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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.  Informing the Uninformed: Optimizing the Consent Message Using a Fractional Factorial Design 
JAMA pediatrics  2013;167(7):640-646.
Objective
Research information should be presented in a manner that promotes understanding. However, many parents and research subjects have difficulty understanding and making informed decisions. This study was designed to examine the effect of different communication strategies on parental understanding of research information.
Participants
640 parents of children scheduled for elective surgery
Design
Observational study using a fractional factorial design
Setting
Large tertiary care children's hospital
Interventions
Parents were randomized to receive information about a hypothetical pain trial presented in one of 16 consent documents containing different combinations of 5 selected communication strategies (i.e., length, readability, processability [formatting], graphical display, and supplemental verbal disclosure).
Main outcome measures
Parents were interviewed to determine their understanding of the study elements (e.g., protocol, alternatives etc.) and their gist (main point) and verbatim (actual) understanding of the risks and benefits.
Results
Main effects for understanding were found for processability, readability, message length, use of graphics, and verbal discussion. Consent documents with high processability, 8th grade reading level, and graphics resulted in significantly greater gist and verbatim understanding compared with forms without these attributes (mean difference, 95% CI = 0.57, 0.26–0.88, correct responses out of 7 and 0.54, 0.20–0.88 correct responses out of 4 for gist and verbatim, respectively).
Conclusions
Results identified several communication strategy combinations that improved parents' understanding of research information. Adoption of these active strategies by investigators, clinicians, IRBs, and study sponsors represents a simple, practical, and inexpensive means to optimize the consent message and enhance parental, participant, and patient understanding.
doi:10.1001/jamapediatrics.2013.1385
PMCID: PMC3700595  PMID: 23700028
8.  A Phase I Trial of Immunostimulatory CpG 7909 Oligodeoxynucleotide and 90Yttrium Ibritumomab Tiuxetan Radioimmunotherapy for Relapsed B-cell Non-Hodgkin Lymphoma 
American journal of hematology  2013;88(7):589-593.
Radioimmunotherapy (RIT) for relapsed indolent non-Hodgkin lymphoma produces overall response rates (ORR) of 80% with mostly partial remissions. Synthetic CpG oligonucleotides change the phenotype of malignant B-cells, are immunostimulatory, and can produce responses when injected intratumorally and combined with conventional radiation. In this phase I trial we tested systemic administration of both CpG and RIT. Eligible patients had biopsy-proven previously treated CD20+ B-cell NHL and met criteria for RIT. Patients received rituximab 250 mg/m2 days 1,8, and 15; 111In-ibritumomab tiuxetan days 1, 8; CpG 7909 days 6, 13, 20, 27; and 0.4 mCi/kg of 90Y-ibritumomab tiuxetan day 15. The doses of CpG 7909 tested were 0.08, 0.16, 0.32 (six patients each) and 0.48 mg/kg (12 patients) IV over 2 hours without dose limiting toxicity. The ORR was 93% (28/30) with 63% (19/30) complete remission (CR); median progression free survival of 42.7 months (95% CI 18-NR); and median duration of response (DR) of 35 months (4.6-76+). Correlative studies demonstrated a decrease in IL10 and TNFα, and an increase in IL1β, in response to therapy. CpG 7909 at a dose of 0.48 mg/kg is safe with standard RIT and produces a high CR rate and long DR; these results warrant confirmation.
doi:10.1002/ajh.23460
PMCID: PMC3951424  PMID: 23619698
lymphoma; radioimmunotherapy; rituximab; ibritumomab tiuxetan; CpG 7909
10.  Protocol for a systematic review and meta-analysis of cognitive-behavioural therapy for social anxiety disorder in psychosis 
Systematic Reviews  2014;3:62.
Background
Social anxiety is among the most prevalent and debilitating affective disturbances manifest in people with psychosis. It is usually accompanied by high levels of depression and leads to significant social disability, lower quality of life and poorer prognosis as it raises the possibility of an early relapse. Despite its elevated prevalence and severity in psychosis, social anxiety remains under-recognized and under-treated. Cognitive-behavioural therapy is recommended for the treatment of people with psychosis. However, its focus and evaluation has primarily revolved around the reduction of psychotic symptoms, and not for co-morbid affective disturbances such as social anxiety. There is lack of evidence on the clinical effectiveness and cost-effectiveness of cognitive-behavioural interventions for the treatment of social anxiety disorder in psychosis.
