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1.  How Is Emotional Awareness Related to Emotion Regulation Strategies and Self-Reported Negative Affect in the General Population? 
PLoS ONE  2014;9(3):e91846.
The Levels of Emotional Awareness Scale (LEAS) as a performance task discriminates between implicit or subconscious and explicit or conscious levels of emotional awareness. An impaired awareness of one's feeling states may influence emotion regulation strategies and self-reports of negative emotions. To determine this influence, we applied the LEAS and self-report measures for emotion regulation strategies and negative affect in a representative sample of the German general population.
Sample and Methods
A short version of the LEAS, the Hospital Anxiety and Depression Scale (HADS) and the Emotion Regulation Questionnaire (ERQ), assessing reappraisal and suppression as emotion regulation strategies, were presented to N = 2524 participants of a representative German community study. The questionnaire data were analyzed with regard to the level of emotional awareness.
LEAS scores were independent from depression, but related to self-reported anxiety. Although of small or medium effect size, different correlational patters between emotion regulation strategies and negative affectivity were related to implict and explict levels of emotional awareness. In participants with implicit emotional awareness, suppression was related to higher anxiety and depression, whereas in participants with explicit emotional awareness, in addition to a positive relationship of suppression and depression, we found a negative relationship of reappraisal to depression. These findings were independent of age. In women high use of suppression and little use of reappraisal were more strongly related to negative affect than in men.
Our first findings suggest that conscious awareness of emotions may be a precondition for the use of reappraisal as an adaptive emotion regulation strategy. They encourage further research in the relation between subconsious and conscious emotional awareness and the prefarance of adaptive or maladaptive emotion regulation strategies The correlational trends found in a representative sample of the general population may become more pronounced in clinical samples.
PMCID: PMC3956759  PMID: 24637792
2.  SiLEA14, a novel atypical LEA protein, confers abiotic stress resistance in foxtail millet 
BMC Plant Biology  2014;14(1):290.
Late embryogenesis abundant (LEA) proteins are involved in protecting higher plants from damage caused by environmental stresses. Foxtail millet (Setaria italica) is an important cereal crop for food and feed in semi-arid areas. However, the molecular mechanisms underlying tolerance to these conditions are not well defined.
Here, we characterized a novel atypical LEA gene named SiLEA14 from foxtail millet. It contains two exons separated by one intron. SiLEA14 was expressed in roots, stems, leaves, inflorescences and seeds at different levels under normal growth conditions. In addition, SiLEA14 was dramatically induced by osmotic stress, NaCl and exogenous abscisic acid. The SiLEA14 protein was localized in the nucleus and the cytoplasm. Overexpression of SiLEA14 improved Escherichia coli growth performance compared with the control under salt stress. To further assess the function of SiLEA14 in plants, transgenic Arabidopsis and foxtail millet plants that overexpressed SiLEA14 were obtained. The transgenic Arabidopsis seedlings showed higher tolerance to salt and osmotic stress than the wild type (WT). Similarly, the transgenic foxtail millet showed improved growth under salt and drought stresses compared with the WT. Taken together, our results indicated that SiLEA14 is a novel atypical LEA protein and plays important roles in resistance to abiotic stresses in plants.
We characterized a novel atypical LEA gene SiLEA14 from foxtail millet, which plays important roles in plant abiotic stress resistance. Modification of SiLEA14 expression may improve abiotic stress resistance in agricultural crops.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0290-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4243736  PMID: 25404037
3.  Functional, structural, and emotional correlates of impaired insight in cocaine addiction 
JAMA psychiatry  2014;71(1):61-70.
Individuals with cocaine use disorder (CUD) have difficulty monitoring ongoing behavior, possibly stemming from dysfunction of brain regions subserving insight and self-awareness [e.g., anterior cingulate cortex (ACC)].
To test the hypothesis that CUD with impaired insight (iCUD) would show abnormal (A) ACC activity during error processing, assessed with functional magnetic resonance imaging during a classic inhibitory control task; (B) ACC gray matter integrity assessed with voxel-based morphometry; and (C) awareness of one’s own emotional experiences, assessed with the Levels of Emotional Awareness Scale (LEAS). Using a previously validated probabilistic choice task, we grouped 33 CUD according to insight [iCUD: N=15; unimpaired insight CUD: N=18]; we also studied 20 healthy controls, all with unimpaired insight.
Multimodal imaging design.
Clinical Research Center at Brookhaven National Laboratory.
Thirty-three CUD and 20 healthy controls.
Main Outcome Measure
Functional magnetic resonance imaging, voxel-based morphometry, LEAS, and drug use variables.
Compared with the other two study groups, iCUD showed lower (A) error-induced rostral ACC (rACC) activity as associated with more frequent cocaine use; (B) gray matter within the rACC; and (C) LEAS scores.
These results point to rACC functional and structural abnormalities, and diminished emotional awareness, in a subpopulation of CUD characterized by impaired insight. Because the rACC has been implicated in appraising the affective/motivational significance of errors and other types of self-referential processing, functional and structural abnormalities in this region could result in lessened concern (frequently ascribed to minimization and denial) about behavioral outcomes that could potentially culminate in increased drug use. Treatments targeting this CUD subgroup could focus on enhancing the salience of errors (e.g., lapses).
PMCID: PMC4193926  PMID: 24258223
cocaine addiction; insight; fMRI; VBM; emotional awareness; anterior cingulate cortex; color-word Stroop
4.  Age and gender effect on alexithymia in large, Japanese community and clinical samples: a cross-validation study of the Toronto Alexithymia Scale (TAS-20) 
The construct validity of alexithymia and its assessment using the 20-item Toronto Alexithymia Scale (TAS-20) in Japan is unknown. Low reliability has been found for the third factor of the TAS-20 in some cultures, and the factor structure for psychosomatic disorder patients has not been adequately investigated. Although alexithymia most likely has certain developmental aspects, this has infrequently been investigated.
