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1.  The Metabolism and Secretion of Aldosterone in Elderly Subjects* 
Journal of Clinical Investigation  1967;46(6):960-966.
The secretion rates [34 ± 6 (SE) μg per day, 9 subjects] and metabolic clearance rates (MCR) [1,288 ± 120 (SE) L of plasma per day, 9 subjects] of aldosterone in elderly subjects are significantly lower than those of young subjects [77 ± 7 (SE) μg per day and 1,631 ± 106 (SE) L per day, respectively]. There is a correlation of the MCR and secretion rate values (p = 0.02), but the calculated plasma concentrations (secretion rate/MCR) are also significantly low in the elderly subjects [2.6 ± 0.3 (SE) compared with concentrations in the plasma from young subjects of 4.7 ± 0.6 (SE) μg per 100 ml plasma].
The urinary excretion of radioactivity from oral and intravenously administered labeled aldosterone as aldosterone in the neutral extract, as aldosterone released by acid hydrolysis, and as tetrahydroaldosterone released by incubation with β-glucuronidase is generally similar for young and elderly subjects except that a larger portion of the oral compared with the intravenous dose is excreted as free aldosterone in the elderly subjects, indicating that the splanchnic extraction is reduced. The calculated splanchnic blood flow (assuming no alteration in extrasplanchnic metabolism) is also slightly lowered.
Therefore, as in patients with mild cardiac dysfunction, the lowered MCR of subjects is due to both reduced splanchnic extraction and blood flow. However, unlike the heart failure patients, in the elderly subjects the plasma concentration of aldosterone is also reduced.
PMCID: PMC297100  PMID: 6026101
2.  A Comparison of the Metabolism of Radioactive 17-Isoaldosterone and Aldosterone Administered Intravenously and Orally to Normal Human Subjects* 
Journal of Clinical Investigation  1967;46(5):717-727.
After intravenous and oral administration of radioactive aldosterone to normal subjects, 7.3 ± 0.4 (SE) and 5.4 ± 0.5 (SE)%, respectively, of the dose was recovered from a 48-hour collection of urine as aldosterone released by mild acid hydrolysis (from aldosterone 18-glucuronide), and 35 ± 5 (SE) and 39 ± 4 (SE)%, respectively, was recovered as tetrahydroaldosterone after incubation with β-glucuronidase.
After intravenous and oral administration of 17-isoaldosterone-4-14C to a similar group of subjects, 35 ± 3 (SE) and 53 ± 4 (SE)%, respectively, of the dose was recovered as 17-isoaldosterone released by acid and less than 5% as total metabolites after incubation with β-glucuronidase. No detectable radioactivity (< 0.5%) could be recovered as tetrahydroaldosterone or as a compound with the expected chromatographic properties of tetrahydro-17-isoaldosterone.
The total radioactivity in the neutral extracts was also relatively small (< 2%) after administration of either labeled aldosterone or 17-isoaldosterone. The radioactivity as aldosterone in the neutral extract was much lower after oral [0.017 ± 0.003 (SE)%] than after intravenous [0.21 ± 0.04 (SE)%] administration of labeled aldosterone. The radioactivity as 17-isoaldosterone in the neutral extract was similar after intravenous [0.20 ± 0.02 (SE)%] and after oral [0.38 ± 0.18 (SE)%] administration of 17-isoaldosterone.
These results indicated that, due to lack of A-ring reduction of the molecule and the consequent slowing of hepatic clearance, 17-isoaldosterone is converted to an acid-labile conjugate (presumably 17-isoaldosterone 18-glucuronide) as the major metabolite. 17-Isoaldosterone was not secreted or converted to aldosterone to any significant extent in the normal subjects investigated.
PMCID: PMC297074  PMID: 6025478
6.  An Interactive Individualized Intervention to Promote Behavioral Change to Increase Personal Well-Being in US Surgeons 
Annals of surgery  2014;259(1):82-88.
Evaluate the utility of a computer-based, interactive, and individualized intervention for promoting well-being in US surgeons.
Distress and burnout are common among US surgeons. Surgeons experiencing distress are unlikely to seek help on their own initiative. A belief that distress and burnout are a normal part of being a physician and lack of awareness of distress level relative to colleagues may contribute to this problem.
Surgeons who were members of the American College of Surgeons were invited to participate in an intervention study. Participating surgeons completed a 3-step, interactive, electronic intervention. First, surgeons subjectively assessed their well-being relative to colleagues. Second, surgeons completed the 7-item Mayo Clinic Physician Well-Being Index and received objective, individualized feedback about their well-being relative to national physician norms. Third, surgeons evaluated the usefulness of the feedback and whether they intended to make specific changes as a result.
