Safety of lamivudine treatment for chronic hepatitis B in early pregnancy.
To evaluate the safety of lamivudine (LAM) treatment for chronic hepatitis B in early pregnancy. A total of 92 pregnant women who received LAM treatment either before pregnancy or in early pregnancy were enrolled in this study. All of the pregnant women volunteered to take lamivudine during pregnancy and were not co-infected with hepatitis C virus, human immunodeficiency virus, cytomegalovirus, or other viruses. All infants received passive-active immunoprophylaxis with 200 IU hepatitis B immunoglobulin and three doses of 10 μg hepatitis B vaccines (0-1-6 mo) according to the guidelines for the prevention and treatment of chronic hepatitis B. Adverse events were observed throughout the entire pregnancy and perinatal period, and the effectiveness of lamivudine treatment for blocking mother-to-infant transmission of hepatitis B virus (HBV) was evaluated. All adverse events in mothers and infants during pregnancy and the perinatal period and the HBV mother-to-infant transmission blocking rate were compared with the literature. Among the 92 pregnant women, spontaneous abortions occurred in 11 cases, while 3 mothers had a second pregnancy after the initial abortion; 72 mothers delivered 73 live infants, of whom 68 infants were followed up for no less than 6 mo, and 12 mothers were still pregnant. During pregnancy, the main maternal adverse events were vaginitis (12/72, 16.7%), spontaneous abortion (11/95, 11.6%), and gestational diabetes (6/72, 8.3%); only one case had 1-2 degree elevation of the creatine kinase level (195 U/L). During the perinatal period, the main maternal adverse events were premature rupture of the membranes (8/72, 11.1%), preterm delivery (5/72, 6.9%), and meconium staining of the amniotic fluid (4/72, 5.6%). In addition, 2 infants were found to have congenital abnormalities; 1 had a scalp hemangioma that did not change in size until 7 mo, and the other had early cerebral palsy, but with rehabilitation training, the infant's motor functions became totally normal at 2 years of age. The incidence of adverse events among the mothers or abnormalities in the infants was not higher than that of normal mothers or HBV-infected mothers who did not receive lamivudine treatment. In only 2 cases, mother-to-infant transmission blocking failed; the blocking rate was 97.1% (66/68), which was higher than has been previously reported. Lamivudine treatment is safe for chronic HBV-infected pregnant mothers and their fetuses with a gestational age of less than 12 wk or throughout the entire pregnancy.


Factors associated with educational mobility in mid-age Australian women.
The educational mobility of mid-age women is rarely studied. We analysed the baseline socio-economic position (SEP) and health factors associated with obtaining further education in 4117 mid-age Australian women between 1996 and 2010 (aged 45-50 at baseline, 62-67 at follow-up) from a population-based study. Women either unemployed or working part-time at baseline had higher odds of a stable low and middle education over time (ORs ranging from 1.61 to 3.86) versus educational mobility. Apart from obesity, characteristics that may signal an unhealthy lifestyle in early mid-life were not useful indicators of women's future educational mobility.


Should tetracycline treatment be used more extensively for rheumatoid arthritis? Metaanalysis demonstrates clinical benefit with reduction in disease activity.
To compare the effectiveness of tetracycline antibiotics versus control (placebo or conventional treatment) in rheumatoid arthritis (RA) for the reduction of disease activity as defined by American College of Rheumatology criteria. We searched Medline (1966-February 2002), Embase (1980-February 2002), and the Cochrane Controlled Trials Register (Issue 1, 2002 Cochrane Library). Reference lists of published trials were searched by hand for further identification of published reports and presentations at scientific meetings. Randomized controlled trials comparing tetracyclines to control (placebo or conventional disease modifying antirheumatic therapy) were selected for inclusion if at least one of the following outcomes was reported: tender joint count (TJC), swollen joint count, patient pain score by visual analog scale, patient global assessment of disease activity, physician global assessment of disease activity, eosinophil sedimentation rate (ESR) and C-reactive protein (CRP), joint space narrowing and erosions, adverse events, and quality of life as measured by the Health Assessment Questionnaire. Subjects were required to have RA as defined by the 1987 ARA criteria. Ten randomized controlled trials including 535 individuals were reviewed. Only 3 trials were considered high quality; elements of bias could not be excluded in the remainder. Tetracyclines, when administered for > or = 3 months, were associated with a significant reduction in disease activity in RA as follows: for TJC, standardized mean difference (SMD) = -0.39, 95% CI -0.74, -0.05; and for acute phase reactants, ESR, SMD = -8.96, 95% CI -14.51, -3.42. The treatment effect was more marked in the subgroup of patients with disease duration < 1 year who were seropositive. There was no absolute increased risk of adverse events associated with tetracyclines: absolute risk difference = 0.10, 95% confidence interval (CI) -0.01, 0.21. No beneficial effect was seen on radiological progression of disease: for erosions, SMD = 0.17, 95% CI -0.29, 0.64. In addition, subgroup analysis excluding trials with doxycycline showed that minocycline alone had a greater effect on reduction of disease activity: for TJC, SMD = -0.69, 95% CI -0.89, -0.49; and for ESR, SMD = -10.14, 95% CI -14.72, -5.57. Tetracyclines, in particular minocycline, were associated with a clinically significant improvement in disease activity in RA with no absolute increased risk of side effects. Unfortunately, the information available was inadequate to allow a detailed analysis of individual side effects in the studies. Further research is warranted to compare these agents to newer disease modifying drugs for comparable safety, efficacy, and cost-effectiveness.