The newly-developed Japanese TAS-20 was administered to a normative sample (n = 2,718; 14–84 y.o.), along with the NEO Five-Factor Inventory (NEO-FFI) for cross validation. Psychosomatic patients (n = 1,924, 12–87 y.o.) were tested to evaluate the factor structure in a clinical sample. College students (n = 196) were used for a test-retest study. Internal reliability and consistency were assessed, and the factorial structure was evaluated using confirmatory and exploratory factor analyses for both the normative and the clinical samples. The correlations between the TAS-20 and the NEO-FFI factor scores were evaluated. Age-related and gender differences in the TAS-20 were explored using analysis of variance in the normative sample.
The original three-factor model of the TAS-20 was confirmed to be valid for these Japanese samples, although a 4-factor solution that included negatively keyed items (NKI) as an additional factor was more effective. Significant correlations of the TAS-20 with the NEO-FFI were found, as has been previously reported. Factor analyses of the normative and patient samples showed similar patterns. The TAS-20 total, difficulty in identifying feelings (DIF), and difficulty in describing feelings (DDF) scores were high for teenagers, decreased with age, and from 30s did not change significantly. In contrast, externally oriented thinking (EOT) scores showed an almost linear positive correlation with age. DIF scores were higher for females, while EOT scores were higher for males, without any interaction between gender and age differences.
The original three-factor concept of the TAS-20 was generally supported for practical use. Age-related differences in TAS-20 scores indicate developmental aspects of alexithymia. Alexithymia is made up of two components with different developmental paths: DIF/DDF and EOT.
PMCID: PMC1838425  PMID: 17371586
5.  Developing and Validating a Risk Score for Lower-Extremity Amputation in Patients Hospitalized for a Diabetic Foot Infection 
Diabetes Care  2011;34(8):1695-1700.
Diabetic foot infection is the predominant predisposing factor to nontraumatic lower-extremity amputation (LEA), but few studies have investigated which specific risk factors are most associated with LEA. We sought to develop and validate a risk score to aid in the early identification of patients hospitalized for diabetic foot infection who are at highest risk of LEA.
Using a large, clinical research database (CareFusion), we identified patients hospitalized at 97 hospitals in the U.S. between 2003 and 2007 for culture-documented diabetic foot infection. Candidate risk factors for LEA included demographic data, clinical presentation, chronic diseases, and recent previous hospitalization. We fit a logistic regression model using 75% of the population and converted the model coefficients to a numeric risk score. We then validated the score using the remaining 25% of patients.
Among 3,018 eligible patients, 21.4% underwent an LEA. The risk factors most highly associated with LEA (P < 0.0001) were surgical site infection, vasculopathy, previous LEA, and a white blood cell count >11,000 per mm3. The model showed good discrimination (c-statistic 0.76) and excellent calibration (Hosmer-Lemeshow, P = 0.63). The risk score stratified patients into five groups, demonstrating a graded relation to LEA risk (P < 0.0001). The LEA rates (derivation and validation cohorts) were 0% for patients with a score of 0 and ~50% for those with a score of ≥21.
Using a large, hospitalized population, we developed and validated a risk score that seems to accurately stratify the risk of LEA among patients hospitalized for a diabetic foot infection. This score may help to identify high-risk patients upon admission.
PMCID: PMC3142050  PMID: 21680728
6.  Synthesis of sialyl Lewisa (sLea, CA19-9) and construction of an immunogenic sLea vaccine 
Sialyl Lewisa (sLea), also termed CA19-9 antigen, is recognized by murine mAb19-9 and is expressed on the cancer cell surface as a glycolipid and as an O-linked glycoprotein. It is highly expressed in a variety of gastrointestinal epithelial malignancies including colon cancer and pancreatic cancer, and in breast cancer and small cell lung cancer, but has a limited expression on normal tissues. sLea is known to be the ligand for endothelial cell selectins suggesting a role for sLea in cancer metastases and adhesion. For these reasons, sLea may be a good target for antibody mediated immunotherapy including monoclonal antibodies and tumor vaccines. However, sLea is structurally similar to sLex and other blood group related carbohydrates which are widely expressed on polymorphonucleocytes and other circulating cells, raising concern that immunization against sLea will induce antibodies reactive with these more widely expressed autoantigens. We have shown previously both in mice and in patients that conjugation of a variety of carbohydrate cancer antigen to keyhole limpet hemocyanin (KLH) and administration of this conjugate mixed with saponin adjuvants QS-21 or GPI-0100 are the most effective methods for induction of antibodies against these cancer antigens. We describe here for the first time the total synthesis of pentenyl glycoside of sLea hexasaccharide and its conjugation to KLH to construct a sLea-KLH conjugate. Groups of five mice were vaccinated subcutaneously four times over 6 weeks. Sera were tested against sLea-HSA by ELISA and against sLea positive human cell lines adenocarcinoma SW626 and small cell lung cancer (SCLC) DMS79 by FACS. As expected, mice immunized with unconjugated sLea plus GPI-0100 or unconjugated sLea mixed with KLH plus GPI-0100 failed to produce antibodies against sLea. However, mice immunized with sLea-KLH conjugate without GPI-0100 produced low levels of antibodies and mice immunized with sLea-KLH plus GPI-0100 produced significantly higher titer IgG and IgM antibodies against sLea by ELISA. These antibodies were highly reactive by FACS and mediated potent complement mediated cytotoxicity against sLea positive SW626 and DMS79 cells. They showed no detectable cross reactivity against a series of other blood group-related antigens, including Ley, Lex, and sLex by dot blot immune staining. This vaccine is ready for testing as an active immunotherapy for treating sLea positive cancer in clinical settings.