Methods/Design
Electronic databases will be systematically searched for randomised controlled trials and quasi-experimental studies investigating the effectiveness and cost-effectiveness of cognitive-behavioural interventions for the treatment of social anxiety disorder in people with psychosis. Grey literature will also be searched by screening trial registers. Only studies published in English will be included in the review. Date restrictions will not be applied. Eligible studies will have as the primary outcome social anxiety (continuous data) measured using any psychometrically validated scale both self-reported and clinician administered. Secondary outcomes will include general anxiety symptoms, distress, depression, positive and negative symptoms of schizophrenia, and quality of life measured using any psychometrically validated scale, both self-reported and clinician administered, and the cost of cognitive-behaviour therapy (CBT) intervention (with another treatment or treatment-as-usual).
Conclusions
This review will provide an evidence synthesis of the effectiveness and cost-effectiveness of cognitive-behavioural interventions for the treatment of social anxiety disorder in people with psychosis. The review will identify the specific intervention components associated with effectiveness which will facilitate the translation of the existing evidence to the development of new, targeted interventions optimising these components. In doing so, this review will provide recommendations for the treatment of social anxiety and associated distress in psychosis and will further inform the development of future interventions in this area.
Trial registration
PROSPERO registration numberCRD42014009052.
doi:10.1186/2046-4053-3-62
PMCID: PMC4065605  PMID: 24920188
Systematic review; Meta-analysis; Social anxiety; Psychosis; Schizophrenia; Cognitive-behavioural therapy
11.  The STBUR Questionnaire for Predicting Perioperative Respiratory Adverse Events in Children at risk for Sleep Disordered-Breathing 
Paediatric anaesthesia  2013;23(6):510-516.
Background
In the absence of formal polysomnography (PSG), many children with symptoms of sleep-disordered breathing (SDB) go unrecognized and thus may be at risk for perioperative respiratory adverse events (PRAE).
Objectives
To develop a simple practical tool to identify children with symptoms consistent with SDB who may be at risk for PRAE.
Methods
337 parents of children scheduled for surgery completed the Sleep-Related Breathing Disorder (SRBD) questionnaire. Data regarding the incidence and severity of PRAE including airway obstruction, laryngospasm, etc. were collected prospectively.
Results
32 (9.5%) children had a confirmed diagnosis of SDB by PSG and 90 (26.7%) had symptoms consistent with SDB based on the SRBD questionnaire. Principal component analysis identified 5 symptoms from the SRBD questionnaire that were strongly predictive of PRAE and which were incorporated into the STBUR tool (Snoring, Trouble Breathing, Un-Refreshed). The likelihood of PRAE was increased by three-fold (Positive likelihood ratio 3.06 [1.64-5.96] in the presence of any 3 STBUR symptoms and by ten-fold when all 5 symptoms were present (9.74 [1.35-201.8]). In comparison, the likelihood of PRAE based on a PSG-confirmed diagnosis of SDB was 2.63 (1.17-6.23).
Conclusions
Children presenting for surgery with symptoms consistent with SDB may be at risk for PRAE. It is important, therefore, that anesthesia providers identify these individuals prior to surgery to avoid potential complications. The STBUR questionnaire appears promising as a simple, clinically useful tool for identifying children at risk for PRAE. Further studies to validate the STBUR questionnaire as a diagnostic tool may be warranted.
doi:10.1111/pan.12155
PMCID: PMC3648590  PMID: 23551934
Sleep-disordered breathing; child; respiratory adverse events; perioperative
12.  The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host–parasite interaction 
Nucleic Acids Research  2014;42(11):7113-7131.