A total of 1150 US surgeons volunteered to participate in the study. Surgeons’ subjective assessment of their well-being relative to colleagues was poor. A majority of surgeons (89.2%) believed that their well-being was at or above average, including 70.5% with scores in the bottom 30% relative to national norms. After receiving objective, individualized feedback based on the Mayo Clinic Physician Well-Being Index score, 46.6% of surgeons indicated that they intended to make specific changes as a result. Surgeons with lower well-being scores were more likely to make changes in each dimension assessed (all Ps < 0.001).
US surgeons do not reliably calibrate their level of distress. After self-assessment and individualized feedback using the Mayo Clinic Physician Well-Being Index, half of participating surgeons reported that they were contemplating behavioral changes to improve personal well-being.
PMCID: PMC4333681  PMID: 23979287
behavioral change; burnout; intervention; Physician Well-Being Index; physician
7.  Genome Wide Profiling of Dopaminergic Neurons Derived from Human Embryonic and Induced Pluripotent Stem Cells 
Stem Cells and Development  2013;23(4):406-420.
Recent advances in human embryonic stem cell (ESC) and induced pluripotent stem cell (iPSC) biology enable generation of dopaminergic neurons for potential therapy and drug screening. However, our current understanding of molecular and cellular signaling that controls human dopaminergic development and function is limited. Here, we report on a whole genome analysis of gene expression during dopaminergic differentiation of human ESC/iPSC using Illumina bead microarrays. We generated a transcriptome data set containing the expression levels of 28,688 unique transcripts by profiling five lines (three ESC and two iPSC lines) at four stages of differentiation: (1) undifferentiated ESC/iPSC, (2) neural stem cells, (3) dopaminergic precursors, and (4) dopaminergic neurons. This data set provides comprehensive information about genes expressed at each stage of differentiation. Our data indicate that distinct pathways are activated during neural and dopaminergic neuronal differentiation. For example, WNT, sonic hedgehog (SHH), and cAMP signaling pathways were found over-represented in dopaminergic populations by gene enrichment and pathway analysis, and their role was confirmed by perturbation analyses using RNAi (small interfering RNA of SHH and WNT) or small molecule [dibutyryl cyclic AMP (dcAMP)]. In summary, whole genome profiling of dopaminergic differentiation enables systematic analysis of genes/pathways, networks, and cellular/molecular processes that control cell fate decisions. Such analyses will serve as the foundation for better understanding of dopaminergic development, function, and development of future stem cell-based therapies.
PMCID: PMC3920839  PMID: 24074155
8.  The Emergence of Resistance to the Benzimidazole Anthlemintics in Parasitic Nematodes of Livestock Is Characterised by Multiple Independent Hard and Soft Selective Sweeps 
PLoS Neglected Tropical Diseases  2015;9(2):e0003494.
Anthelmintic resistance is a major problem for the control of parasitic nematodes of livestock and of growing concern for human parasite control. However, there is little understanding of how resistance arises and spreads or of the “genetic signature” of selection for this group of important pathogens. We have investigated these questions in the system for which anthelmintic resistance is most advanced; benzimidazole resistance in the sheep parasites Haemonchus contortus and Teladorsagia circumcincta. Population genetic analysis with neutral microsatellite markers reveals that T. circumcincta has higher genetic diversity but lower genetic differentiation between farms than H. contortus in the UK. We propose that this is due to epidemiological differences between the two parasites resulting in greater seasonal bottlenecking of H. contortus. There is a remarkably high level of resistance haplotype diversity in both parasites compared with drug resistance studies in other eukaryotic systems. Our analysis suggests a minimum of four independent origins of resistance mutations on just seven farms for H. contortus, and even more for T. circumincta. Both hard and soft selective sweeps have occurred with striking differences between individual farms. The sweeps are generally softer for T. circumcincta than H. contortus, consistent with its higher level of genetic diversity and consequent greater availability of new mutations. We propose a model in which multiple independent resistance mutations recurrently arise and spread by migration to explain the widespread occurrence of resistance in these parasites. Finally, in spite of the complex haplotypic diversity, we show that selection can be detected at the target locus using simple measures of genetic diversity and departures from neutrality. This work has important implications for the application of genome-wide approaches to identify new anthelmintic resistance loci and the likelihood of anthelmintic resistance emerging as selection pressure is increased in human soil-transmitted nematodes by community wide treatment programs.