Wnt/β-catenin pathway regulates ABCB1 transcription in chronic myeloid leukemia.
The advanced phases of chronic myeloid leukemia (CML) are known to be more resistant to therapy. This resistance has been associated with the overexpression of ABCB1, which gives rise to the multidrug resistance (MDR) phenomenon. MDR is characterized by resistance to nonrelated drugs, and P-glycoprotein (encoded by ABCB1) has been implicated as the major cause of its emergence. Wnt signaling has been demonstrated to be important in several aspects of CML. Recently, Wnt signaling was linked to ABCB1 regulation through its canonical pathway, which is mediated by β-catenin, in other types of cancer. In this study, we investigated the involvement of the Wnt/β-catenin pathway in the regulation of ABCB1 transcription in CML, as the basal promoter of ABCB1 has several β-catenin binding sites. β-catenin is the mediator of canonical Wnt signaling, which is important for CML progression. In this work we used the K562 cell line and its derived MDR-resistant cell line Lucena (K562/VCR) as CML study models. Real time PCR (RT-qPCR), electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), flow cytometry (FACS), western blot, immunofluorescence, RNA knockdown (siRNA) and Luciferase reporter approaches were used. β-catenin was present in the protein complex on the basal promoter of ABCB1 in both cell lines in vitro, but its binding was more pronounced in the resistant cell line in vivo. Lucena cells also exhibited higher β-catenin levels compared to its parental cell line. Wnt1 and β-catenin depletion and overexpression of nuclear β-catenin, together with TCF binding sites activation demonstrated that ABCB1 is positively regulated by the canonical pathway of Wnt signaling. These results suggest, for the first time, that the Wnt/β-catenin pathway regulates ABCB1 in CML.


Dynamic Ischaemic Mitral Regurgitation and the Role of Stress Echocardiography.
This paper aims to explain the main mechanisms that cause ischaemic mitral regurgitation (MR), the pathophysiology, and the role played by stress echocardiography in the evaluation of the dynamic component of MR. Chronic ischaemic MR is a frequent complication of myocardial infarction (MI), and is associated with a poor prognosis and outcome. The more the severity of ischaemic MR, the lower is the survival rate. In recent times, improvements in the management of the acute phase of MI, has increased the survival rate after MI. This, combined with an increase in the incidence of MI, will probably lead to a higher prevalence of ischemic MR in the next decades. As a consequence, ischaemic MR should be thoroughly understood and promptly identified. Furthermore, it is well recognized that ischaemic MR is dynamic. The best way to explore the dynamic nature of ischaemic MR is exercise stress echocardiography, and this test should probably be integrated in the evaluation and the management of patients with chronic ischaemic MR. Based on our experience, exercise stress echocardiography might be of interest in the following subsets of patients: 1) in patients with left ventricular (LV) dysfunction who present exertional dyspnea out of proportion to the severity of resting LV dysfunction or MR severity, 2) in patients in whom acute pulmonary oedema occurs without any obvious cause; 3) to unmask patients at high risk of mortality and heart failure 4) before surgical revascularization in patients with moderate ischaemic MR and, 5) following surgery, to identify persistence of pulmonary hypertension and explain the absence of functional class improvement.


11β-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial.
Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active glucocorticoid, we investigated whether 11β-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.