PMCID: PMC2828770  PMID: 19190907
Sialyl Lewisa; CA19-9; Carbohydrate conjugate vaccine; Cancer vaccine
7.  Expression of sialyl Lewisa relates to poor prognosis in cholangiocarcinoma 
AIM: High levels of serum sialyl Lewisa (sLea) are frequently found in cholangiocarcinoma (CCA) patients and have been suggested to be a serum marker for CCA. However, the significance of this antigen in CCA is unknown. In this study, the clinical significance of sLea expression in CCA tissues and the possible role of sLea in vascular invasion in vitro were elucidated.
METHODS: Expression of sLea in tumor tissues of 77 patients with mass-forming CCA and 33 with periductal infiltrating CCA was determined using immunohistochemistry. The in vitro assays on adhesion and transmigration of CCA cells to human umbilical vein endothelial cells were compared between CCA cell lines with and without sLea expression.
RESULTS: sLea was aberrantly expressed in 60% of CCA tumor tissues. A significant relationship was found between the frequency of sLea expression and the mass-forming type CCA (P = 0.041), well differentiated histological grading (P = 0.029), and vascular invasion (P = 0.030). Patients with positive sLea expression had a significantly poorer prognosis (21.28 wk, 95% CI = 16.75-25.81 wk) than those negative for sLea (37.30 wk, 95% CI = 27.03-47.57 wk) (P<0.001). Multivariate analysis with adjustment for all covariates showed that patients positive for sLea possessed a 2.3-fold higher risk of death than patients negative for sLea (P<0.001). The role of sLea in vascular invasion was demonstrated using in vitro adhesion and transmigration assays. KKU-M213, a human CCA cell-line with a high expression of sLea, adhered and transmigrated to IL-1β-activated endothelial cells of the human umbilical vein more than KKU-100, the line without sLea expression (P<0.001). These processes were significantly diminished when the antibodies specific to either sLea or E-selectin were added to the assays (P<0.001).
CONCLUSION: This study demonstrates the clinical significance of sLea expression in vascular invasion, and an unfavorable outcome in CCA. The role of sLea in vascular invasion which may lead to poor prognosis is supported by the in vitro adhesion and transmigration studies.
PMCID: PMC4205411  PMID: 15633225
Cholangiocarcinoma; Sialyl Lewisa; Poor prognosis
8.  Effects of limiting energy availability via diet and physical activity on mammalian target of rapamycin-related signaling in rat mammary carcinomas 
Carcinogenesis  2012;34(2):378-387.
This study evaluated how different approaches to limiting energy availability (LEA) by 15% affected mammalian target of rapamycin (mTOR)-related signaling in mammary carcinomas. Female Sprague Dawley rats, injected with 50mg 1-methyl-1-nitrosourea per kilogram body weight, were randomized to a control or three LEA interventions: (i) sedentary and restricted rats fed to 85% of energy available to the control or motorized wheel running (37 m/min) for an average of (ii) 1621±55 (WRL) or (iii) 3094±126 (WRH) meters/day with food intake adjusted to provide the same net amount of available energy across LEA interventions. Under these conditions, LEA reduced overall cancer burden by 28% (P = 0.04) and down-regulated mTOR-related signaling (Hotelling multivariate, P = 0.002). Among the regulatory nodes assessed, reduced levels of activated protein kinase B (pAkt) and induction of sirtuin 1 (SIRT1) were the most influential factors in distinguishing between sham control and LEA carcinomas. P-Akt was predictive of observed changes in levels of proteins involved in cell cycle control (r = 0.698, P < 0.0001) and induction of apoptosis (r = –0.429, P = 0.014). Plasma insulin and leptin were strongly associated with carcinoma pAkt levels. Consistent with downregulation of mTOR-related signaling by LEA, evidence of decreased lipid synthesis in carcinomas was observed (Hotelling multivariate, P < 0.001) and was negatively correlated with SIRT1 induction. Despite large differences between control and LEA, effects on mTOR regulation were insufficient to distinguish among LEA intervention groups. Given the modest effects observed on the LKB1/AMP-activated protein kinase regulatory node, NADH and NADPH rather than ATP may be more limiting for tumor growth when LEA is 15%.
PMCID: PMC3564443  PMID: 23125225
9.  Concordance studies between hospital discharge data and medical records for the recording of lower extremity amputation and diabetes in the Republic of Ireland 
BMC Research Notes  2013;6:148.
Hospital discharge data have been used to study trends in Lower Extremity Amputation (LEA) rates in people with and without diabetes. The aim of this study was to assess the reliability of routine hospital discharge data in the Republic of Ireland (RoI) for this purpose by determining the level of agreement between hospital discharge data and medical records for both the occurrence of LEA and diagnosis of diabetes.
Two concordance studies between hospital discharge data (HIPE) and medical records were performed. To determine the level of agreement for LEA occurrence, HIPE records were compared to theatre logbooks in 9 hospitals utilising HIPE over a two-year period in a defined study area. To determine the level of agreement for diabetes diagnosis, HIPE records were compared to laboratory records in each of the 4 largest hospitals utilising HIPE over a one week period in the same study area. The proportions of positive and negative agreement and Cohen’s kappa statistic of agreement were calculated.
