetrazolium bromide; NDGA, nordihydroguaiaretic acid; Nrf2, nuclear factor erythroid 2-related factor 2; OTCA, 2-oxo-l-thiazolidine-4-carboxylic acid; PBS, phosphate-buffered saline; PI, prediction interval; PSA, polar surface area; Res, resveratrol; R-PE, R-phycoerythrin; SOD1, superoxide dismutase 1; TK, thymidine kinase promoter; TRAP, total radical-trapping antioxidant parameter.; Antioxidant; Amyotrophic lateral sclerosis; Mouse; NSC34; Superoxide dismutase; Free radicals
7.  Prevention of renal injury after induction of ozone tolerance in rats submitted to warm ischaemia. 
Mediators of Inflammation  1999;8(1):37-41.
On the basis that ozone (O3) can upregulate cellular antioxidant enzymes, a morphological, biochemical and functional renal study was performed in rats undergoing a prolonged treatment with O3 before renal ischaemia. Rats were divided into four groups: (1) control, a medial abdominal incision was performed to expose the kidneys; (2) ischaemia, in animals undergoing a bilateral renal ischaemia (30 min), with subsequent reperfusion (3 h); (3) O3 + ischaemia, as group 2, but with previous treatment with O3 (0.5 mg/kg per day given in 2.5 ml O2) via rectal administration for 15 treatments; (4) O2 + ischaemia, as group 3, but using oxygen (O2) alone. Biochemical parameters as fructosamine level, phospholipase A, and superoxide dismutases (SOD) activities, as well as renal plasma flow (RPF) and glomerular filtration rate (GFR), were measured by means of plasma clearance of p-amino-hippurate and inulin, respectively. In comparison with groups 1 and 3, the RPF and GFR were significantly decreased in groups 2 and 4. Interestingly, renal homogenates of the latter groups yielded significantly higher values of phospholipase A activity and fructosamine level in comparison with either the control (1) and the O3 (3) treated groups. Moreover renal SOD activity showed a significant increase in group 3 without significant differences among groups 1, 2 and 4. Morphological alterations of the kidney were present in 100%, 88% and 30% of the animals in groups 2, 4 and 3, respectively. It is proposed that the O3 protective effect can be ascribed to the substantial possibility of upregulating the antioxidant defence system capable of counteracting the damaging effect of ischaemia. These findings suggest that, whenever possible, ozone preconditioning may represent a prophylactic approach for minimizing renal damage before transplantation.
PMCID: PMC1781776  PMID: 10704088
8.  Of snarks, boojums and national drug charts 
doi:10.1258/jrsm.2012.120172
PMCID: PMC3556807  PMID: 23358272
11.  Sports Specialization is Associated with An Increased Risk of Developing Anterior Knee Pain in Adolescent Female Athletes 
Objectives
This study sought to determine if sport specialization increases the risk of anterior knee pain in adolescent female athletes.
Design
Retrospective cohort epidemiology study.
Methods
Female basketball, soccer and volleyball players (N=546) were recruited from a single county public school district in Kentucky consisting of five middle schools and four high schools. A total of 357 multi-sport, and 189 single sport (66 basketball, 57 soccer and 66 volleyball) athlete subjects were included due to their diagnosis of patellofemoral pain on physical exam. Testing consisted of completion of a standardized history and physician-administered physical examination to determine the presence of patellofemoral pain (PFP). This study compared self-reported multi-sport athletes with sport specialized athletes participating in only one sport. The sports participation data was normalized by sport season with each sport accounting for one season of exposure. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were calculated and used to determine significant differences between athletes who specialized in sport in early youth and multi-sport athletes.
Results
Specialization in a single sport increased the relative risk of PFP incidence by 1.5 fold (95% CI 1.0 to 2.2; p=0.038) for cumulative PFP diagnoses. Specific diagnoses such as Sinding Larsen Johansson/patellar tendinopathy (95% CI 1.5 to 10.1; p=0.005) and Osgood Schlatter Disease (95% CI 1.5 to 10.1; p=0.005) demonstrated a four-fold greater relative risk in single sport compared to multiple sport athletes. Other specific PFP diagnoses such as Fat Pad, Plica, Trauma, Pes Anserine Bursitis and IT Band Tendonitis incidence were not different between single sport and multiple sport participants (p>0.05).
Conclusion
Early sport specialization in female adolescents is associated with increased risk of anterior knee pain disorders including PFP, Osgood Schlatter, Sinding Larsen-Johansson compared to multi-sport athletes.
doi:10.1123/jsr.2013-0101
PMCID: PMC4247342  PMID: 24622506
sport specialization; knee injury; patellofemoral pain; adolescent athlete; sport injury
12.  Rifampicin pharmacokinetics in extreme prematurity to treat congenital tuberculosis 
BMJ Case Reports  2013;2013:bcr2012008207.