Increasing Efforts to Reduce Cervical Cancer through State-Level Comprehensive Cancer Control Planning.
Reducing cervical cancer disparities in the United States requires intentional focus on structural barriers such as systems and policy that impact access to human papillomavirus (HPV) vaccination, cervical cancer screening, and treatment. Such changes are difficult and often politicized. State comprehensive cancer control (CCC) plans are vehicles that, if designed well, can help build collective focus on structural changes. Study objectives were to identify the prioritization of cervical cancer in state CCC plans, the conceptualization of HPV within these plans, and the focus of plans on structural changes to reduce cervical cancer disparities. Data were gathered by systematic content analysis of CCC plans from 50 states and the District of Columbia from February-June 2014 for evidence of cervical cancer prioritization, conceptualization of HPV, and focus on structural barriers to cervical cancer vaccination, screening or treatment. Findings indicate that prioritization of cervical cancer within state CCC plans may not be a strong indicator of state efforts to reduce screening and treatment disparities. While a majority of plans reflected scientific evidence that HPV causes cervical and other cancers, they did not focus on structural elements impacting access to evidence-based interventions. Opportunities exist to improve state CCC plans by increasing their focus on structural interventions that impact cervical cancer prevention, detection, and treatment, particularly for the 41% of plans ending in 2015 and the 31% ending between 2016 and 2020. Future studies should focus on the use of policy tools in state CCC plans and their application to cervical cancer prevention and treatment.


Differential responses to breath-holding, voluntary deep breathing and hypercapnia in left and right dorsal anterior cingulate.
What is the central question of this study? What is the role of dorsal anterior cingulate cortex (ACC) in respiration control in humans? What is the main finding and its importance? Direct evidence is provided for a role of the ACC in respiratory control in humans. The neurophysiological responses in dorsal ACC to different breathing tasks varied and were different between left and right ACC. The role of subcortical structures and cerebral cortex in the maintenance of respiratory homeostasis in humans remains poorly understood. Emerging evidence suggests an important role of the anterior cingulate cortex (ACC) in respiratory control. In this study, local field potentials (LFPs) from dorsal ACC were recorded in humans through implanted deep brain electrodes during several breathing activities, including voluntary activities of breath-holding and deep breathing, and involuntary activities of inspiration of varying concentrations of carbon dioxide (1%, 3%, 5% and 7%). We found that the breath-holding task induced significant unilateral left-sided ACC changes in LFP power, including an increased activity in lower frequency bands (3-5 Hz) and decreased activity in higher frequency bands (12-26 Hz). The respiratory task involving reflex increase in ventilation due to hypercapnia (raised inspired CO2 ) was associated with bilateral changes in activity of the ACC (again with increased activity in lower frequency bands and reduced activity in higher frequency bands). The voluntary breathing task with associated hypocapnia (deep breathing) induced bilateral changes in activity within low frequency bands. Furthermore, probabilistic diffusion tractography analysis showed left-sided connection of the ACC with the insula and frontal operculum, and bilateral connections within subsections of the cingulate gyrus and the thalamus. This electrophysiological analysis provides direct evidence for a role of the ACC in respiratory control in humans.


A Unique Approach to Project-Based Learning (PjBL) in a Veterinary Anatomy Course.
Project-based learning (PjBL) is a teaching methodology designed to engage students in solving real-world problems, acknowledging that students are active agents of their learning process. This methodology has historically been popular in architecture and industrial sciences; however, its use in teaching veterinary anatomy is scarcely published. Using information and communication technologies, the PjBL methodology was implemented in a first-year veterinary anatomy course. The methodology included teamwork and the selection of a routine object in the veterinary clinic at the beginning of the academic semester. The project's goal was to analyze the object and associate it with both a domestic animal species and an anatomical region, along with making and presenting a video or a simulation model about the object. More than 80% of students prefer active learning classes compared to traditional classes. In addition, 66% and 86% of students indicate that PjBL allowed them to improve their understanding of theoretical content for the first and second years of post-implementation, respectively. Students' self-assessment indicates that more than 80% of the students (first and second year post-implementation) felt they were responsible for the execution of the project, able to conduct research, and able to develop autonomous learning skills. After 2 years of PjBL implementation, failure rates in the course decreased by 21%. In general, PjBL results show that veterinary students prefer active learning activities that allow them to learn in a team-based learning process as well as to develop soft skills such as self-learning, responsibility, and teamwork. The online version contains supplementary material available at 10.1007/s40670-021-01205-1.