Author Summary
Parasitic nematodes (roundworms) are major causes of disease in both domestic animals and humans. Strategic treatments with anthelmintic drugs have been used to control livestock parasites for several decades resulting in widespread drug resistance. Drug treatments have, until recently, been applied at a relatively low level to control human parasites. However, in recent years community wide treatment programs have been massively increased for the 1–2 billion people infected with roundworms. Hence, for both human and animal health, there is an urgent need to understand how resistance emerges and spreads and how we can detect resistance mutations in this important group of pathogens. In this study, we investigated how drug resistance mutations appear and spread in the two livestock parasites for which resistance is most widespread. We have found that resistance appears repeatedly and frequently in parasite populations, and propose a model to explain the high capacity of these pathogens to develop drug resistance. Our work suggests that anthelmintic resistance is likely to occur when repeated drug treatment is relied upon to control this group of pathogens. Our results also suggest that resistance mutations should be detectable when modern genome-wide approaches are used to scan the genomes of resistant parasites.
PMCID: PMC4319741  PMID: 25658086
9.  Acquired Chromosomal Anomalies in Chronic Lymphocytic Leukemia (CLL) Patients Compared to >50,000 Quasi-normal Subjects 
Cancer genetics  2014;207(0):19-30.
Pre-therapy CLL patients from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The four CLL-typical anomalies (11q-, +12, 13q- and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected and their number per subject has a significant effect on progression-free survival after adjusting for the effects of 17p- (and other covariates). These results were compared with a previous study of >50,000 subjects from the GENEVA consortium of genome-wide association studies, which analyzed individuals with a variety of medical conditions and healthy controls. The percentage of individuals with acquired anomalies is vastly different between the two studies (GENEVA 0.8%; E2997 80%). The composition also differs, with GENEVA having a higher percentage of acquired uniparental disomies and a lower percentage of deletions. The four common CLL anomalies are among the most frequent in GENEVA subjects, some of whom may have CLL-precursor conditions or early stages of CLL. However, the patients from E2997 (and other studies of symptomatic CLL) have recurrent acquired anomalies that were not found in GENEVA subjects, thus identifying genomic changes that may be unique to symptomatic stages of CLL.
PMCID: PMC4074414  PMID: 24613276
Chromosomal aberration; Chromosomal mosaic; Chronic Lymphocytic Leukemia; Cancer precursor condition; Cytogenetics
10.  The Impact of a Dedicated Research Education Month for Anesthesiology Residents 
An educational intervention was implemented at the University of Michigan starting in 2008, in which anesthesiology interns complete a dedicated month-long didactic rotation in evidence-based medicine (EBM) and research methodology. We sought to assess its utility. Scores on a validated EBM test before and after the rotation were compared and assessed for significance of improvement. A survey was also given to gauge satisfaction with the quality of the rotation and self-reported improvement in understanding of EBM topics. Fourteen consecutive interns completed the research rotation during the study period. One hundred percent completed both the pre- and postrotation test. The mean pretest score was 7.78 ± 2.46 (median = 7.5, 0–15 scale, and interquartile range 7.0–10.0) and the mean posttest score was 10.00 ± 2.35 (median = 9.5, interquartile range 8.0–12.3), which represented a statistically significant increase (P = 0.011, Wilcoxon signed-rank test). All fourteen of the residents “agreed” or “strongly agreed” that they would recommend the course to future interns and that the course increased their ability to critically review the literature. Our findings demonstrate that this can be an effective means of improving understanding of EBM topics and anesthesiology research.
PMCID: PMC4309211  PMID: 25653678
11.  Adolescents with current major depressive disorder show dissimilar patterns of age-related differences in ACC and thalamus 
NeuroImage : Clinical  2015;7:391-399.
There is little understanding of the neural system abnormalities subserving adolescent major depressive disorder (MDD). In a cross-sectional study we compare currently unipolar depressed with healthy adolescents to determine if group differences in grey matter volume (GMV) were influenced by age and illness severity.
Structural neuroimaging was performed on 109 adolescents with current MDD and 36 healthy controls, matched for age, gender, and handedness. GMV differences were examined within the anterior cingulate cortex (ACC) and across the whole-brain. The effects of age and self-reported depressive symptoms were also examined in regions showing significant main or interaction effects.