Babesia spp. are tick-borne, intraerythrocytic hemoparasites that use antigenic variation to resist host immunity, through sequential modification of the parasite-derived variant erythrocyte surface antigen (VESA) expressed on the infected red blood cell surface. We identified the genomic processes driving antigenic diversity in genes encoding VESA (ves1) through comparative analysis within and between three Babesia species, (B. bigemina, B. divergens and B. bovis). Ves1 structure diverges rapidly after speciation, notably through the evolution of shortened forms (ves2) from 5′ ends of canonical ves1 genes. Phylogenetic analyses show that ves1 genes are transposed between loci routinely, whereas ves2 genes are not. Similarly, analysis of sequence mosaicism shows that recombination drives variation in ves1 sequences, but less so for ves2, indicating the adoption of different mechanisms for variation of the two families. Proteomic analysis of the B. bigemina PR isolate shows that two dominant VESA1 proteins are expressed in the population, whereas numerous VESA2 proteins are co-expressed, consistent with differential transcriptional regulation of each family. Hence, VESA2 proteins are abundant and previously unrecognized elements of Babesia biology, with evolutionary dynamics consistently different to those of VESA1, suggesting that their functions are distinct.
doi:10.1093/nar/gku322
PMCID: PMC4066756  PMID: 24799432
13.  Evaluation of the smoking ban in public places in France one year and five years after its implementation: Findings from the ITC France survey 
France implemented a comprehensive smoke-free policy in public places in February 2007 for workplaces, shopping centres, airports, train stations, hospitals and schools. On January 2008, it was extended to meeting places (bars, restaurants, hotels, casinos, nightclubs).
This paper evaluates France’s smoke-free law based on the International Tobacco Control Policy Evaluation Project in France (the ITC France Project), which conducted a cohort survey of approximately 1,500 smokers and 500 non-smokers before the implementation of the laws (Wave 1, conducted December 2006 to February 2007) and two waves after the implementation (Wave 2, conducted between September-November 2008; and Wave 3, conducted between September-December 2012).
Results show that the smoke-free law led to a very significant and near total elimination of indoor smoking in key venues such as bars (from 95.9% to 3.7%) and restaurants (from 64.7% to 2.3%) at Wave 2, which was sustained four years later at Wave 3 (1.4% in restaurants; 6.6% in bars). Smoking in workplaces declined significantly after the law (from 42.6% to 19.3%), which continued to decline at Wave 3 (to 12.8%). Support for the smoke-free law increased significantly after their implementation and continued to increase at Wave 3 (among smokers for bars and restaurants; among smokers and non-smokers for workplaces).
The findings demonstrate that smoke-free policies that are implemented in ways consistent with the Guidelines for Article 8 of the WHO Framework Convention on Tobacco Control (WHO FCTC) lead to substantial and sustained reductions in tobacco smoke in public places while also leading to high levels of support by the public.
PMCID: PMC4009376  PMID: 24803715
Tobacco; second-hand smoke; smoking ban; meeting place; workplace; evaluation of public policies
14.  Ocimum gratissimum retards breast cancer growth and progression and is a natural inhibitor of matrix metalloproteases 
Cancer Biology & Therapy  2013;14(5):417-427.
Ocimum genus (a.k.a holy basil or tulsi) is a dietary herb used for its multiple beneficial pharmacologic properties including anti-cancer activity. Here we show that crude extract of Ocimum gratissimum (OG) and its hydrophobic and hydrophilic fractions (HB and HL) differentially inhibit breast cancer cell chemotaxis and chemoinvasion in vitro and retard tumor growth and temporal progression of MCF10ADCIS.com xenografts, a model of human breast comedo-ductal carcinoma in situ (comedo-DCIS). OG-induced inhibition of tumor growth was associated with decreases in basement membrane disintegration, angiogenesis and MMP-2 and MMP-9 activities as confirmed by in situ gelatin zymography and cleavage of galectin-3. There was also decrease in MMP-2 and MMP-9 activities in the conditioned media of OG-treated MCF10AT1 and MCF10AT1-EIII8 premalignant human breast cancer cells as compared with control. The MMP-2 and MMP-9 inhibitory activities of OG were verified in vitro using gelatin, a synthetic fluorogenic peptide and recombinant galectin-3 as MMP substrates. Mice fed on OG-supplemented drinking water showed no adverse effects compared with control. These data suggest that OG is non-toxic and that the anti-cancer therapeutic activity of OG may in part be contributed by its MMP inhibitory activity.