An Examination of the Role of Socioeconomic Status in the Relationship between Depression and Prostate Cancer Survivorship in a Population-Based Sample of Men from Atlantic Canada.
Prostate and skin cancer are among the most prevalent forms of cancer among men and have favorable survival rates compared to other, more aggressive forms of cancers. Recent studies have shown that the odds of depression among men with a lifetime history of prostate cancer are higher compared to men without a lifetime history of prostate cancer. Here we extend previous findings and examine the role of socioeconomic status in the relationship between depression and cancer survivorship status in a population-based sample of men from Atlantic Canada. A cross-sectional analysis was conducted on a subsample of 6,585 male participants aged 49-69 years from the 2009-2015 survey cycle of the Atlantic PATH study. The primary outcome was screening positive for mild, moderate or severe depression using the Patient Health Questionnaire (PHQ-9). The main predictor variable was cancer survivorship status (the presence of a lifetime history of prostate cancer, skin cancer, forms of cancer other than prostate or skin cancer, or absence of a lifetime cancer diagnosis). Covariates included age, education, marital status, household income, province, ethnicity, comorbidity, and survivorship time. An estimated 14.7% of men in this sample screened positive for mild, moderate or severe depression. Men with a history of prostate cancer were 2.60 (95% CI: 1.02, 6.65) times more likely to screen positive for depression than men with a history of any other form of cancer. The odds ratios were 10.23 (95% CI: 2.82, 37.49) or 4.00 (95% CI: 1.20, 13.34) times higher for survivors of prostate or skin cancer who reported a low household income to screen positive for depression compared to men with a history of any other form of cancer and high household income. These results extend current evidence of the association between prostate cancer survivorship and depression compared with men who never had a history of cancer diagnosis by indicating that this association still stands when the survivors of prostate cancer are compared to survivors of any other form of cancer, and further indicates that this association is moderated by household income. The findings highlight the importance of delivering mental health screening and support to prostate cancer survivors during the cancer journey, especially those with low household incomes.


Exploring health providers' and community perceptions and experiences with malaria tests in South-East Nigeria: a critical step towards appropriate treatment.
The adoption of ACT as the first line treatment for uncomplicated malaria in Nigeria has concentrated attention on the role of testing in appropriate malaria treatment. There are calls at both national and global level for malaria treatment to be based on test result, but it is still unclear how testing can be incorporated into treatment-seeking and practices of health providers. This study explored community members and health providers' perceptions and experiences with malaria tests in south east Nigeria. The study was conducted in urban and rural areas of Enugu state in south-eastern Nigeria. A total of 18 focus group discussions with 179 community members including sub-groups of primary caregivers, adult men and adult women aged 15 years and above. Twenty-six (26) In-depth interviews were held with public and private health providers involved in prescribing medicines at public and private health facilities in the study area. Both providers and community members were familiar with malaria tests and identified malaria tests as an important step to distinguish malaria from other illnesses with similar symptoms and as a means of delivering appropriate treatment. However, the logic of test-directed treatment was undermined by cost of test and a lack of testing facilities but above all concerns over the reliability of negative test results, with community members and providers observing inconsistencies between results and symptoms, and providers attributing inaccurate results to incompetencies of technicians. Recognition of malaria symptoms was deemed most important in determining the use of antimalarial drugs rather than the result of a malaria test. The results highlight important areas of intervention to promote appropriate malaria treatment. If tests are to play a role in patient management, demand and supply side interventions are needed to change people's attitude towards malaria test results.


Harmonizing national abortion and pregnancy prevention laws and policies for sexual violence survivors with the Maputo Protocol: proceedings of a 2016 regional technical meeting in sub-Saharan Africa.
In April 2016, the Population Council, in partnership with the World Health Organization (WHO) and the International Consortium for Emergency Contraception, convened a regional meeting in Lusaka, Zambia, geared toward supporting countries in East and Southern Africa in meeting their obligations under the Maputo Protocol. These obligations include expanding access to women's reproductive health services - especially women survivors of sexual violence. Government and civil society representatives from six countries participated: Botswana, Ethiopia, Kenya, Malawi, Rwanda, and Zambia. Countries were selected based on to their being priority settings for the projects that sponsored the meeting, coupled with the fact that they were each far enough along in addressing post-rape care to be able to develop concrete policy, programming, and/or legal action plans by the end of the meeting. The meeting was the first activity in a joint project of technical assistance by the conveners, aimed at strengthening access to comprehensive post-rape care for survivors of sexual violence. It aimed to sensitize Member States to their obligations under the Maputo Protocol to expand women's access to emergency contraception (EC) and safe abortion services, and to inspire them to do so by providing information, research evidence, and a platform for discussion. The meeting deliberations fostered a better understanding of opportunities to broaden access to EC and safe abortion for survivors in the region. Discussions on EC in this regard centered on strengthening EC delivery in the clinical context, decentralizing EC services, increasing community awareness, and overcoming policy barriers. Safe abortion discussions focused primarily on legislation, policy, and integrating these services into existing services for sexual violence survivors. Country-specific action plans were developed to address gaps and weaknesses. The regional technical meeting concluded with a discussion of practical steps that participants could take to facilitate legal, policy, and program reform with respect to pregnancy prevention and safe abortion in their respective countries. The steps revolved around three mainly areas, namely: establishing an evidence base to inform action; creating forums for discussing the issues; and drafting action points to carry the momentum from the meeting forward. This paper details the proceedings from this regional technical meeting - proceedings that are of interest to the field of sexual and gender-based violence (and reproductive health, more broadly) as challenges faced by countries in implementing the Maputo Protocol are outlined, and evidence-informed and practice-based strategies for addressing these challenges are provided.