Little evidence is available on the pharmacokinetics of antituberculous medication in premature infants. We report rifampicin (RMP) pharmacokinetics in an extremely premature, low-birthweight female infant born to a mother with known miliary tuberculosis. Intravenous RMP, isoniazid (INH), ciprofloxacin and amikacin were used, as the enteral route was not possible. Area under the curve calculations revealed low average RMP concentrations at doses of 5–10 mg/kg. We review the literature with regard to the dosing regimen and therapeutic drug levels of RMP and INH in premature infants and discuss issues of management. Evidence from this case suggests 10 mg/kg/day is the minimum dose required.
doi:10.1136/bcr-2012-008207
PMCID: PMC3604510  PMID: 23355589
13.  Role of IL-6 in Mycobacterium avium associated Immune Reconstitution Inflammatory Syndrome 
Immune Reconstitution Inflammatory Syndrome (IRIS) is a major adverse event of antiretroviral therapy (ART) in HIV infection, and paradoxically occurs as HIV viremia is suppressed and CD4 T cell numbers recover. IRIS reflects pathogenic immune responses against opportunistic infections acquired during the period of immunodeficiency, but little is understood about the mechanisms of inflammatory pathology. Here we show that IL-6 and CRP levels transiently rise at the time of the IRIS event in HIV-infected patients umasking Mycobacterium avium complex (MAC) infection after starting ART. To directly test the role of IL-6 in IRIS pathology, we employed a model of experimentally inducible IRIS in which M. avium infected T cell deficient mice undergo a fatal inflammatory disease after reconstitution with CD4 T cells. We find that IL-6 neutralization reduces CRP levels, alleviates wasting disease and extends host survival during experimental IRIS. Moreover, we show that combined blockade of IL-6 and IFNγ further reduces IRIS pathology, even after the onset of wasting disease. The combination of these clinical and experimental-model data show that the IL-6 pathway is not only a biomarker of mycobacterial IRIS but also a major mediator of pathology distinct from IFNγ, and may be a useful target for therapeutic intervention.
doi:10.4049/jimmunol.1301004
PMCID: PMC3947368  PMID: 24337386
14.  Development of Organometallic S6K1 Inhibitors 
Journal of medicinal chemistry  2014;58(1):305-314.
Aberrant activation of S6 kinase 1 (S6K1) is found in many diseases, including diabetes, aging, and cancer. We developed ATP competitive organometallic kinase inhibitors, EM5 and FL772, which are inspired by the structure of the pan-kinase inhibitor staurosporine, to specifically inhibit S6K1 using a strategy previously used to target other kinases. Biochemical data demonstrate that EM5 and FL772 inhibit the kinase with IC50 value in the low nanomolar range at 100 μM ATP and that the more potent FL772 compound has a greater than 100-fold specificity over S6K2. The crystal structures of S6K1 bound to staurosporine, EM5, and FL772 reveal that the EM5 and FL772 inhibitors bind in the ATP binding pocket and make S6K1-specific contacts, resulting in changes to the p-loop, αC helix, and αD helix when compared to the staurosporine-bound structure. Cellular data reveal that FL772 is able to inhibit S6K phosphorylation in yeast cells. Together, these studies demonstrate that potent, selective, and cell permeable S6K1 inhibitors can be prepared and provide a scaffold for future development of S6K inhibitors with possible therapeutic applications.
doi:10.1021/jm5011868
PMCID: PMC4289024  PMID: 25356520
15.  Parasite Biomass-Related Inflammation, Endothelial Activation, Microvascular Dysfunction and Disease Severity in Vivax Malaria 
PLoS Pathogens  2015;11(1):e1004558.
Plasmodium vivax can cause severe malaria, however its pathogenesis is poorly understood. In contrast to P. falciparum, circulating vivax parasitemia is low, with minimal apparent sequestration in endothelium-lined microvasculature, and pathogenesis thought unrelated to parasite biomass. However, the relationships between vivax disease-severity and total parasite biomass, endothelial autocrine activation and microvascular dysfunction are unknown. We measured circulating parasitemia and markers of total parasite biomass (plasma parasite lactate dehydrogenase [pLDH] and PvLDH) in adults with severe (n = 9) and non-severe (n = 53) vivax malaria, and examined relationships with disease-severity, endothelial activation, and microvascular function. Healthy controls and adults with non-severe and severe falciparum malaria were enrolled for comparison. Median peripheral parasitemia, PvLDH and pLDH were 2.4-fold, 3.7-fold and 6.9-fold higher in severe compared to non-severe vivax malaria (p = 0.02, p = 0.02 and p = 0.015, respectively), suggesting that, as in falciparum malaria, peripheral P. vivax parasitemia underestimates total parasite biomass, particularly in severe disease. P. vivax schizonts were under-represented in peripheral blood. Severe vivax malaria was associated with increased angiopoietin-2 and impaired microvascular reactivity. Peripheral vivax parasitemia correlated with endothelial activation (angiopoietin-2, von-Willebrand-Factor [VWF], E-selectin), whereas markers of total vivax biomass correlated only with systemic inflammation (IL-6, IL-10). Activity of the VWF-cleaving-protease, ADAMTS13, was deficient in proportion to endothelial activation, IL-6, thrombocytopenia and vivax disease-severity, and associated with impaired microvascular reactivity in severe disease. Impaired microvascular reactivity correlated with lactate in severe vivax malaria. Findings suggest that tissue accumulation of P. vivax may occur, with the hidden biomass greatest in severe disease and capable of mediating systemic inflammatory pathology. The lack of association between total parasite biomass and endothelial activation is consistent with accumulation in parts of the circulation devoid of endothelium. Endothelial activation, associated with circulating parasites, and systemic inflammation may contribute to pathology in vivax malaria, with microvascular dysfunction likely contributing to impaired tissue perfusion.