doi:10.4161/cbt.23762
PMCID: PMC3672186  PMID: 23380593
Ocimum gratissimum; MMP; Breast Cancer; Tumor progression
15.  GENDER DIFFERENCES IN BRAIN SUSCEPTIBILITY TO OXIDATIVE STRESS ARE MEDIATED BY LEVELS OF PARAOXONASE-2 (PON2) EXPRESSION 
Paraoxonase 2 (PON2), a member of a gene family that also includes PON1 and PON3, is expressed in most tissues, including the brain. In mouse brain, PON2 levels are highest in dopaminergic areas (e.g. striatum), and are higher in astrocytes than in neurons. PON2 is primarily located in mitochondria and exerts a potent antioxidant effect, protecting mouse CNS cells against oxidative stress. The aim of this study was to characterize PON2 expression and functions in the brains of male and female mice. Levels of PON2 (protein, mRNA, and lactonase activity) were higher in brain regions and cells of female mice. Astrocytes and neurons from male mice were significantly more sensitive (by 3–4-fold) to oxidative stress-induced toxicity than the same cells from female mice. Glutathione levels did not differ between genders. Importantly, no significant gender differences in susceptibility to the same oxidants were seen in cells from PON2−/− mice. Treatment with estradiol induced a time- and concentration-dependent increase in the levels of PON2 protein and mRNA in male (4.5-fold) and female (1.8-fold) astrocytes, which was dependent on activation of estrogen receptor alpha. In ovariectomized mice, PON2 protein and mRNA were decreased to male levels in brain regions and in liver. Estradiol protected astrocytes from wild-type mice against oxidative stress-induced neurotoxicity, but did not protect cells from PON2−/− mice. These results suggest that PON2 is a novel major intracellular factor that protects CNS cells against oxidative stress, and confers gender-dependent susceptibility to such stress. The lower expression of PON2 in males may have broad ramifications for susceptibility to diseases involving oxidative stress, including neurodegenerative diseases.
doi:10.1016/j.freeradbiomed.2013.01.019
PMCID: PMC3622778  PMID: 23376469
Paraoxonase 2; oxidative stress; gender difference; estrogen; neuroprotection
16.  The “Backbone” of Stigma: Identifying the Global Core of Public Prejudice Associated With Mental Illness 
American journal of public health  2013;103(5):853-860.
Objectives
We used the Stigma in Global Context–Mental Health Study to assess the core sentiments that represent consistent, salient public health intervention targets.
Methods
Data from 16 countries employed a nationally representative sampling strategy, international collaboration for instrument development, and case vignettes with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition depression and schizophrenia criteria. We measured knowledge and prejudice with existing questions and scales, and employed exploratory data analysis to examine the public response to 43 items.
Results
Across countries, levels of recognition, acceptance of neurobiological attributions, and treatment endorsement were high. However, a core of 5 prejudice items was consistently high, even in countries with low overall stigma levels. The levels were generally lower for depression than schizophrenia, and exclusionary sentiments for more intimate venues and in authority-based roles showed the greatest stigma. Negative responses to schizophrenia and depression were highly correlated across countries.
Conclusions
These results challenge researchers to reconfigure measurement strategies and policymakers to reconsider efforts to improve population mental health. Efforts should prioritize inclusion, integration, and competences for the reduction of cultural barriers to recognition, response, and recovery.
doi:10.2105/AJPH.2012.301147
PMCID: PMC3698809  PMID: 23488508
17.  Widespread mitochondrial depletion via mitophagy does not compromise necroptosis 
Cell reports  2013;5(4):878-885.
Summary
Programmed necrosis (or necroptosis) is a form of cell death triggered by the activation of receptor interacting protein kinase-3 (RIPK3). Several reports have implicated mitochondria and mitochondrial reactive oxygen species (ROS) generation as effectors of RIPK3-dependent cell death. Here, we directly test this idea by employing a method for the specific removal of mitochondria via mitophagy. Mitochondria-deficient cells were resistant to the mitochondrial pathway of apoptosis, but efficiently died via TNF-induced, RIPK3-dependent programmed necrosis or as a result of direct oligomerization of RIPK3. Although the ROS scavenger butylated hydroxyanisol (BHA) delayed TNF-induced necroptosis, it had no effect on necroptosis induced by RIPK3 oligomerization. Further, while TNF-induced ROS production was dependent on mitochondria, the inhibition of TNF-induced necroptosis by BHA was observed in mitochondria-depleted cells. Our data indicate that mitochondrial ROS production accompanies, but does not cause, RIPK3-dependent necroptotic cell death.
doi:10.1016/j.celrep.2013.10.034
PMCID: PMC4005921  PMID: 24268776
18.  Identification of BDNF Sensitive Electrophysiological Markers of Synaptic Activity and Their Structural Correlates in Healthy Subjects Using a Genetic Approach Utilizing the Functional BDNF Val66Met Polymorphism 
PLoS ONE  2014;9(4):e95558.