Examination of the dimerization states of the single-stranded RNA recognition protein pentatricopeptide repeat 10 (PPR10).
Pentatricopeptide repeat (PPR) proteins, particularly abundant in plastids and mitochrondria of angiosperms, include a large number of sequence-specific RNA binding proteins that are involved in diverse aspects of organelle RNA metabolisms. PPR proteins contain multiple tandom repeats, and each repeat can specifically recognize a RNA base through residues 2, 5, and 35 in a modular fashion. The crystal structure of PPR10 from maize chloroplast exhibits dimeric existence both in the absence and presence of the 18-nucleotide psaJ RNA element. However, previous biochemical analysis suggested a monomeric shift of PPR10 upon RNA binding. In this report, we show that the amino-terminal segments of PPR10 determine the dimerization state of PPR10. A single amino acid alteration of cysteine to serine within repeat 10 of PPR10 further drives dimerization of PPR10. The biochemical elucidation of the determinants for PPR10 dimerization may provide an important foundation to understand the working mechanisms of PPR proteins underlying their diverse physiological functions.


Learning about climate change uncertainty enables flexible water infrastructure planning.
Water resources planning requires decision-making about infrastructure development under uncertainty in future regional climate conditions. However, uncertainty in climate change projections will evolve over the 100-year lifetime of a dam as new climate observations become available. Flexible strategies in which infrastructure is proactively designed to be changed in the future have the potential to meet water supply needs without expensive over-building. Evaluating tradeoffs between flexible and traditional static planning approaches requires extension of current paradigms for planning under climate change uncertainty which do not assess opportunities to reduce uncertainty in the future. We develop a new planning framework that assesses the potential to learn about regional climate change over time and therefore evaluates the appropriateness of flexible approaches today. We demonstrate it on a reservoir planning problem in Mombasa, Kenya. This approach identifies opportunities to reliably use incremental approaches, enabling adaptation investments to reach more vulnerable communities with fewer resources.


Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging.
Mutations in mitochondrial DNA (mtDNA) accumulate in tissues of mammalian species and have been hypothesized to contribute to aging. We show that mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g (POLG) accumulate mtDNA mutations and display features of accelerated aging. Accumulation of mtDNA mutations was not associated with increased markers of oxidative stress or a defect in cellular proliferation, but was correlated with the induction of apoptotic markers, particularly in tissues characterized by rapid cellular turnover. The levels of apoptotic markers were also found to increase during aging in normal mice. Thus, accumulation of mtDNA mutations that promote apoptosis may be a central mechanism driving mammalian aging.


Helicobacter pylori infection is associated with an increased rate of diabetes.
Chronic infections could be contributing to the socioeconomic gradient in chronic diseases. Although chronic infections have been associated with increased levels of inflammatory cytokines and cardiovascular disease, there is limited evidence on how infections affect risk of diabetes. We examined the association between serological evidence of chronic viral and bacterial infections and incident diabetes in a prospective cohort of Latino elderly. We analyzed data on 782 individuals aged >60 years and diabetes-free in 1998-1999, whose blood was tested for antibodies to herpes simplex virus 1, varicella virus, cytomegalovirus, Helicobacter pylori, and Toxoplasma gondii and who were followed until June 2008. We used Cox proportional hazards regression to estimate the relative incidence rate of diabetes by serostatus, with adjustment for age, sex, education, cardiovascular disease, smoking, and cholesterol levels. Individuals seropositive for herpes simplex virus 1, varicella virus, cytomegalovirus, and T. gondii did not show an increased rate of diabetes, whereas those who were seropositive for H. pylori at enrollment were 2.7 times more likely at any given time to develop diabetes than seronegative individuals (hazard ratio 2.69 [95% CI 1.10-6.60]). Controlling for insulin resistance, C-reactive protein and interleukin-6 did not attenuate the effect of H. pylori infection. We demonstrated for the first time that H. pylori infection leads to an increased rate of incident diabetes in a prospective cohort study. Our findings implicate a potential role for antibiotic and gastrointestinal treatment in preventing diabetes.