Whole-brain voxel based morphometry revealed no significant group differences. At the whole-brain level, both groups showed a main effect of age on GMV, although this effect was more pronounced in controls. Significant group-by-age interactions were noted: A significant regional group-by-age interaction was observed in the ACC. GMV in the ACC showed patterns of age-related differences that were dissimilar between adolescents with MDD and healthy controls. GMV in the thalamus showed an opposite pattern of age-related differences in adolescent patients compared to healthy controls. In patients, GMV in the thalamus, but not the ACC, was inversely related with self-reported depressive symptoms.
The depressed adolescent brain shows dissimilar age-related and symptom-sensitive patterns of GMV differences compared with controls. The thalamus and ACC may comprise neural markers for detecting these effects in youth. Further investigations therefore need to take both age and level of current symptoms into account when disaggregating antecedent neural vulnerabilities for MDD from the effects of MDD on the developing brain.
•Adolescents with MDD show no group differences in GMV compared with controls.•MDD show dissimilar patterns of age-related GMV differences in ACC than controls.•Opposing case–control patterns of age-related GMV differences are shown in thalamus.•GMV differences in thalamus were evident following whole brain examination.•In MDD, thalamic, but not ACC, GMV inversely correlates with depressive symptoms.
PMCID: PMC4309951
Depression; Adolescence; Thalamus; Cingulate; Voxel-based morphometry; MRI
12.  A Survey of U.S. Physicians and Their Partners Regarding the Impact of Work–Home Conflict 
Work–home conflicts (WHC) threaten work–life balance among physicians, especially those in dual career relationships. In this study, we analyzed factors associated with WHC for physicians and their employed partners.
We surveyed 89,831 physicians from all specialty disciplines listed in the Physician Masterfile. Of the 7,288 (27.7 %) physicians who completed the survey, 1,644 provided the e-mail contact information of their partner. We surveyed these partners and 891 (54 %) responded. Burnout, quality of life (QOL), and depression were measured using validated instruments in both surveys. Satisfaction with career, work–life balance, and personal relationships, as well as experience of WHC were also evaluated.
WHC within the previous 3 weeks were commonly experienced by physicians and their employed partners (44.3 % and 55.7 %, respectively). On multivariate analysis, greater work hours for physicians and their employed partners were independently associated with WHC (OR 1.31 and 1.23 for each additional 10 h, respectively, both p < 0.0001). Physicians and partners who had experienced a recent WHC were more likely to have symptoms of burnout (47.1 % vs. 26.6 % for physicians with and without WHC; 42.4 % vs. 23.8 % for partners with and without WHC, both p < 0.0001).
WHC are commonly experienced by physicians and their employed partners. These conflicts may be a major contributor to personal distress for physicians and their partners.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2581-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3889954  PMID: 24043567
physician; spouses; work–home conflict; burnout; quality of life; career satisfaction
13.  Down-regulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung 
Mucosal immunology  2013;7(4):857-868.
Phagocytes coordinate acute inflammation and host defence at mucosal sites but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein rich edema fluid causing impaired lung function. We hypothesised that targeting the intracellular protein Mcl-1 by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (E. Coli). Down-regulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (Ri) from 19h to 7h and improved organ dysfunction with enhanced alveolar-capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 down-regulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (Ri; 50h to 16h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defence against bacteria, and represents a target for treating infection-associated inflammation.
PMCID: PMC3940382  PMID: 24280938
Mcl-1; neutrophil; apoptosis; resolution of inflammation
15.  Essential versus accessory aspects of cell death: recommendations of the NCCD 2015 
Galluzzi, L | Bravo-San Pedro, J M | Vitale, I | Aaronson, S A | Abrams, J M | Adam, D | Alnemri, E S | Altucci, L | Andrews, D | Annicchiarico-Petruzzelli, M | Baehrecke, E H | Bazan, N G | Bertrand, M J | Bianchi, K | Blagosklonny, M V | Blomgren, K | Borner, C | Bredesen, D E | Brenner, C | Campanella, M | Candi, E | Cecconi, F | Chan, F K | Chandel, N S | Cheng, E H | Chipuk, J E | Cidlowski, J A | Ciechanover, A | Dawson, T M | Dawson, V L | De Laurenzi, V | De Maria, R | Debatin, K-M | Di Daniele, N | Dixit, V M | Dynlacht, B D | El-Deiry, W S | Fimia, G M | Flavell, R A | Fulda, S | Garrido, C | Gougeon, M-L | Green, D R | Gronemeyer, H | Hajnoczky, G | Hardwick, J M | Hengartner, M O | Ichijo, H | Joseph, B | Jost, P J | Kaufmann, T | Kepp, O | Klionsky, D J | Knight, R A | Kumar, S | Lemasters, J J | Levine, B | Linkermann, A | Lipton, S A | Lockshin, R A | López-Otín, C | Lugli, E | Madeo, F | Malorni, W | Marine, J-C | Martin, S J | Martinou, J-C | Medema, J P | Meier, P | Melino, S | Mizushima, N | Moll, U | Muñoz-Pinedo, C | Nuñez, G | Oberst, A | Panaretakis, T | Penninger, J M | Peter, M E | Piacentini, M | Pinton, P | Prehn, J H | Puthalakath, H | Rabinovich, G A | Ravichandran, K S | Rizzuto, R | Rodrigues, C M | Rubinsztein, D C | Rudel, T | Shi, Y | Simon, H-U | Stockwell, B R | Szabadkai, G | Tait, S W | Tang, H L | Tavernarakis, N | Tsujimoto, Y | Vanden Berghe, T | Vandenabeele, P | Villunger, A | Wagner, E F | Walczak, H | White, E | Wood, W G | Yuan, J | Zakeri, Z | Zhivotovsky, B | Melino, G | Kroemer, G
Cell Death and Differentiation  2014;22(1):58-73.