Author Summary
How vivax parasites cause severe malaria is not known. In contrast to falciparum parasites, the number of vivax parasites circulating in peripheral blood is low, and there is thought to be little sequestration of parasitized red cells within endothelium-lined small blood vessels in vital organs. Total parasite burden (circulating plus hidden) and activation and dysfunction of the endothelial cells lining blood vessels all contribute to severe disease in falciparum malaria, but have not been evaluated in severe vivax malaria. We measured parasite lactate dehydrogenase (pLDH) and P. vivax-pLDH (PvLDH) as proxies of total parasite biomass and found that, as in falciparum malaria, the total biomass of vivax parasites is underestimated by counting parasites circulating in peripheral blood, suggesting a hidden burden of vivax parasites. Markers of total vivax biomass were strongly associated with illness-severity and inflammatory cytokines, suggesting that this hidden burden is capable of contributing to generalised inflammation and hence severe disease. Number of peripheral vivax parasites, but not total biomass, correlated with activation of endothelial cells, suggesting that the hidden vivax-infected red cells may accumulate in parts of organs without endothelium, such as the slow-circulation of the spleen or non-blood-vessel parts of the bone marrow. Severe vivax malaria was associated with increased endothelial activation and impaired microvascular function, suggesting that these processes also contribute to impaired blood flow and disease.
doi:10.1371/journal.ppat.1004558
PMCID: PMC4287532  PMID: 25569250
16.  Antagonism of EGFR and HER3 Enhances the Response to Inhibitors of the PI3K-Akt Pathway in Triple-Negative Breast Cancer 
Science signaling  2014;7(318):ra29.
Both abundant epidermal growth factor receptor (EGFR or ErbB1) and high activity of the phosphatidyl-inositol 3-kinase (PI3K)–Akt pathway are common and therapeutically targeted in triple-negative breast cancer (TNBC). However, activation of another EGFR family member [human epidermal growth factor receptor 3 (HER3) (or ErbB3)] may limit the antitumor effects of these drugs. We found that TNBC cell lines cultured with the EGFR or HER3 ligand EGF or heregulin, respectively, and treated with either an Akt inhibitor (GDC-0068) or a PI3K inhibitor (GDC-0941) had increased abundance and phosphorylation of HER3. The phosphorylation of HER3 and EGFR in response to these treatments was reduced by the addition of a dual EGFR and HER3 inhibitor (MEHD7945A). MEHD7945A also decreased the phosphorylation (and activation) of EGFR and HER3 and the phosphorylation of downstream targets that occurred in response to the combination of EGFR ligands and PI3K-Akt pathway inhibitors. In culture, inhibition of the PI3K-Akt pathway combined with either MEHD7945A or knockdown of HER3 decreased cell proliferation compared with inhibition of the PI3K-Akt pathway alone. Combining either GDC-0068 or GDC-0941 with MEHD7945A inhibited the growth of xenografts derived from TNBC cell lines or from TNBC patient tumors, and this combination treatment was also more effective than combining either GDC-0068 or GDC-0941 with cetuximab, an EGFR-targeted antibody. After therapy with EGFR-targeted antibodies, some patients had residual tumors with increased HER3 abundance and EGFR/HER3 dimerization (an activating interaction). Thus, we propose that concomitant blockade of EGFR, HER3, and the PI3K-Akt pathway in TNBC should be investigated in the clinical setting.
doi:10.1126/scisignal.2005125
PMCID: PMC4283215  PMID: 24667376
17.  High knee abduction moments are common risk factors for patellofemoral pain (PFP) and anterior cruciate ligament (ACL) injury in girls: Is PFP itself a predictor for subsequent ACL injury? 
Background
Identifying risk factors for knee pain and anterior cruciate ligament (ACL) injury can be an important step in the injury prevention cycle.
Objective
We evaluated two unique prospective cohorts with similar populations and methodologies to compare the incidence rates and risk factors associated with patellofemoral pain (PFP) and ACL injury.