Activation of heat shock factor 2 during hemin-induced differentiation of human erythroleukemia cells.
Hemin induces nonterminal differentiation of human K562 erythroleukemia cells, which is accompanied by the expression of certain erythroid cell-specific genes, such as the embryonic and fetal globins, and elevated expression of the stress genes hsp70, hsp90, and grp78/BiP. Previous studies revealed that, as during heat shock, transcriptional induction of hsp70 in hemin-treated cells is mediated by activation of heat shock transcription factor (HSF), which binds to the heat shock element (HSE). We report here that hemin activates the DNA-binding activity of HSF2, whereas heat shock induces predominantly the DNA-binding activity of a distinct factor, HSF1. This constitutes the first example of HSF2 activation in vivo. Both hemin and heat shock treatments resulted in equivalent levels of HSF-HSE complexes as analyzed in vitro by gel mobility shift assay, yet transcription of the hsp70 gene was stimulated much less by hemin-induced HSF than by heat shock-induced HSF. Genomic footprinting experiments revealed that hemin-induced HSF and heat shock-induced HSF, HSF2, and HSF1, respectively, occupy the HSE of the human hsp70 promoter in a similar yet not identical manner. We speculate that the difference in occupancy and/or in the transcriptional abilities of HSF1 and HSF2 accounts for the observed differences in the stimulation of hsp70 gene transcription.


A new tetracyclic lactam building block for thick, broad-bandgap photovoltaics.
A new tetracyclic lactam building block for polymer semiconductors is reported that was designed to combine the many favorable properties that larger fused and/or amide-containing building blocks can induce, including improved solid-state packing, high charge carrier mobility, and improved charge separation. Copolymerization with thiophene resulted in a semicrystalline conjugated polymer, PTNT, with a broad bandgap of 2.2 eV. Grazing incidence wide-angle X-ray scattering of PTNT thin films revealed a strong tendency for face-on π-stacking of the polymer backbone, which was retained in PTNT:fullerene blends. Corresponding solar cells featured a high open-circuit voltage of 0.9 V, a fill factor around 0.6, and a power conversion efficiency as high as 5% for >200 nm thick active layers, regardless of variations in blend stoichiometry and nanostructure. Moreover, efficiencies of >4% could be retained when thick active layers of ∼400 nm were employed. Overall, these values are the highest reported for a conjugated polymer with such a broad bandgap and are unprecedented in materials for tandem and particularly ternary blend photovoltaics. Hence, the newly developed tetracyclic lactam unit has significant potential as a conjugated building block in future organic electronic materials.


Learning a hierarchical deformable template for rapid deformable object parsing.
In this paper, we address the tasks of detecting, segmenting, parsing, and matching deformable objects. We use a novel probabilistic object model that we call a hierarchical deformable template (HDT). The HDT represents the object by state variables defined over a hierarchy (with typically five levels). The hierarchy is built recursively by composing elementary structures to form more complex structures. A probability distribution--a parameterized exponential model--is defined over the hierarchy to quantify the variability in shape and appearance of the object at multiple scales. To perform inference--to estimate the most probable states of the hierarchy for an input image--we use a bottom-up algorithm called compositional inference. This algorithm is an approximate version of dynamic programming where approximations are made (e.g., pruning) to ensure that the algorithm is fast while maintaining high performance. We adapt the structure-perceptron algorithm to estimate the parameters of the HDT in a discriminative manner (simultaneously estimating the appearance and shape parameters). More precisely, we specify an exponential distribution for the HDT using a dictionary of potentials, which capture the appearance and shape cues. This dictionary can be large and so does not require handcrafting the potentials. Instead, structure-perceptron assigns weights to the potentials so that less important potentials receive small weights (this is like a "soft" form of feature selection). Finally, we provide experimental evaluation of HDTs on different visual tasks, including detection, segmentation, matching (alignment), and parsing. We show that HDTs achieve state-of-the-art performance for these different tasks when evaluated on data sets with groundtruth (and when compared to alternative algorithms, which are typically specialized to each task).