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
PMCID: PMC4262782  PMID: 25236395
16.  Educational interventions for general practitioners to identify and manage depression as a suicide risk factor in young people: a systematic review and meta-analysis protocol 
Systematic Reviews  2014;3(1):145.
Suicide is a major public health problem and globally is the second leading cause of death in young adults. Globally, there are 164,000 suicides per year in young people under 25 years. Depression is a strong risk factor for suicide. Evidence shows that 45% of those completing suicide, including young adults, contact their general practitioner rather than a mental health professional in the month before their death. Further evidence indicates that risk factors or early warning signs of suicide in young people go undetected and untreated by general practitioners. Healthcare-based suicide prevention interventions targeted at general practitioners are designed to increase identification of at-risk young people. The rationale of this type of intervention is that early identification and improved clinical management of at-risk individuals will reduce morbidity and mortality. This systematic review will synthesise evidence on the effectiveness of education interventions for general practitioners in identifying and managing depression as a suicide risk factor in young people.
We shall conduct a systematic review and meta-analysis following the Cochrane Handbook for Systematic Reviews of Interventions guidelines and conform to the reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. Electronic databases will be systematically searched for randomised controlled trials and quasi-experimental studies investigating the effectiveness of interventions for general practitioners in identifying and managing depression as a suicide risk factor in young people in comparison to any other intervention, no intervention, usual care or waiting list. Grey literature will be searched by screening trial registers. Only studies published in English will be included. No date restrictions will be applied. Two authors will independently screen titles and abstracts of potential studies. The primary outcome is identification and management of depression. Secondary outcomes are suicidal ideation, suicide attempts, deliberate self-harm, knowledge of suicide risk factors and suicide-related behaviours, attitudes towards suicide risk and suicide-related behaviours, confidence in dealing with suicide risk factors and suicide-related behaviour.
Our study will inform the development of future education interventions and provide feasibility and acceptability evidence, to help general practitioners identify and manage suicidal behaviour in young people.
Systematic review registration
PROSPERO registration number: CRD42014009110.
Electronic supplementary material
The online version of this article (doi:10.1186/2046-4053-3-145) contains supplementary material, which is available to authorized users.
PMCID: PMC4276044  PMID: 25510820
Systematic review; Meta-analysis; Suicide; Prevention; Adolescents; Young adult; General practice
17.  Thymic stromal lymphopoietin-mediated extramedullary hematopoiesis promotes allergic inflammation 
Immunity  2013;39(6):1158-1170.
Extramedullary hematopoiesis (EMH) refers to the differentiation of hematopoietic stem cells (HSCs) into effector cells that occurs in compartments outside of the bone marrow. Previous studies linked pattern recognition receptor (PRR)-expressing HSCs, EMH and immune responses to microbial stimuli. However, whether EMH operates in broader immune contexts remains unknown. Here, we demonstrate a previously unrecognized role for thymic stromal lymphopoietin (TSLP) in promoting the population expansion of progenitor cells in the periphery and identify that TSLP-elicited progenitors differentiated into effector cells including macrophages, dendritic cells and granulocytes; and that these cells contributed to type 2 cytokine responses. The frequency of circulating progenitor cells was also increased in allergic patients with a gain-of-function polymorphism in TSLP, suggesting the TSLP-EMH pathway may operate in human disease. These data identify that TSLP-induced EMH contributes to the development of allergic inflammation and indicate that EMH is a conserved mechanism of innate immunity.