During a two-year study period in 9 hospitals, 216 LEAs were recorded in both data sources. Sixteen LEAs were recorded in medical records alone and 25 LEAs were recorded in hospital discharge records alone. The proportion of positive agreement was 0.91 (95% CI 0.88-0.94), the proportion of negative agreement was 0.99 (95% CI 0.98-0.99) and the kappa statistic was 0.91 (95% CI 0.88-0.94).
During a one-week study period in 4 hospitals, 49 patients with diabetes and 716 patients without diabetes were recorded in both data sources. Eighteen patients had diabetes in medical records alone and 2 patients had diabetes in hospital discharge records alone. The proportion of positive agreement was 0.83 (95% CI 0.76-0.9), the proportion of negative agreement was 0.99 (95% CI 0.98-0.99) and the kappa statistic was 0.82 (95% CI 0.75-0.89).
This study detected high levels of agreement between hospital discharge data and medical records for LEA and diabetes in a defined study area. Based on these findings, we suggest that HIPE is sufficiently reliable to monitor trends in LEAs in people with and without diabetes in the RoI.
PMCID: PMC3640954  PMID: 23587134
Concordance study; Lower extremity amputation; Diabetes; Hospital discharge data; Medical records; Agreement statistics
10.  A review of the foot function index and the foot function index – revised 
The Foot Function Index (FFI) is a self-report, foot-specific instrument measuring pain and disability and has been widely used to measure foot health for over twenty years. A revised FFI (FFI-R) was developed in response to criticism of the FFI. The purpose of this review was to assess the uses of FFI and FFI-R as were reported in medical and surgical literature and address the suggestions found in the literature to improve the metrics of FFI-R.
A systematic literature search of PubMed/Medline and Embase databases from October 1991 through December 2010 comprised the main sources of literature. To enrich the bibliography, the search was extended to BioMedLib and Scopus search engines and manual search methods. Search terms included FFI, FFI scores, FFI-R. Requirements included abstracts/full length articles, English-language publications, and articles containing the term "foot complaints/problems." Articles selected were scrutinized; EBM abstracted data from literature and collected into tables designed for this review. EBM analyzed tables, KJC, JM, RMS reviewed and confirmed table contents. KJC and JM reanalyzed the original database of FFI-R to improve metrics.
Seventy-eight articles qualified for this review, abstracts were compiled into 12 tables. FFI and FFI-R were used in studies of foot and ankle disorders in 4700 people worldwide. FFI Full scale or the Subscales and FFI-R were used as outcome measures in various studies; new instruments were developed based on FFI subscales. FFI Full scale was adapted/translated into other cultures. FFI and FFI-R psychometric properties are reported in this review. Reanalysis of FFI-R subscales' confirmed unidimensionality, and the FFI-R questionnaires' response categories were edited into four responses for ease of use.
This review was limited to articles published in English in the past twenty years. FFI is used extensively worldwide; this instrument pioneered a quantifiable measure of foot health, and thus has shifted the paradigm of outcome measure to subjective, patient-centered, valid, reliable and responsive hard data endpoints. Edited FFI-R into four response categories will enhance its user friendliness for measuring foot health.
PMCID: PMC3579714  PMID: 23369667
FFI; FFI-R; FFI adaptation/translation; FFI scores; Foot health measures
11.  Association between trait emotional awareness and dorsal anterior cingulate activity during emotion is arousal-dependent 
NeuroImage  2008;41(2):648.
The dorsal anterior cingulate cortex (dACC) is commonly thought to subserve primarily cognitive functions, but has been strongly implicated in the allocation of attention to emotional information. In a previous positron emission tomography (PET) study, we observed that women with higher emotional awareness as measured by the Levels of Emotional Awareness Scale (LEAS) showed greater changes in regional cerebral blood flow (rCBF) in dACC induced by emotional films and recall. In the current study, we tested whether these effects were due to the processing of any non-neutral stimulus, or were specific to conditions of high emotional arousal. Our results extend the previous finding by demonstrating a positive correlation between emotional awareness and dACC activity only in the context of viewing highly arousing pictures. No such relationship was observed when comparing pleasant or unpleasant pictures to neutral or to each other. We also observed that the relationship between LEAS and dACC activity was present in both sexes but stronger in women than men. These results reinforce the concept that greater trait awareness of one's own emotional experiences is associated with greater engagement of the dACC during emotional arousal, which we suggest may reflect greater attentional processing of emotional information.
PMCID: PMC2821667  PMID: 18406175
12.  The Impact of Labour Epidural Analgesia on the Childbirth Expectation and Experience at a Tertiary Care Center in Southern India. 
Background: Labour epidural analgesia is increasingly used as a means of pain relief for women during labour and delivery. The significant pain during labour and delivery can be terrifying for mothers-to-be and the prospect of relief from pain can help reduce fear of childbirth to an extent. However, it is not necessary that reduced fear of childbirth may lead to an increased satisfaction with the childbirth experience.
Aim: To determine the influence of labour epidural analgesia (LEA) on the experience of childbirth in pregnant women at a tertiary care center in southern India
Materials and Methods: A pre-post interventional non-randomized study design at a tertiary care perinatal institute that used the Wijma Delivery Expectation and Experience questionnaires to determine baseline expectations of labour and childbirth and the actual experience in pregnant women. Labour analgesia was provided on maternal request or demand. Total and domain scores were compared between the two groups using non-parametric tests and a generalized linear repeated measures model after adjusting for factors that were found significant in the bivariate model.
Results: The study included 235 pregnant women who opted for LEA and 219 pregnant women who opted against LEA. Overall, 37 (15.74%) of woman with LEA and 30 (13.70%) of women without LEA had a worse than expected experience of childbirth. Significant pain relief (p<0.001) was provided with LEA, however, the post-delivery scores did not differ significantly between the two groups (F=0.90, p=0.34) in a generalized linear repeated measures model.