Suprabasal expression of a 64-kilodalton keratin (no. 3) in developing human corneal epithelium.
We have previously shown that a basic 64-kilodalton (no. 3 in the catalog of Moll et al.) and an acidic 55-kilodalton (no. 12) keratin are characteristic of suprabasal cell layers in cultured rabbit corneal epithelial colonies, and therefore may be regarded as markers for an advanced stage of corneal epithelial differentiation. Moreover, using an AE5 mouse monoclonal antibody, we showed that the 64-kilodalton keratin marker is expressed suprabasally in limbal epithelium but uniformly (basal layer included) in central corneal epithelium, suggesting that corneal basal cells are in a more differentiated state than limbal basal cells. In conjunction with previous data implicating the centripetal migration of corneal epithelial cells, our data support a model of corneal epithelial maturation in which corneal epithelial stem cells are located in the limbus, the transitional zone between the cornea and conjunctiva. In the present study, we analyzed the expression of the 64-kilodalton keratin in developing human corneal epithelium by immunohistochemical staining. At 8 weeks of gestation, the presumptive corneal epithelium is composed of a single layer of cuboidal cells with an overlying periderm; neither of these cell layers is AE5 positive. At 12-13 weeks of gestation, some superficial cells of the three- to four-layered epithelium become AE5 positive, providing the earliest sign of overt corneal epithelial differentiation. At 36 weeks, although the epithelium is morphologically mature (four to six layers), AE5 produces a suprabasal staining pattern, this being in contrast to the adult epithelium which exhibits uniform staining.(ABSTRACT TRUNCATED AT 250 WORDS)


Cell cycle kinesis in lymphocytes in the diagnosis of Alzheimer's disease.
The currently available clinical diagnostic tools do not allow an accurate and reliable diagnosis of Alzheimer's disease (AD) in other than demented patients. Furthermore, they do not allow the identification of subjects with pre-clinical AD. Cell cycle regulatory failure in neurones appears to be a very early event in the pathogenesis of AD. Our earlier findings indicate that there is a specific failure of the G1/S transition checkpoint that may not be restricted to neurones alone. We tested the possibility that lymphocytes of AD sufferers may also show signs of G1 regulatory failure. We found that the in vitro responsiveness of lymphocytes to G1 inhibitor treatment was significantly less effective in AD patients than in control subjects. Additionally, in subjects showing neuropsychological signs of pre-clinical AD, the lymphocyte response was similar to that seen in AD patients. We present direct evidence to support the hypothesis that the failure of the G1/S transition control is not restricted to neurones in AD patients, but occurs in peripheral cells, such as lymphocytes, as well. Our findings could provide the basis for new clinical tests that rely on eliciting the activation of the G1/S transition checkpoint in lymphocyte cultures. We propose that the introduction of the test could be useful in identifying people who do not yet fulfil the requirements of the NINCDS criteria for dementia, but who would benefit from the use of preventive measures for AD.


Eddy/wind interactions stimulate extraordinary mid-ocean plankton blooms.
Episodic eddy-driven upwelling may supply a significant fraction of the nutrients required to sustain primary productivity of the subtropical ocean. New observations in the northwest Atlantic reveal that, although plankton blooms occur in both cyclones and mode-water eddies, the biological responses differ. Mode-water eddies can generate extraordinary diatom biomass and primary production at depth, relative to the time series near Bermuda. These blooms are sustained by eddy/wind interactions, which amplify the eddy-induced upwelling. In contrast, eddy/wind interactions dampen eddy-induced upwelling in cyclones. Carbon export inferred from oxygen anomalies in eddy cores is one to three times as much as annual new production for the region.


Posttraumatic Stress Disorder After a Psychedelic Experience, a Case Report.
In the last 2 decades, there is a renaissance in the scientific investigation of the therapeutic potential of psychedelic compounds. It is studied for the treatment of many psychiatric disorders, including posttraumatic stress disorder. The treatment is always done in the setting of psychedelic-assisted psychotherapy. A little is known about the potential effects, outside of the setting of psychedelic-assisted psychotherapy, on people diagnosed with a mental disorder or have a significant trauma history. In this case report, we present a young man who developed posttraumatic stress disorder after a psychedelic experience, induced by both Lysergic Acid Diethylamide (LSD) and N, N Dimethyltryptamine (DMT). In the psychedelic experience, a repressed memory of childhood sexual abuse was recovered. To our knowledge, this is the first report on posttraumatic stress disorder onset after a psychedelic experience. We believe that this case report is important since the history of trauma is prevalent among individuals with substance use disorder. Medical staff that treat people with either substance use disorder or trauma should be familiar with irregular presentations, such as the one described in this case.