PMCID: PMC3959827  PMID: 24332033
TSLP; allergic inflammation; extramedullary hematopoiesis
18.  Innate lymphoid cells and allergic inflammation 
Current opinion in immunology  2013;25(6):738-744.
Group 2 innate lymphoid cells (ILC2s) play critical roles in anti-helminth immunity and airway epithelial repair. Recently, these cells have also emerged as key players in the development of allergic inflammation at multiple barrier surfaces. ILC2s arise from common lymphoid progenitors in the bone marrow, are dependent on the transcription factors RORα, GATA3 and TCF-1 and produce the type 2 cytokines IL-4, IL-5, IL-9 and/or IL-13. The epithelial cell-derived cytokines IL-25, IL-33 and TSLP regulate the activation and effector functions of ILC2s, and recent studies suggest that their responsiveness to these cytokines and other factors may depend on their tissue environment. In this review, we focus on recent advances in our understanding of how ILC2s are differentially regulated in the context of allergic inflammation and discuss the therapeutic potential of targeting ILC2s in the treatment of allergic diseases.
PMCID: PMC3989991  PMID: 24001372
19.  Shining Light on Benthic Macroalgae: Mechanisms of Complementarity in Layered Macroalgal Assemblages 
PLoS ONE  2014;9(12):e114146.
Phototrophs underpin most ecosystem processes, but to do this they need sufficient light. This critical resource, however, is compromised along many marine shores by increased loads of sediments and nutrients from degraded inland habitats. Increased attenuation of total irradiance within coastal water columns due to turbidity is known to reduce species' depth limits and affect the taxonomic structure and architecture of algal-dominated assemblages, but virtually no attention has been paid to the potential for changes in spectral quality of light energy to impact production dynamics. Pioneering studies over 70 years ago showed how different pigmentation of red, green and brown algae affected absorption spectra, action spectra, and photosynthetic efficiency across the PAR (photosynthetically active radiation) spectrum. Little of this, however, has found its way into ecological syntheses of the impacts of optically active contaminants on coastal macroalgal communities. Here we test the ability of macroalgal assemblages composed of multiple functional groups (including representatives from the chlorophyta, rhodophyta and phaeophyta) to use the total light resource, including different light wavelengths and examine the effects of suspended sediments on the penetration and spectral quality of light in coastal waters. We show that assemblages composed of multiple functional groups are better able to use light throughout the PAR spectrum. Macroalgal assemblages with four sub-canopy species were between 50–75% more productive than assemblages with only one or two sub-canopy species. Furthermore, attenuation of the PAR spectrum showed both a loss of quanta and a shift in spectral distribution with depth across coastal waters of different clarity, with consequences to productivity dynamics of diverse layered assemblages. The processes of light complementarity may help provide a mechanistic understanding of how altered turbidity affects macroalgal assemblages in coastal waters, which are increasingly threatened by diminishing light quantity and altered spectral distributions through sedimentation and eutrophication.
PMCID: PMC4250189  PMID: 25438045
20.  Dietary mineral supplies in Africa 
Physiologia Plantarum  2014;151(3):208-229.
Dietary micronutrient deficiencies (MNDs) are widespread, yet their prevalence can be difficult to assess. Here, we estimate MND risks due to inadequate intakes for seven minerals in Africa using food supply and composition data, and consider the potential of food-based and agricultural interventions. Food Balance Sheets (FBSs) for 46 countries were integrated with food composition data to estimate per capita supply of calcium (Ca), copper (Cu), iron (Fe), iodine (I), magnesium (Mg), selenium (Se) and zinc (Zn), and also phytate. Deficiency risks were quantified using an estimated average requirement (EAR) ‘cut-point’ approach. Deficiency risks are highest for Ca (54% of the population), followed by Zn (40%), Se (28%) and I (19%, after accounting for iodized salt consumption). The risk of Cu (1%) and Mg (<1%) deficiency are low. Deficiency risks are generally lower in the north and west of Africa. Multiple MND risks are high in many countries. The population-weighted mean phytate supply is 2770 mg capita−1 day−1. Deficiency risks for Fe are lower than expected (5%). However, ‘cut-point’ approaches for Fe are sensitive to assumptions regarding requirements; e.g. estimates of Fe deficiency risks are 43% under very low bioavailability scenarios consistent with high-phytate, low-animal protein diets. Fertilization and breeding strategies could greatly reduce certain MNDs. For example, meeting harvestplus breeding targets for Zn would reduce dietary Zn deficiency risk by 90% based on supply data. Dietary diversification or direct fortification is likely to be needed to address Ca deficiency risks.