Conclusion: Maternal satisfaction with the process of childbirth is a complex dynamic that is not limited to the significant relief from pain provided by LEA.
PMCID: PMC4003692  PMID: 24783086
Maternal satisfaction; Labour epidural analgesia; Pain relief; Childbirth; Delivery
13.  Associations between Medical Student Empathy and Personality: A Multi-Institutional Study 
PLoS ONE  2014;9(3):e89254.
More empathetic physicians are more likely to achieve higher patient satisfaction, adherence to treatments, and health outcomes. In the context of medical education, it is thus important to understand how personality might condition the empathetic development of medical students. Single institutional evidence shows associations between students' personality and empathy. This multi-institutional study aimed to assess such associations across institutions, looking for personality differences between students with high empathy and low empathy levels.
Participants were 472 students from three medical schools in Portugal. They completed validated adaptations to Portuguese of self-report measures of the NEO-Five Factor Inventory(NEO-FFI) and the Jefferson Scale of Physician Empathy(JSPE-spv). Students were categorized into two groups: “Bottom” (low empathy, N = 165) and “Top” (high empathy, N = 169) according to their empathy JSPE-spv total score terciles. Correlation analysis, binary logistic regression analysis and ROC curve analysis were conducted.
A regression model with gender, age and university had a predictive power (pseudo R2) for belonging to the top or bottom group of 6.4%. The addition of personality dimensions improved the predictive power to 16.8%. Openness to experience and Agreeableness were important to predict top or bottom empathy scores when gender, age and university were considered.” Based on the considered predictors the model correctly classified 69.3% of all students.
The present multi-institutional cross-sectional study in Portugal revealed across-school associations between the Big5 dimensions Agreeableness and Openness to experience and the empathy of medical students and that personality made a significant contribution to identify the more empathic students. Therefore, medical schools may need to pay attention to the personality of medical students to understand how to enhance the empathy of medical students.
PMCID: PMC3956603  PMID: 24637613
Journal of vascular surgery  2013;58(6):10.1016/j.jvs.2013.06.069.
To examine the association between use of statin and non-statin cholesterol-lowering medications and risk of nontraumatic major lower-extremity amputations (LEA) and treatment failure (LEA or death).
Design of Study
A retrospective cohort of patients with Type I and Type 2 diabetes mellitus (diabetes) was followed for five years between 2004 and 2008. The follow-up exposure duration was divided into 90-day periods. Use of cholesterol-lowering agents, diabetic medications, hemoglobin A1c, body mass index, and systolic and diastolic blood pressures were observed in each period. Demographic factors were observed at baseline. Major risk factors of LEA including peripheral neuropathy, PAD, and foot ulcers were observed at baseline and were updated for each period. LEA and deaths were assessed in each period and their hazard ratios were estimated.
US Department of Veterans Affairs Healthcare system (VA)
Cholesterol drug-naïve patients with Type I or II diabetes who were treated in the VA in 2003 and were <65 years old at the end of follow-up.
Of 83,593 patients in the study cohort, 217 (0.3%) patients experienced a major LEA and 11,716 (14.0%) patients experienced an LEA or death (treatment failure) after a mean follow-up of 4.6 years. Compared to patients who did not use cholesterol-lowering agents, statin users were 35% - 43% less likely to experience an LEA (HR = 0.65; 95% CI, 0.42–0.99) and a treatment failure (HR = 0.57; 95% CI, 0.54–0.60). Users of other cholesterol-lowering medications were not significantly different in LEA risk (HR = 0.95; 95% CI, 0.35–2.60) but had a 41% lower risk of treatment failure (HR = 0.59; 95% CI, 0.51–0.68).
This is the first study to report a significant association between statin use and diminished amputation risk among patients with diabetes. In this non-randomized cohort, beneficial effects of statin therapy were similar to that seen in large-scale clinical trial experience. For LEA risk, those given non-statins did not have a statistically significant benefit and its effect on LEA risk was much smaller compared to statins.. Unanswered questions to be explored in future studies include a comparison of statins of moderate versus high potency in those with high risk of coronary heart disease and an exploration of whether the effects seen in this study are simply effects of cholesterol-lowering or possibly pleiotropic effects.
PMCID: PMC3844128  PMID: 23932803
cholesterol therapy; diabetes; statins; lower-extremity amputation; amputation-free survival
Light exposure at night is now considered a probable carcinogen. To study the effects of light on chronic diseases like cancer, methods to measure light exposure in large observational studies are needed. We aimed to investigate the validity of self-reported current light exposure.
We developed a self-administered semiquantitative light questionnaire, the Harvard Light Exposure Assessment (H-LEA) questionnaire, and compared photopic scores derived from this questionnaire with actual photopic and circadian measures obtained from a real-life 7-day light meter application among 132 women (85 rotating night shift workers and 47 day workers) participating in the Nurses' Health Study II.
After adjustment for age, BMI, collection day, and night work status, the overall partial Spearman correlation between self-report of light exposure and actual photopic light measurements was 0.72 (P<0.001; Kendall τ =0.57) and 0.73 (P<0.0001; Kendall τ =0.58) when correlating circadian light measurements. There were only minimal differences in accuracy of self-report of light exposure and photopic or circadian light measurement between day (r=0.77 and 0.78, respectively) and rotating night shift workers (r=0.68 and 0.69, respectively).
The results of this study provide evidence of the criterion validity of self-reported light exposure using the H-LEA questionnaire. Impact: This questionnaire is a practical method of assessing light exposure in large scale epidemiologic studies.