Methods
The ‘PFP cohort’ consisted of 240 middle and high school female athletes. They were evaluated by a physician and underwent anthropometric assessment, strength testing and three-dimensional landing biomechanical analyses prior to their basketball season. 145 of these athletes met inclusion for surveillance of incident (new) PFP by certified athletic trainers during their competitive season. The ‘ACL cohort’ included 205 high school female volleyball, soccer and basketball athletes who underwent the same anthropometric, strength and biomechanical assessment prior to their competitive season and were subsequently followed up for incidence of ACL injury. A one-way analysis of variance was used to evaluate potential group (incident PFP vs ACL injured) differences in anthropometrics, strength and landing biomechanics. Knee abduction moment (KAM) cut-scores that provided the maximal sensitivity and specificity for prediction of PFP or ACL injury risk were also compared between the cohorts.
Results
KAM during landing above 15.4 Nm was associated with a 6.8% risk to develop PFP compared to a 2.9% risk if below the PFP risk threshold in our sample. Likewise, a KAM above 25.3 Nm was associated with a 6.8% risk for subsequent ACL injury compared to a 0.4% risk if below the established ACL risk threshold. The ACL-injured athletes initiated landing with a greater knee abduction angle and a reduced hamstrings-to-quadriceps strength ratio relative to the incident PFP group. Also, when comparing across cohorts, the athletes who suffered ACL injury also had lower hamstring/quadriceps ratio than the players in the PFP sample (p<0.05).
Conclusions
In adolescent girls aged 13.3 years, >15 Nm of knee abduction load during landing is associated with greater likelihood of developing PFP. Also, in girls aged 16.1 years who land with >25 Nm of knee abduction load during landing are at increased risk for both PFP and ACL injury.
doi:10.1136/bjsports-2013-092536
PMCID: PMC4182160  PMID: 24687011
18.  Dietary Fat Intake, Pesticide Use, and Parkinson’s Disease 
Background
Dietary fat intake may modify Parkinson’s disease (PD) risk directly or by altering the response to environmental neurotoxicants including pesticides.
Methods
We conducted a case-control study of PD nested in the Agricultural Health Study (AHS), a cohort of pesticide applicators and spouses. We evaluated diet and pesticide use before diagnosis in 89 PD cases, confirmed by movement disorder specialists, or a corresponding date in 336 frequency-matched controls. Associations were evaluated using multivariate logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs).
Results
In the AHS, PD was inversely associated with N-3 polyunsaturated fatty acids (PUFAs) (OR 0.4,95% CI 0.2-0.8 for highest vs lowest tertile) and the N-3 precursor α-linolenic acid (0.4, 0.2-0.8). In a meta-analysis of nine studies, including the present one, PD was inversely associated with α-linolenic acid (0.81, 0.68-0.96). In the AHS, associations of PD with the pesticides paraquat and rotenone were modified by fat intake. The OR for paraquat was 4.2 (1.5-12) in individuals with PUFA intake below the median but 1.2 (0.4-3.4) in those with higher intake (p-interaction=0.10). The OR for rotenone was 5.8 (2.3-15) in those with saturated fat intake above the median but 1.5 (0.5-4.2) in those with lower intake p-interaction=0.02).
Conclusions
PUFA intake was consistently associated with lower PD risk, and dietary fats modified the association of PD risk with pesticide exposure. If confirmed, these findings suggest that a diet high in PUFAs and low in saturated fats might reduce risk of PD.
doi:10.1016/j.parkreldis.2013.09.023
PMCID: PMC3936597  PMID: 24120951
Parkinson’s disease; dietary fat; polyunsaturated fatty acids; pesticides
19.  Expression of FcγRIIB Tempers Memory CD8 T-cell Function in vivo 
Journal of immunology (Baltimore, Md. : 1950)  2013;192(1):10.4049/jimmunol.1302232.
During re-infection high-affinity IgG antibodies form complexes with both soluble antigen and antigen displayed on the surface of infected cells. These interactions regulate cellular activation of both innate cells and B cells, which express specific combinations of activating Fc gamma receptors (FcγRI, FcγRIII, FcγRIV) and/or the inhibitory Fc gamma receptor (FcγRIIB). Direct proof for functional expression of FcγR by antigen-specific CD8 T-cells is lacking. Here, we show that the majority of memory CD8 T-cells generated by bacterial or viral infection express only FcγRIIB and that FcγRIIB could be detected on previously activated human CD8 T-cells. Of note, FcγR stimulation during in vivo antigen challenge not only inhibited the cytotoxicity of memory CD8 T-cells against peptide-loaded or virus-infected targets, but FcγRIIB blockade during homologous virus challenge enhanced the secondary CD8 T-cell response. Thus, memory CD8 T-cells intrinsically express a functional FcγRIIB, permitting antigen-antibody complexes to regulate secondary CD8 T-cell responses.