PMCID: PMC4235459  PMID: 24524331
21.  Alginate Inhibits Iron Absorption from Ferrous Gluconate in a Randomized Controlled Trial and Reduces Iron Uptake into Caco-2 Cells 
PLoS ONE  2014;9(11):e112144.
Previous in vitro results indicated that alginate beads might be a useful vehicle for food iron fortification. A human study was undertaken to test the hypothesis that alginate enhances iron absorption. A randomised, single blinded, cross-over trial was carried out in which iron absorption was measured from serum iron appearance after a test meal. Overnight-fasted volunteers (n = 15) were given a test meal of 200 g cola-flavoured jelly plus 21 mg iron as ferrous gluconate, either in alginate beads mixed into the jelly or in a capsule. Iron absorption was lower from the alginate beads than from ferrous gluconate (8.5% and 12.6% respectively, p = 0.003). Sub-group B (n = 9) consumed the test meals together with 600 mg calcium to determine whether alginate modified the inhibitory effect of calcium. Calcium reduced iron absorption from ferrous gluconate by 51%, from 11.5% to 5.6% (p = 0.014), and from alginate beads by 37%, from 8.3% to 5.2% (p = 0.009). In vitro studies using Caco-2 cells were designed to explore the reasons for the difference between the previous in vitro findings and the human study; confirmed the inhibitory effect of alginate. Beads similar to those used in the human study were subjected to simulated gastrointestinal digestion, with and without cola jelly, and the digestate applied to Caco-2 cells. Both alginate and cola jelly significantly reduced iron uptake into the cells, by 34% (p = 0.009) and 35% (p = 0.003) respectively. The combination of cola jelly and calcium produced a very low ferritin response, 16.5% (p<0.001) of that observed with ferrous gluconate alone. The results of these studies demonstrate that alginate beads are not a useful delivery system for soluble salts of iron for the purpose of food fortification.
Trial Registration NCT01528644
PMCID: PMC4229116  PMID: 25391138
22.  Ofatumumab-based chemoimmunotherapy is effective and well tolerated in patients with previously untreated CLL 
Cancer  2013;119(21):3788-3796.
Although rituximab-based chemoimmunotherapy (CIT) has substantially improved clinical outcomes in chronic lymphocytic leukemia (CLL), only 40-50% of patients achieve a complete remission (CR). There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a fully human anti-CD20 monoclonal antibody with greater apparent single agent activity than rituximab in CLL patients.
Previously untreated CLL patients in need of therapy received 6 cycles of CIT induction with pentostatin, cyclophosphamide and ofatumumab (PCO) followed by response assessment.
Of the 48 patients enrolled, 77% completed PCO induction. Adverse events during induction included grade 3+ hematologic toxicity (27%) and grade 3+ non-hematologic toxicity (23%). Median CD4 count post induction and 6 months later were 186 ×106/L and 272 ×106/L. The overall response rate was 96% (46/48) and the CR rate was 46% (22/48). Among the 38 patients who underwent minimal residual disease (MRD) evaluation, 7 (18%) were MRD negative. After median follow-up of 24 months, 10 (21%) patients have progressed and 8 (17%) have required retreatment. The efficacy and toxicity of ofatumumab-based CIT compare favorably to our historical trials of rituximab-based CIT using an identical chemotherapy backbone (n=64). Time to retreatment also appeared longer for ofatumumab-based CIT (free of retreatment at 24 months: 86% [95%CI: 75-99] vs 68% [95% CI: 56-81]).
Ofatumumab-based CIT is well tolerated in patients with previously untreated CLL. The efficacy of ofatumumab-based CIT compares favorably to historical trials of rituximab-based CIT suggesting randomized trials comparing ofatumumab-based CIT and rituximab-based CIT should be considered.
PMCID: PMC3894149  PMID: 23922059
chronic lymphocytic leukemia(CLL; small lymphocytic lymphoma(SLL); treatment; ofatumumab; chemoimmunotherapy
23.  Patients with chronic lymphocytic leukaemia and clonal deletion of both 17p13.1 and 11q22.3 have a very poor prognosis 
British journal of haematology  2013;163(3):326-333.