PMCID: PMC3340010  PMID: 21737411
light; melatonin; validation; questionnaire
16.  Temperament and personality: the German version of the Adult Temperament Questionnaire (ATQ) 
The psychobiological orientation inherent in temperament concepts permits a close tie between temperament and the rapidly proliferating research areas of neurosciences and behavioural genetics. Based on developmental and psychobiological studies, the Adult Temperament Questionnaire (ATQ) by Rothbart measures self-regulatory processes in addition to constitutionally based individual reactivity. The purpose of this paper is to validate a German version of the short form of the ATQ with 77 items. 213 psychosomatic inpatients and outpatients and 116 control subjects took part in this study. The study included standardized measures of personality and symptoms. The German version reliably measures the four dimensions negative affect, extraversion, orienting sensitivity and effortful control; subscales were moderately correlated. We found a consistent pattern of correlation to personality (NEO-FFI) and interpersonal problems (IIP), negative affect strongly correlated with neuroticism; effortful control correlated with conscientiousness, orienting sensitivity with openness, and extraversion correlated with the corresponding scale of the NEO-FFI. According to our hypothesis, negative affect was positively correlated with higher distress and physical complaints, while effortful control was negatively correlated with them. When negative affect and effortful control were combined, effortful control had a moderating effect on distress. Clinical and non-clinical samples differed significantly on all dimensions; the ATQ appears to be suitable for differentiating subgroups of patients according to self-regulation.
PMCID: PMC2736500  PMID: 19742070
temperament; personality; Adult Temperament Questionnaire; validation
17.  Isolation and functional characterization of a Medicago sativa L. gene, MsLEA3-1 
Molecular Biology Reports  2011;39(3):2883-2892.
A full-length cDNA of 1,728 nt, called MsLEA3-1, was cloned from alfalfa by rapid amplification of cDNA ends from an expressed sequence tag homologous to soybean pGmPM10 (accession No. AAA91965.1). MsLEA3-1, encodes a deduced protein of 436 amino acids, a calculated molecular weight of 47.0 kDa, a theoretical isoelectric point of 5.18, and closest homology with late embryogenesis abundant proteins in soybean. Sequence homology suggested a signal peptide in the N terminus, and subcellular localization with GFP revealed that MsLEA3-1 was localized preferentially to the nucleolus. The transcript titre of MsLEA3-1 was strongly enriched in leaves compared with roots and stems of mature alfalfa plants. Gene expression of MsLEA3-1 was strongly induced when seedlings were treated with NaCl and ABA. Expression of the MsLEA3-1 transgenic was detected in transgenic tobacco. Malondialdehyde content and, electrical conductivity content were reduced and electrical conductivity and proline content were increased in transgenic tobacco compared with non-transgenic tobacco under salt stress. The results showed that accumulation of the MsLEA3-1 protein in the vegetative tissues of transgenic plants enhanced their tolerance to salt stress. These results demonstrate a role for the MsLEA3-1 protein in stress protection and suggest the potential of the MsLEA3-1 gene for genetic engineering of salt tolerance.
Electronic supplementary material
The online version of this article (doi:10.1007/s11033-011-1048-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3271230  PMID: 21681426
Medicago sativa L.; Late embryogenesis abundant protein; Gene expression; Subcellular localization; Expression; Salt stress; Transgenic tobacco
18.  A LEA Gene Regulates Cadmium Tolerance by Mediating Physiological Responses 
In this study, the function of a LEA gene (TaLEA1) from Tamrix androssowii in response to heavy metal stress was characterized. Time-course expression analyses showed that NaCl, ZnCl2, CuSO4, and CdCl2 considerably increased the expression levels of the TaLEA1 gene, thereby suggesting that this gene plays a role in the responses to these test stressors. To analyze the heavy metal stress-tolerance mechanism regulated by TaLEA1, TaLEA1-overexpressing transgenic poplar plants (Populus davidiana Dode × P. bollena Lauche) were generated. Significant differences were not observed between the proline content of the transgenic and wild-type (WT) plants before and after CdCl2 stress. However, in comparison with the WT plants, the TaLEA1-transformed poplar plants had significantly higher superoxide dismutase (SOD) and peroxidase (POD) activities, and lower malondialdehyde (MDA) levels under CdCl2 stress. Further, the transgenic plants showed better growth than the WT plants did, indicating that TaLEA1 provides tolerance to cadmium stress. These results suggest that TaLEA1 confers tolerance to cadmium stress by enhancing reactive oxygen species (ROS)-scavenging ability and decreasing lipid peroxidation. Subcellular-localization analysis showed that the TaLEA1 protein was distributed in the cytoplasm and nucleus.
PMCID: PMC3382805  PMID: 22754308
LEA gene; cadmium stress; stress tolerance; gene transformation; physiological response
19.  Vesicle Size and Stability of Biomimetic Liposomes from 3’-Sulfo-Lewis a (SuLea)-Containing Glycolipids 
We report on the use of a natural Lewis type saccharide ligand, 3’-sulfo-Lewis a (SuLea) for glycocalyx-mimetic surface modification of liposomes. Two SuLea–containing glycolipids, monovalent SuLea-lipid and trivalent SuLea (TSuLea)-lipid, were synthesized, and used with 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol to prepare unilaminar vesicles (ULVs) by a freeze-thaw and extrusion method. The effects of the glycolipid concentrations and the pore sizes of extrusion membranes on vesicle size and stability were investigated by photon correlation spectroscopy (PCS). Glycoliposomes, with 5% SuLea- or TSuLea-lipids obtained by 50 nm extrusion, had 25-30% more vesicles less than 100 nm in diameter compared with the 100 nm extrusion. TSuLea-liposomes always produced larger vesicle size than SuLea-liposomes, which we attribute to the larger TSuLea headgroup. Both SuLea- and TSuLea-liposomes increased their vesicle size with increasing glycolipid concentration from 5% to 15%, and demonstrated good stability at room temperature for over one month. Further increasing the glycolipid concentration to 20% resulted in large vesicle aggregation after 5 days for TSuLea-liposomes, while the SuLea-liposomes remained stable for 10 days. SuLea- and TSuLea-liposomes with 15% glycolipids demonstrated better stability due to the electrostatic effect from the negatively charged SuLea and TSuLea headgroups. The results indicate that the biomimetic liposomes with SuLea- and TSuLea-lipids with 5 to 15% incorporation are sufficiently stable for the potential applications in targeted drug delivery.