doi:10.4049/jimmunol.1302232
PMCID: PMC3874719  PMID: 24285839
20.  The risk of unintended pregnancy among young women with mental health symptoms 
Depression and stress have been linked with poor contraceptive behavior, but whether existing mental health symptoms influence women's subsequent risk of unintended pregnancy is unclear. We prospectively examined the effect of depression and stress symptoms on young women's pregnancy risk over one year. We used panel data from a longitudinal study of 992 U.S. women ages 18-20 years who reported a strong desire to avoid pregnancy. Weekly journal surveys measured relationship, contraceptive use and pregnancy outcomes. We examined 27,572 journal surveys from 940 women over the first study year. Our outcome was self-reported pregnancy. At baseline, we assessed moderate/severe depression (CESD-5) and stress (PSS-4) symptoms. We estimated the effect of baseline mental health symptoms on pregnancy risk with discrete-time, mixed-effects, proportional hazard models using logistic regression. At baseline, 24% and 23% of women reported moderate/severe depression and stress symptoms, respectively. Ten percent of young women not intending pregnancy became pregnant during the study. Rates of pregnancy were higher among women with baseline depression (14% vs. 9%, p=0.04) and stress (15% vs. 9%, p=0.03) compared to women without symptoms. In multivariable models, the risk of pregnancy was 1.6 times higher among women with stress symptoms compared to those without stress (aRR 1.6, CI 1.1,2.7). Women with co-occurring stress and depression symptoms had over twice the risk of pregnancy (aRR 2.1, CI 1.1,3.8) compared to those without symptoms. Among women without a prior pregnancy, having co-occurring stress and depression symptoms was the strongest predictor of subsequent pregnancy (aRR 2.3, CI 1.2,4.3), while stress alone was the strongest predictor among women with a prior pregnancy (aRR 3.0, CI 1.1,8.8). Depression symptoms were not independently associated with young women's pregnancy risk. In conclusion, stress, and especially co-occurring stress and depression symptoms, consistently and adversely influenced these young women's risk of unintended pregnancy over one year.
doi:10.1016/j.socscimed.2013.10.037
PMCID: PMC3898511  PMID: 24444840
United States; unintended pregnancy; mental health; depression; stress; adolescent women
21.  NRF2 plays a protective role in diabetic retinopathy in mice 
Diabetologia  2013;57(1):204-213.
Aims/hypothesis
Although much is known about the pathophysiological processes contributing to diabetic retinopathy (DR), the role of protective pathways has received less attention. The transcription factor nuclear factor erythroid-2-related factor 2 (also known as NFE2L2 or NRF2) is an important regulator of oxidative stress and also has anti-inflammatory effects. The objective of this study was to explore the potential role of NRF2 as a protective mechanism in DR.
Methods
Retinal expression of NRF2 was investigated in human donor and mouse eyes by immunohistochemistry. The effect of NRF2 modulation on oxidative stress was studied in the human Müller cell line MIO-M1. Non-diabetic and streptozotocin-induced diabetic wild-type and Nrf2 knockout mice were evaluated for multiple DR endpoints.
Results
NRF2 was expressed prominently in Müller glial cells and astrocytes in both human and mouse retinas. In cultured MIO-M1 cells, NRF2 inhibition significantly decreased antioxidant gene expression and exacerbated tert-butyl hydroperoxide- and hydrogen peroxide-induced oxidative stress. NRF2 activation strongly increased NRF2 target gene expression and suppressed oxidant-induced reactive oxygen species. Diabetic mice exhibited retinal NRF2 activation, indicated by nuclear translocation. Superoxide levels were significantly increased by diabetes in Nrf2 knockout mice as compared with wild-type mice. Diabetic Nrf2 knockout mice exhibited a reduction in retinal glutathione and an increase in TNF-α protein compared with wild-type mice. Nrf2 knockout mice exhibited early onset of blood–retina barrier dysfunction and exacerbation of neuronal dysfunction in diabetes.
Conclusions/interpretation
These results indicate that NRF2 is an important protective mechanism regulating the progression of DR and suggest enhancement of the NRF2 pathway as a potential therapeutic strategy.
doi:10.1007/s00125-013-3093-8
PMCID: PMC4039644  PMID: 24186494
Diabetic retinopathy; Inflammation; Müller glial cells; Neuronal dysfunction; NF-E2-related factor-2; Reactive oxygen species; Transcription factor; Vascular permeability
22.  An experimental investigation into the effects of traffic noise on distributions of birds: avoiding the phantom road 
Many authors have suggested that the negative effects of roads on animals are largely owing to traffic noise. Although suggestive, most past studies of the effects of road noise on wildlife were conducted in the presence of the other confounding effects of roads, such as visual disturbance, collisions and chemical pollution among others. We present, to our knowledge, the first study to experimentally apply traffic noise to a roadless area at a landscape scale—thus avoiding the other confounding aspects of roads present in past studies. We replicated the sound of a roadway at intervals—alternating 4 days of noise on with 4 days off—during the autumn migratory period using a 0.5 km array of speakers within an established stopover site in southern Idaho. We conducted daily bird surveys along our ‘Phantom Road’ and in a nearby control site. We document over a one-quarter decline in bird abundance and almost complete avoidance by some species between noise-on and noise-off periods along the phantom road and no such effects at control sites—suggesting that traffic noise is a major driver of effects of roads on populations of animals.
doi:10.1098/rspb.2013.2290
PMCID: PMC3826227  PMID: 24197411
anthropogenic noise; road ecology; noise pollution; traffic noise; bird migration; stopover habitat
23.  Imaging tumour heterogeneity of the consequences of a PKCα–substrate interaction in breast cancer patients 
Biochemical Society transactions  2014;42(6):1498-1505.