Detection of a 17p13.1 deletion (loss of TP53) or 11q22.3 deletion (loss of ATM), by fluorescence in situ hybridization (FISH), in chronic lymphocytic leukaemia (CLL) patients is associated with a poorer prognosis. Because TP53 and ATM are integral to the TP53 pathway, we hypothesized that 17p13.1- (17p-) and 11q22.3- (11q-) occurring in the same cell (clonal 17p-/11q-) would confer a worse prognosis than either 17p- or 11q-. We studied 2184 CLL patients with FISH (1995–2012) for the first occurrence of 17p-, 11q-, or clonal 17p-/11q-. Twenty (1%) patients had clonal 17p-/11q-, 158 (7%) had 17p- (including 4 with 17p- and 11q- in separate clones), 247 (11%) had 11q-, and 1759 (81%) had neither 17p- nor 11q-. Eleven of 15 (73%) tested patients with clonal 17p-/11q- had dysfunctional TP53 mutations. Overall survival for clonal 17p-/11q- was significantly shorter (1.9 years) than 17p- (3.1 years, p = 0.04), 11q- (4.8 years, p = <0.0001), or neither 17p- nor 11q- (9.3 years, p = <0.0001). Clonal 17p-/11q- thus conferred significantly worse prognosis, suggesting that loss of at least one copy of both TP53 and ATM causes more aggressive disease. Use of an ATM/TP53 combination FISH probe set could identify these very-high risk patients.
PMCID: PMC3907074  PMID: 24032430
Chronic lymphocytic leukaemia; prognostic factors; fluorescencein situ hybridization (FISH); TP53; ATM
24.  Characterization of a novel mouse model with genetic deletion of CD177 
Protein & Cell  2014;6(2):117-126.
Neutrophils play an essential role in the innate immune response to infection. Neutrophils migrate from the vasculature into the tissue in response to infection. Recently, a neutrophil cell surface receptor, CD177, was shown to help mediate neutrophil migration across the endothelium through interactions with PECAM1. We examined a publicly available gene array dataset of CD177 expression from human neutrophils following pulmonary endotoxin instillation. Among all 22,214 genes examined, CD177 mRNA was the most upregulated following endotoxin exposure. The high level of CD177 expression is also maintained in airspace neutrophils, suggesting a potential involvement of CD177 in neutrophil infiltration under infectious diseases. To determine the role of CD177 in neutrophils in vivo, we constructed a CD177-genetic knockout mouse model. The mice with homozygous deletion of CD177 have no discernible phenotype and no significant change in immune cells, other than decreased neutrophil counts in peripheral blood. We examined the role of CD177 in neutrophil accumulation using a skin infection model with Staphylococcus aureus. CD177 deletion reduced neutrophil counts in inflammatory skin caused by S. aureus. Mechanistically we found that CD177 deletion in mouse neutrophils has no significant impact in CXCL1/KC- or fMLP-induced migration, but led to significant cell death. Herein we established a novel genetic mouse model to study the role of CD177 and found that CD177 plays an important role in neutrophils.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0109-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4312768  PMID: 25359465
CD177; neutrophil; mouse model; genetic deletion
25.  Characterization of a novel mouse model with genetic deletion of CD177 
Protein & Cell  2014;6(2):117-126.
Neutrophils play an essential role in the innate immune response to infection. Neutrophils migrate from the vasculature into the tissue in response to infection. Recently, a neutrophil cell surface receptor, CD177, was shown to help mediate neutrophil migration across the endothelium through interactions with PECAM1. We examined a publicly available gene array dataset of CD177 expression from human neutrophils following pulmonary endotoxin instillation. Among all 22,214 genes examined, CD177 mRNA was the most upregulated following endotoxin exposure. The high level of CD177 expression is also maintained in airspace neutrophils, suggesting a potential involvement of CD177 in neutrophil infiltration under infectious diseases. To determine the role of CD177 in neutrophils in vivo, we constructed a CD177-genetic knockout mouse model. The mice with homozygous deletion of CD177 have no discernible phenotype and no significant change in immune cells, other than decreased neutrophil counts in peripheral blood. We examined the role of CD177 in neutrophil accumulation using a skin infection model with Staphylococcus aureus. CD177 deletion reduced neutrophil counts in inflammatory skin caused by S. aureus. Mechanistically we found that CD177 deletion in mouse neutrophils has no significant impact in CXCL1/KC- or fMLP-induced migration, but led to significant cell death. Herein we established a novel genetic mouse model to study the role of CD177 and found that CD177 plays an important role in neutrophils.
Electronic supplementary material
The online version of this article (doi:10.1007/s13238-014-0109-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4312768  PMID: 25359465
CD177; neutrophil; mouse model; genetic deletion

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