Increasing evidence suggests that synaptic dysfunction is a core pathophysiological hallmark of neurodegenerative disorders. Brain-derived neurotropic factor (BDNF) is key synaptogenic molecule and targeting synaptic repair through modulation of BDNF signalling has been suggested as a potential drug discovery strategy. The development of such “synaptogenic” therapies depend on the availability of BDNF sensitive markers of synaptic function that could be utilized as biomarkers for examining target engagement or drug efficacy in humans. Here we have utilized the BDNF Val66Met genetic polymorphism to examine the effect of the polymorphism and genetic load (i.e. Met allele load) on electrophysiological (EEG) markers of synaptic activity and their structural (MRI) correlates. Sixty healthy adults were prospectively recruited into the three genetic groups (Val/Val, Val/Met, Met/Met). Subjects also underwent fMRI, tDCS/TMS, and cognitive assessments as part of a larger study. Overall, some of the EEG markers of synaptic activity and brain structure measured with MRI were the most sensitive markers of the polymorphism. Met carriers showed decreased oscillatory activity and synchrony in the neural network subserving error-processing, as measured during a flanker task (ERN); and showed increased slow-wave activity during resting. There was no evidence for a Met load effect on the EEG measures and the polymorphism had no effects on MMN and P300. Met carriers also showed reduced grey matter volume in the anterior cingulate and in the (left) prefrontal cortex. Furthermore, anterior cingulate grey matter volume, and oscillatory EEG power during the flanker task predicted subsequent behavioural adaptation, indicating a BDNF dependent link between brain structure, function and behaviour associated with error processing and monitoring. These findings suggest that EEG markers such as ERN and resting EEG could be used as BDNF sensitive functional markers in early clinical development to examine target engagement or drug related efficacy of synaptic repair therapies in humans.
doi:10.1371/journal.pone.0095558
PMCID: PMC3997566  PMID: 24760076
19.  Future Climate Scenarios for a Coastal Productive Planktonic Food Web Resulting in Microplankton Phenology Changes and Decreased Trophic Transfer Efficiency 
PLoS ONE  2014;9(4):e94388.
We studied the effects of future climate change scenarios on plankton communities of a Norwegian fjord using a mesocosm approach. After the spring bloom, natural plankton were enclosed and treated in duplicates with inorganic nutrients elevated to pre-bloom conditions (N, P, Si; eutrophication), lowering of 0.4 pH units (acidification), and rising 3°C temperature (warming). All nutrient-amended treatments resulted in phytoplankton blooms dominated by chain-forming diatoms, and reached 13–16 μg chlorophyll (chl) a l−1. In the control mesocosms, chl a remained below 1 μg l−1. Acidification and warming had contrasting effects on the phenology and bloom-dynamics of autotrophic and heterotrophic microplankton. Bacillariophyceae, prymnesiophyceae, cryptophyta, and Protoperidinium spp. peaked earlier at higher temperature and lower pH. Chlorophyta showed lower peak abundances with acidification, but higher peak abundances with increased temperature. The peak magnitude of autotrophic dinophyceae and ciliates was, on the other hand, lowered with combined warming and acidification. Over time, the plankton communities shifted from autotrophic phytoplankton blooms to a more heterotrophic system in all mesocosms, especially in the control unaltered mesocosms. The development of mass balance and proportion of heterotrophic/autotrophic biomass predict a shift towards a more autotrophic community and less-efficient food web transfer when temperature, nutrients and acidification are combined in a future climate-change scenario. We suggest that this result may be related to a lower food quality for microzooplankton under acidification and warming scenarios and to an increase of catabolic processes compared to anabolic ones at higher temperatures.
doi:10.1371/journal.pone.0094388
PMCID: PMC3983207  PMID: 24721992
20.  A TSC signaling node at the peroxisome regulates mTORC1 and autophagy in response to ROS 
Nature cell biology  2013;15(10):1186-1196.
Subcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signaling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by PEX19 and PEX5, respectively, and peroxisome-localized TSC functioned as a Rheb GAP to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, abrogated peroxisome localization, Rheb GAP activity, and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS and peroxisome-localization deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signaling organelle involved in regulation of mTORC1.
doi:10.1038/ncb2822
PMCID: PMC3789865  PMID: 23955302
21.  TSLP-elicited basophil responses can mediate the pathogenesis of eosinophilic esophagitis 
Nature medicine  2013;19(8):1005-1013.
Eosinophilic esophagitis (EoE) is a food allergy-associated inflammatory disease characterized by esophageal eosinophilia. EoE has become increasingly common, but current management strategies are nonspecific. Thus, there is an urgent need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis remains unknown. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE but was dependent on TSLP-elicited basophils. Therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. Critically, in human subjects with EoE, we observed elevated TSLP levels and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses. Together, these data suggest that the TSLP-basophil axis could be therapeutically targeted to treat EoE.
doi:10.1038/nm.3281
PMCID: PMC3951204  PMID: 23872715
22.  Onychophoran Hox genes and the evolution of arthropod Hox gene expression 
Frontiers in Zoology  2014;11:22.
Introduction
Onychophora is a relatively small phylum within Ecdysozoa, and is considered to be the sister group to Arthropoda. Compared to the arthropods, that have radiated into countless divergent forms, the onychophoran body plan is overall comparably simple and does not display much in-phylum variation. An important component of arthropod morphological diversity consists of variation of tagmosis, i.e. the grouping of segments into functional units (tagmata), and this in turn is correlated with differences in expression patterns of the Hox genes. How these genes are expressed in the simpler onychophorans, the subject of this paper, would therefore be of interest in understanding their subsequent evolution in the arthropods, especially if an argument can be made for the onychophoran system broadly reflecting the ancestral state in the arthropods.
Results
The sequences and embryonic expression patterns of the complete set of ten Hox genes of an onychophoran (Euperipatoides kanangrensis) are described for the first time. We find that they are all expressed in characteristic patterns that suggest a function as classical Hox genes. The onychophoran Hox genes obey spatial colinearity, and with the exception of Ultrabithorax (Ubx), they all have different and distinct anterior expression borders. Notably, Ubx transcripts form a posterior to anterior gradient in the onychophoran trunk. Expression of all onychophoran Hox genes extends continuously from their anterior border to the rear end of the embryo.
Conclusions
The spatial expression pattern of the onychophoran Hox genes may contribute to a combinatorial Hox code that is involved in giving each segment its identity. This patterning of segments in the uniform trunk, however, apparently predates the evolution of distinct segmental differences in external morphology seen in arthropods. The gradient-like expression of Ubx may give posterior segments their specific identity, even though they otherwise express the same set of Hox genes. We suggest that the confined domains of Hox gene expression seen in arthropods evolved from an ancestral onychophoran-like Hox gene pattern. Reconstruction of the ancestral arthropod Hox pattern and comparison with the patterns in the different arthropod classes reveals phylogenetic support for Mandibulata and Tetraconata, but not Myriochelata and Atelocerata.
doi:10.1186/1742-9994-11-22
PMCID: PMC4015684  PMID: 24594097
Development; Segmentation; Body patterning; Phylogeny; Tagmosis
23.  Utility of a Brief Screening Tool to Identify Physicians in Distress 
ABSTRACT
BACKGROUND
Despite a high prevalence of distress, few physicians seek help. Earlier identification of physicians in distress has been hampered by the lack of a brief screening instrument to assess the common forms of distress.
OBJECTIVE
To evaluate the ability of the seven-item Physician Well-Being Index (PWBI) to i) stratify physician well-being in several important dimensions (mental quality of life [QOL], fatigue, suicidal ideation); and ii) identify physicians whose degree of distress may negatively impact their practice (career satisfaction, intent to leave current position, medical errors).