PMCID: PMC2041829  PMID: 17499486
Liposomes; saccharides; 3’-sulfo-Lewis a; glycolipids; vesicle size
20.  Personality and Medical Illness Burden Among Older Adults in Primary Care 
Psychosomatic medicine  2007;69(3):10.1097/PSY.0b013e3180313975.
To examine the association between Five Factor Model personality traits (Neuroticism, Extraversion, Openness to experience, Agreeableness, Conscientiousness) and physician-quantified aggregate morbidity in a sample of older adults in primary care.
A total of 449 primary care patients, ranging in age from 65 to 97 years (75 ± 6.9 (mean ± standard deviation)), completed the Neo-Five Factor Inventory (NEO-FFI) and extensive interviews. A physician-investigator completed the Cumulative Illness Rating Scale (CIRS), a well-validated measure of aggregate morbidity based on a review of medical records.
Bivariate analyses demonstrated that all five domains of the NEO-FFI were associated with CIRS scores. Multivariate regression controlling for age, gender, education, depression, smoking, hypertension, total cholesterol, alcohol or substance misuse, and other personality traits showed that greater Conscientiousness was independently associated with lower CIRS scores (β = −0.10, t(435) = −1.96, p = .05). Other independent predictors of less morbidity were younger age, absence of hypertension, and lower levels of depression.
Our results point toward the necessity of considering Conscientiousness and other personality traits in studies of risk factors for aggregate morbidity. More detailed characterization of at-risk populations will increase the likelihood of constructing informed and effective prevention, intervention, and policy initiatives.
PMCID: PMC3807736  PMID: 17401059
personality; older adults; medical illnesses; primary care
21.  HbA1c and Lower-Extremity Amputation Risk in Low-Income Patients With Diabetes 
Diabetes Care  2013;36(11):3591-3598.
Diabetes confers a very high risk of lower-extremity amputation (LEA); however, few studies have assessed whether blood glucose control can reduce LEA risk among patients with diabetes, especially in practice settings where low-income patients predominate.
We performed a prospective cohort study (2000–2009) on patients with diabetes that included 19,808 African Americans and 15,560 whites. The cohort was followed though 31 May 2012. Cox proportional hazards regression models were used to estimate the association of HbA1c with LEA risk.
During a mean follow-up of 6.83 years, 578 LEA incident cases were identified. The multivariable-adjusted hazard ratios of LEA associated with different levels of HbA1c at baseline (<6.0% [reference group], 6.0–6.9, 7.0–7.9, 8.0–8.9, 9.0–9.9, and ≥10.0%) were 1.00, 1.73 (95% CI 1.07–2.80), 1.65 (0.99–2.77), 1.96 (1.14–3.36), 3.02 (1.81–5.04), and 3.30 (2.10–5.20) (P trend <0.001) for African American patients with diabetes and 1.00, 1.16 (0.66–2.02), 2.28 (1.35–3.85), 2.38 (1.36–4.18), 2.99 (1.71–5.22), and 3.25 (1.98–5.33) (P trend <0.001) for white patients with diabetes, respectively. The graded positive association of HbA1c during follow-up with LEA risk was observed among both African American and white patients with diabetes (all P trend <0.001). With stratification by sex, age, smoking status, blood pressure, LDL cholesterol, BMI, use of glucose-lowering agents, and income, this graded association of HbA1c with LEA was still present.
The current study conducted in a low-income population suggests a graded association between HbA1c and the risk of LEA among both African American and white patients with type 2 diabetes.
PMCID: PMC3816880  PMID: 24062322
22.  A comparison of thoracic or lumbar patient-controlled epidural analgesia methods after thoracic surgery 
We aimed to compare patient-controlled thoracic or lumbar epidural analgesia methods after thoracotomy operations.
One hundred and twenty patients were prospectively randomized to receive either thoracic epidural analgesia (TEA group) or lumbar epidural analgesia (LEA group). In both groups, epidural catheters were administered. Hemodynamic measurements, visual analog scale scores at rest (VAS-R) and after coughing (VAS-C), analgesic consumption, and side effects were compared at 0, 2, 4, 8, 16, and 24 hours postoperatively.
The VAS-R and VAS-C values were lower in the TEA group in comparison to the LEA group at 2, 4, 8, and 16 hours after surgery (for VAS-R, P = 0.001, P = 0.01, P = 0.008, and P = 0.029, respectively; and for VAS-C, P = 0.035, P = 0.023, P = 0.002, and P = 0.037, respectively). Total 24-hour analgesic consumption was different between groups (175 +/- 20 mL versus 185 +/- 31 mL; P = 0.034). The comparison of postoperative complications revealed that the incidence of hypotension (21/57, 36.8% versus 8/63, 12.7%; P = 0.002), bradycardia (9/57, 15.8% versus 2/63, 3.2%; P = 0.017), atelectasis (1/57, 1.8% versus 7/63, 11.1%; P = 0.04), and the need for intensive care unit (ICU) treatment (0/57, 0% versus 5/63, 7.9%; P = 0.03) were lower in the TEA group in comparison to the LEA group.