Breast cancer heterogeneity demands that prognostic models must be biologically driven and recent clinical evidence indicates that future prognostic signatures need evaluation in the context of early compared with late metastatic risk prediction. In pre-clinical studies, we and others have shown that various protein–protein interactions, pertaining to the actin microfilament-associated proteins, ezrin and cofilin, mediate breast cancer cell migration, a prerequisite for cancer metastasis. Moreover, as a direct substrate for protein kinase Cα, ezrin has been shown to be a determinant of cancer metastasis for a variety of tumour types, besides breast cancer; and has been described as a pivotal regulator of metastasis by linking the plasma membrane to the actin cytoskeleton. In the present article, we demonstrate that our tissue imaging-derived parameters that pertain to or are a consequence of the PKC–ezrin interaction can be used for breast cancer prognostication, with inter-cohort reproducibility. The application of fluorescence lifetime imaging microscopy (FLIM) in formalin-fixed paraffin-embedded patient samples to probe protein proximity within the typically <10 nm range to address the oncological challenge of tumour heterogeneity, is discussed.
doi:10.1042/BST20140165
PMCID: PMC4259014  PMID: 25399560
breast cancer; cofilin; ezrin; Förster resonance energy transfer (FRET)/fluorescence-lifetime imaging microscopy (FLIM); protein kinase Cα (PKCα)
24.  Global, regional, and national levels and causes of maternal mortality during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013 
Kassebaum, Nicholas J | Bertozzi-Villa, Amelia | Coggeshall, Megan S | Shackelford, Katya A | Steiner, Caitlyn | Heuton, Kyle R | Gonzalez-Medina, Diego | Barber, Ryan | Huynh, Chantal | Dicker, Daniel | Templin, Tara | Wolock, Timothy M | Ozgoren, Ayse Abbasoglu | Abd-Allah, Foad | Abera, Semaw Ferede | Abubakar, Ibrahim | Achoki, Tom | Adelekan, Ademola | Ademi, Zanfina | Adou, Arsène Kouablan | Adsuar, José C | Agardh, Emilie E | Akena, Dickens | Alasfoor, Deena | Alemu, Zewdie Aderaw | Alfonso-Cristancho, Rafael | Alhabib, Samia | Ali, Raghib | Al Kahbouri, Mazin J | Alla, François | Allen, Peter J | AlMazroa, Mohammad A | Alsharif, Ubai | Alvarez, Elena | Alvis-Guzmán, Nelson | Amankwaa, Adansi A | Amare, Azmeraw T | Amini, Hassan | Ammar, Walid | Antonio, Carl A T | Anwari, Palwasha | Ärnlöv, Johan | Arsenijevic, Valentina S Arsic | Artaman, Ali | Asad, Majed Masoud | Asghar, Rana J | Assadi, Reza | Atkins, Lydia S | Badawi, Alaa | Balakrishnan, Kalpana | Basu, Arindam | Basu, Sanjay | Beardsley, Justin | Bedi, Neeraj | Bekele, Tolesa | Bell, Michelle L | Bernabe, Eduardo | Beyene, Tariku J | Bhutta, Zulfiqar | Abdulhak, Aref Bin | Blore, Jed D | Basara, Berrak Bora | Bose, Dipan | Breitborde, Nicholas | Cárdenas, Rosario | Castañeda-Orjuela, Carlos A | Castro, Ruben Estanislao | Catalá-López, Ferrán | Cavlin, Alanur | Chang, Jung-Chen | Che, Xuan | Christophi, Costas A | Chugh, Sumeet S | Cirillo, Massimo | Colquhoun, Samantha M | Cooper, Leslie Trumbull | Cooper, Cyrus | da Costa Leite, Iuri | Dandona, Lalit | Dandona, Rakhi | Davis, Adrian | Dayama, Anand | Degenhardt, Louisa | De Leo, Diego | del Pozo-Cruz, Borja | Deribe, Kebede | Dessalegn, Muluken | deVeber, Gabrielle A | Dharmaratne, Samath D | Dilmen, Uğur | Ding, Eric L | Dorrington, Rob E | Driscoll, Tim R | Ermakov, Sergei Petrovich | Esteghamati, Alireza | Faraon, Emerito Jose A | Farzadfar, Farshad | Felicio, Manuela Mendonca | Fereshtehnejad, Seyed-Mohammad | de Lima, Graça Maria Ferreira | Forouzanfar, Mohammad H | França, Elisabeth B | Gaffikin, Lynne | Gambashidze, Ketevan | Gankpé, Fortuné Gbètoho | Garcia, Ana C | Geleijnse, Johanna M | Gibney, Katherine B | Giroud, Maurice | Glaser, Elizabeth L | Goginashvili, Ketevan | Gona, Philimon | González-Castell, Dinorah | Goto, Atsushi | Gouda, Hebe N | Gugnani, Harish Chander | Gupta, Rahul | Gupta, Rajeev | Hafezi-Nejad, Nima | Hamadeh, Randah Ribhi | Hammami, Mouhanad | Hankey, Graeme J | Harb, Hilda L | Havmoeller, Rasmus | Hay, Simon I | Heredia Pi, Ileana B | Hoek, Hans W | Hosgood, H Dean | Hoy, Damian G | Husseini, Abdullatif | Idrisov, Bulat T | Innos, Kaire | Inoue, Manami | Jacobsen, Kathryn H | Jahangir, Eiman | Jee, Sun Ha | Jensen, Paul N | Jha, Vivekanand | Jiang, Guohong | Jonas, Jost B | Juel, Knud | Kabagambe, Edmond Kato | Kan, Haidong | Karam, Nadim E | Karch, André | Karema, Corine Kakizi | Kaul, Anil | Kawakami, Norito | Kazanjan, Konstantin | Kazi, Dhruv S | Kemp, Andrew H | Kengne, Andre Pascal | Kereselidze, Maia | Khader, Yousef Saleh | Khalifa, Shams Eldin Ali Hassan | Khan, Ejaz Ahmed | Khang, Young-Ho | Knibbs, Luke | Kokubo, Yoshihiro | Kosen, Soewarta | Defo, Barthelemy Kuate | Kulkarni, Chanda | Kulkarni, Veena S | Kumar, G Anil | Kumar, Kaushalendra | Kumar, Ravi B | Kwan, Gene | Lai, Taavi | Lalloo, Ratilal | Lam, Hilton | Lansingh, Van C | Larsson, Anders | Lee, Jong-Tae | Leigh, James | Leinsalu, Mall | Leung, Ricky | Li, Xiaohong | Li, Yichong | Li, Yongmei | Liang, Juan | Liang, Xiaofeng | Lim, Stephen S | Lin, Hsien-Ho | Lipshultz, Steven E | Liu, Shiwei | Liu, Yang | Lloyd, Belinda K | London, Stephanie J | Lotufo, Paulo A | Ma, Jixiang | Ma, Stefan | Machado, Vasco Manuel Pedro | Mainoo, Nana Kwaku | Majdan, Marek | Mapoma, Christopher Chabila | Marcenes, Wagner | Marzan, Melvin Barrientos | Mason-Jones, Amanda J | Mehndiratta, Man Mohan | Mejia-Rodriguez, Fabiola | Memish, Ziad A | Mendoza, Walter | Miller, Ted R | Mills, Edward J | Mokdad, Ali H | Mola, Glen Liddell | Monasta, Lorenzo | de la Cruz Monis, Jonathan | Hernandez, Julio Cesar Montañez | Moore, Ami R | Moradi-Lakeh, Maziar | Mori, Rintaro | Mueller, Ulrich O | Mukaigawara, Mitsuru | Naheed, Aliya | Naidoo, Kovin S | Nand, Devina | Nangia, Vinay | Nash, Denis | Nejjari, Chakib | Nelson, Robert G | Neupane, Sudan Prasad | Newton, Charles R | Ng, Marie | Nieuwenhuijsen, Mark J | Nisar, Muhammad Imran | Nolte, Sandra | Norheim, Ole F | Nyakarahuka, Luke | Oh, In-Hwan | Ohkubo, Takayoshi | Olusanya, Bolajoko O | Omer, Saad B | Opio, John Nelson | Orisakwe, Orish Ebere | Pandian, Jeyaraj D | Papachristou, Christina | Park, Jae-Hyun | Caicedo, Angel J Paternina | Patten, Scott B | Paul, Vinod K | Pavlin, Boris Igor | Pearce, Neil | Pereira, David M | Pesudovs, Konrad | Petzold, Max | Poenaru, Dan | Polanczyk, Guilherme V | Polinder, Suzanne | Pope, Dan | Pourmalek, Farshad | Qato, Dima | Quistberg, D Alex | Rafay, Anwar | Rahimi, Kazem | Rahimi-Movaghar, Vafa | Rahman, Sajjad ur | Raju, Murugesan | Rana, Saleem M | Refaat, Amany | Ronfani, Luca | Roy, Nobhojit | Sánchez Pimienta, Tania Georgina | Sahraian, Mohammad Ali | Salomon, Joshua A | Sampson, Uchechukwu | Santos, Itamar S | Sawhney, Monika | Sayinzoga, Felix | Schneider, Ione J C | Schumacher, Austin | Schwebel, David C | Seedat, Soraya | Sepanlou, Sadaf G | Servan-Mori, Edson E | Shakh-Nazarova, Marina | Sheikhbahaei, Sara | Shibuya, Kenji | Shin, Hwashin Hyun | Shiue, Ivy | Sigfusdottir, Inga Dora | Silberberg, Donald H | Silva, Andrea P | Singh, Jasvinder A | Skirbekk, Vegard | Sliwa, Karen | Soshnikov, Sergey S | Sposato, Luciano A | Sreeramareddy, Chandrashekhar T | Stroumpoulis, Konstantinos | Sturua, Lela | Sykes, Bryan L | Tabb, Karen M | Talongwa, Roberto Tchio | Tan, Feng | Teixeira, Carolina Maria | Tenkorang, Eric Yeboah | Terkawi, Abdullah Sulieman | Thorne-Lyman, Andrew L | Tirschwell, David L | Towbin, Jeffrey A | Tran, Bach X | Tsilimbaris, Miltiadis | Uchendu, Uche S | Ukwaja, Kingsley N | Undurraga, Eduardo A | Uzun, Selen Begüm | Vallely, Andrew J | van Gool, Coen H | Vasankari, Tommi J | Vavilala, Monica S | Venketasubramanian, N | Villalpando, Salvador | Violante, Francesco S | Vlassov, Vasiliy Victorovich | Vos, Theo | Waller, Stephen | Wang, Haidong | Wang, Linhong | Wang, XiaoRong | Wang, Yanping | Weichenthal, Scott | Weiderpass, Elisabete | Weintraub, Robert G | Westerman, Ronny | Wilkinson, James D | Woldeyohannes, Solomon Meseret | Wong, John Q | Wordofa, Muluemebet Abera | Xu, Gelin | Yang, Yang C | Yano, Yuichiro | Yentur, Gokalp Kadri | Yip, Paul | Yonemoto, Naohiro | Yoon, Seok-Jun | Younis, Mustafa Z | Yu, Chuanhua | Jin, Kim Yun | El SayedZaki, Maysaa | Zhao, Yong | Zheng, Yingfeng | Zhou, Maigeng | Zhu, Jun | Zou, Xiao Nong | Lopez, Alan D | Naghavi, Mohsen | Murray, Christopher J L | Lozano, Rafael
Lancet  2014;384(9947):980-1004.
Summary
Background
The fifth Millennium Development Goal (MDG 5) established the goal of a 75% reduction in the maternal mortality ratio (MMR; number of maternal deaths per 100 000 livebirths) between 1990 and 2015. We aimed to measure levels and track trends in maternal mortality, the key causes contributing to maternal death, and timing of maternal death with respect to delivery.
Methods
We used robust statistical methods including the Cause of Death Ensemble model (CODEm) to analyse a database of data for 7065 site-years and estimate the number of maternal deaths from all causes in 188 countries between 1990 and 2013. We estimated the number of pregnancy-related deaths caused by HIV on the basis of a systematic review of the relative risk of dying during pregnancy for HIV-positive women compared with HIV-negative women. We also estimated the fraction of these deaths aggravated by pregnancy on the basis of a systematic review. To estimate the numbers of maternal deaths due to nine different causes, we identified 61 sources from a systematic review and 943 site-years of vital registration data. We also did a systematic review of reports about the timing of maternal death, identifying 142 sources to use in our analysis. We developed estimates for each country for 1990–2013 using Bayesian meta-regression. We estimated 95% uncertainty intervals (UIs) for all values.
Findings
292 982 (95% UI 261 017–327 792) maternal deaths occurred in 2013, compared with 376 034 (343 483–407 574) in 1990. The global annual rate of change in the MMR was −0·3% (−1·1 to 0·6) from 1990 to 2003, and −2·7% (−3·9 to −1·5) from 2003 to 2013, with evidence of continued acceleration. MMRs reduced consistently in south, east, and southeast Asia between 1990 and 2013, but maternal deaths increased in much of sub-Saharan Africa during the 1990s. 2070 (1290–2866) maternal deaths were related to HIV in 2013, 0·4% (0·2–0·6) of the global total. MMR was highest in the oldest age groups in both 1990 and 2013. In 2013, most deaths occurred intrapartum or postpartum. Causes varied by region and between 1990 and 2013. We recorded substantial variation in the MMR by country in 2013, from 956·8 (685·1–1262·8) in South Sudan to 2·4 (1·6–3·6) in Iceland.
Interpretation
Global rates of change suggest that only 16 countries will achieve the MDG 5 target by 2015. Accelerated reductions since the Millennium Declaration in 2000 coincide with increased development assistance for maternal, newborn, and child health. Setting of targets and associated interventions for after 2015 will need careful consideration of regions that are making slow progress, such as west and central Africa.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S0140-6736(14)60696-6
PMCID: PMC4255481  PMID: 24797575
25.  Elevated IgE and atopy in patients treated for early onset ADA-SCID 
The Journal of allergy and clinical immunology  2013;132(6):10.1016/j.jaci.2013.05.040.
doi:10.1016/j.jaci.2013.05.040
PMCID: PMC3844080  PMID: 23895897
Early-onset ADA-SCID; primary immunodeficiency; atopy; IgE; T cell signaling; Th2 cytokines

Results 1-25 (1585)