DESIGN
Cross-sectional study.
PARTICIPANTS
National sample of 6,994 U.S. physicians.
MAIN MEASURES
PWBI, Mental QOL, fatigue, suicidal ideation, career satisfaction,and clinical practice measures.
KEY RESULTS
Physicians with low mental QOL, high fatigue, or recent (< 12 months) suicidal ideation were more likely to endorse each of the seven PWBI items and a greater number of total items (all P < 0 .001). Assuming a prevalence of 19 %, the PWBI could reduce the post-test probability of a physician having low mental QOL to < 1 % or raise it to > 75 %. The likelihood ratio for low mental QOL among physicians with PWBI scores ≥ 4 was 3.85 in comparison to 0.33 for those with scores < 4. At a threshold score of >4, the PWBI’s specificity for identifying physicians with low mental QOL, high fatigue, or recent suicidal ideation were 85.8 %. PWBI score also stratified physicians’ career satisfaction, reported intent to leave current practice, and self-reported medical errors.
CONCLUSIONS
The seven-item PWBI appears to be a useful screening index to identify physicians with distress in a variety of dimensions and whose degree of distress may negatively impact their practice.
doi:10.1007/s11606-012-2252-9
PMCID: PMC3579983  PMID: 23129161
physicians;  quality of life; mental health; self-assessment tool; physician well-being index;  PWBI
24.  Mapping of the IRF8 gene identifies a 3’ UTR variant associated with risk of chronic lymphocytic leukemia but not other common non-Hodgkin lymphoma subtypes 
Background
Our genome-wide association study (GWAS) of chronic lymphocytic leukemia (CLL) identified 4 highly-correlated intronic variants within the IRF8 gene that were associated with CLL. These results were further supported by a recent meta-analysis of our GWAS with two other GWAS of CLL, supporting the IRF8 gene as a strong candidate for CLL risk.
Methods
To refine the genetic association of CLL risk, we performed Sanger sequencing of IRF8 in 94 CLL cases and 96 controls. We then performed fine-mapping by genotyping 39 variants (of which 10 were identified from sequencing) in 745 CLL cases and 1521 controls. We also assessed these associations with risk of other non-Hodgkin lymphoma (NHL) subtypes.
Results
The strongest association with CLL risk was observed with a common SNP located within the 3’ UTR of IRF8 (rs1044873, log additive odds ratio = 0.7, P=1.81×10−6). This SNP was not associated with the other NHL subtypes (all P>0.05).
Conclusions
We provide evidence that rs1044873 in the IRF8 gene accounts for the initial GWAS signal for CLL risk. This association appears to be unique to CLL with little support for association with other common NHL subtypes. Future work is needed to assess functional role of IRF8 in CLL etiology.
Impact
These data provide support that a functional variant within the 3’ UTR of IRF8 may be driving the GWAS signal seen on 16q24.1 for CLL risk.
doi:10.1158/1055-9965.EPI-12-1217
PMCID: PMC3596428  PMID: 23307532
CLL; NHL; SNPs; IRF8; risk locus
25.  Phase II Trials of Single Agent Anti-VEGF Therapy for Patients with Chronic Lymphocytic Leukemia (CLL) 
Leukemia & lymphoma  2010;51(12):2222-2229.
Between 2005 and 2008, we conducted separate phase II clinical testing of 3 distinct anti-VEGF therapies for patients with relapsed/refractory CLL. Collectively, 46 patients were accrued to trials of single-agent anti-VEGF antibody (bevacizumab, n=13) or 1 of 2 receptor tyrosine kinase inhibitors (AZD2171, n=15; sunitinib malate, n=18). All patients have completed treatment. Patients received a median of 2 cycles of bevacizumab, AZD2171, or sunitinib malate. All 3 trials were closed early due to lack of efficacy. No complete or partial remissions were observed. Individually and collectively, these studies indicate single-agent anti-VEGF therapy has minimal clinical activity for patients with relapsed/refractory CLL.
doi:10.3109/10428194.2010.524327
PMCID: PMC3928074  PMID: 21054149
chronic lymphocytic leukemia; angiogenesis; vascular endothelial growth factor (VEGF); therapy; bevacizumab; receptor tyrosine kinase inhibitor

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