TEA has beneficial hemostatic effects in comparison to LEA after thoracotomies along with more satisfactory pain relief profile.
PMCID: PMC4063422  PMID: 24885545
Thoracic epidural analgesia; Lumbar epidural analgesia; Cardiac enzymes; Visual analog scale
23.  A comparison of Lea Symbols versus ETDRS letter distance visual acuity in a population of young children with a high prevalence of astigmatism 
To compare visual acuity results obtained using the Lea Symbols chart with results obtained using Early Treatment Diabetic Retinopathy Study (ETDRS) charts in young children who are members of a population with a high prevalence of astigmatism.
Subjects were 438 children aged 5 through 7 years who were enrolled in kindergarten or 1st grade on the Tohono O’odham Reservation: 241 (55%) had astigmatism ≥1.00 D in one or both eyes (range, 0.00 to 6.75 D). While wearing best correction, each child had right eye visual acuity tested with the 62 cm by 65 cm Lea Symbols chart at 3 m and with the 62 cm by 65 cm ETDRS chart at 4 m. Visual acuity was scored as the smallest optotype size at which the child correctly identified 3 out of a maximum of 5 optotypes. ETDRS visual acuity was also scored based on the total number of letters that the child correctly identified.
Correlation between Lea Symbols visual acuity and ETDRS visual acuity was 0.78 (p < 0.001). Mean Lea Symbols visual acuity was one-half line (0.04 to 0.06 logMAR) better than mean ETDRS visual acuity (p < 0.001). Difference between Lea Symbols and ETDRS visual acuity was not correlated with the mean of the Lea Symbols and ETDRS visual acuity scores, which ranged from −0.3 logMAR (20/10) to 0.74 logMAR (20/110).
In this population of young children, in whom the primary source of reduced visual acuity is astigmatism-related amblyopia, the Lea Symbols chart produced visual acuity scores that were about 0.5 line better than visual acuity scores obtained with ETDRS charts.
PMCID: PMC2764356  PMID: 19345596
24.  Validity issues in the assessment of alexithymia related to the developmental stages of emotional cognition and language 
We examined developmental aspects of the emotional awareness of adolescents by evaluating their responses to a self-reported questionnaire based on the Toronto Alexithymia Scale-20 (TAS-20).
The items of the TAS-20 were modified to make them more understandable by adolescents, and nine new items related to a limited capacity for imagination were added. The Japanese Linguistic Ability Test and the multi-dimensional empathy scale for adolescents were administered to examine concurrent validity. Two hundred and two normative young adolescents and thirty-two adolescent patients with psychosomatic and/or behavioral problems participated in the study. Eighty junior high school students also participated in a separate examination of test-retest reliability.
Thirteen items were extracted after exploratory and confirmatory factor analyses, and four core factors were identified in the resulting scale: Difficulty Identifying Feelings (DIF), Difficulty Describing Feelings (DDF), Externally-Oriented Thinking (EOT) and Constricted Imaginal Capacities (CIC). Interestingly, scores on the multi-dimensional empathy scale correlated positively with DIF and DDF, but negatively with EOT and CIC. Higher DDF scores were associated with higher Japanese linguistic abilities. DIF/DDF scores were higher for females than males, irrespective of linguistic ability. Test-retest reliability coefficients were significant. The patient group showed significantly higher DIF scores than the normative students.
The present findings indicated that subjective difficulties in identifying and describing feelings are associated with empathetic and linguistic abilities. The developmental aspect to emotional awareness herein described suggests that self-reported questionnaires for alexithymia must be carefully constructed and examined, even for adults.
PMCID: PMC2777913  PMID: 19886981
25.  Overexpression of TaLEA Gene from Tamarix androssowii Improves Salt and Drought Tolerance in Transgenic Poplar (Populus simonii × P. nigra) 
PLoS ONE  2013;8(6):e67462.
Late embryogenesis abundant (LEA) genes were confirmed to confer resistance to drought and water deficiency. An LEA gene from Tamarixandrossowii (named TaLEA) was transformed into Xiaohei poplar (Populussimonii × P. nigra) via Agrobacterium. Twenty-five independent transgenic lines were obtained that were resistant to kanamycin, and 11 transgenic lines were randomly selected for further analysis. The polymerase chain reaction (PCR) and ribonucleic acid (RNA) gel blot indicated that the TaLEA gene had been integrated into the poplar genome. The height growth rate, malondialdehyde (MDA) content, relative electrolyte leakage and damages due to salt or drought to transgenic and non-transgenic plants were compared under salt and drought stress conditions. The results showed that the constitutive expression of the TaLEA gene in transgenic poplars could induce an increase in height growth rate and a decrease in number and severity of wilted leaves under the salt and drought stresses. The MDA content and relative electrolyte leakage in transgenic lines under salt and drought stresses were significantly lower compared to those in non-transgenic plants, indicating that the TaLEA gene may enhance salt and drought tolerance by protecting cell membranes from damage. Moreover, amongst the lines analyzed for stress tolerance, the transgenic line 11 (T11) showed the highest tolerance levels under both salinity and drought stress conditions. These results indicated that the TaLEA gene could be a salt and drought tolerance candidate gene and could confer a broad spectrum of tolerance under abiotic stresses in poplars.
PMCID: PMC3696074  PMID: 23840708

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