Traditional Chinese Medicine Use and Health in Community-Dwelling Chinese-American Older Adults in Chicago.
Chinese people have practiced traditional Chinese medicine (TCM) for thousands of years, but there is a paucity of research regarding TCM use in Chinese older adult immigrants in the United States. This study aims to provide an overall estimate of TCM use for Chinese older adults in the United States and to examine associations between sociodemographic characteristics, health measures, and TCM use. Data were collected through the Population Study of Chinese Elderly in Chicago, a community-based participant research study that surveyed 3,158 Chinese older adults aged 60 and older. TCM use was measured using an eight-item scale that examined eight kinds of TCM. Seventy-six percent of participants reported any use of TCM within the past year. After adjusting for potential confounding factors, health status was associated with greater use of acupuncture (odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.06-1.68) and massage therapy (OR = 1.53, 95% CI = 1.21-1.93), and quality of life was associated with less use of prescribed herbal products (OR 0.69, 95% CI = 0.55-0.87), tai chi (OR = 0.62, 95% CI = 0.50-0.78), and other traditional medicine (OR = 0.47, 95% CI = 0.40-0.56). These findings call for further investigation of TCM use by Chinese older adults, especially those with poor health and those with better quality of life. In the clinical setting, physicians should have awareness of TCM when treating Chinese older adults and look toward possible integration with Western medicine for more culturally appropriate, patient-centered care.


Molecular genetics of the Drosophila melanogaster ovo locus, a gene required for sex determination of germline cells.
The Drosophila melanogaster ovo gene is required for survival and differentiation of female germline cells, apparently playing a role in germline sex determination. We recovered 60 kb of genomic DNA from its genetic location at 4E1,2 on the X chromosome. A transcription unit coding for an apparently female-specific germline-dependent 5-kb poly(A)+ RNA size class is located substantially in a 7-kb region, within which three DNA-detectable lesions for mutations that inactivate the ovo function are located at two sites approximately 4 kb apart. The breakpoint of a deficiency that removes the neighboring lethal complementation group shavenbaby (svb) but leaves the ovo function intact maps approximately 5 kb to the molecular left of the leftmost ovo mutant site. A class of mutations that inactivates both the svb function and the ovo function affects genomic DNA between the two ovo sites. Sequences required for the two genetic functions are partly overlapping. In spite of this overlap, P element-mediated gene transfer of a 10-kb genomic DNA segment containing the 5-kb poly(A)+ RNA transcription unit rescues the female sterility phenotypes of ovo mutations, but not the svb lethality.


Factors influencing vascular and hepatic enhancement at CT: experimental study on injection protocol using a canine model.
The purpose of this work was to evaluate the effects of contrast medium injection parameters on aortic, portal vein, and hepatic enhancement at spiral CT and to assess optimal injection protocol for hepatic CT. Ten 15 kg dogs underwent single level dynamic CT through the hepatic hilum at 5 s intervals just after the injection of contrast medium for 3 min. With use of different volumes (1, 2, and 3 ml/kg), injection rates (0.5, 1, and 2 ml/s), and concentrations (150, 200, and 300 mg/ml), a total of 270 spiral CT scans were performed. In each scan, time-attenuation curves of aorta, portal vein, and liver were obtained. The degree of maximum contrast enhancement (Imax), time to maximum enhancement (Tmax), and time to equilibrium phase (Teq) for to each injection protocol were analyzed. Alterations in contrast material volume, injection rate, and concentration had significant impact on contrast enhancement of the liver. With increasing volume of contrast medium, Imax, Tmax, and Teq of aorta, portal vein, and liver increased (p < 0.005). With increasing rate of injection, on the other hand, Imax of aorta and liver increased (p < 0.05), but Tmax and Teq decreased (p < 0.005). Change of concentration of contrast medium had a significant effect on Imax of vessels (p < 0.05). Maximum contrast enhancement of liver and vessels was influenced mainly by injection volume of contrast medium and the time to peak enhancement by injection rate of contrast medium. Under given amounts of contrast medium, therefore, the strategy of increasing volume by dilution and faster injection might give better Imax values without penalty for the duration of an optimal temporal window (Tmax and Teq).


Medical cost analysis: application to colorectal cancer data from the SEER Medicare database.
Incompleteness is a key feature of most survival data. Numerous well established statistical methodologies and algorithms exist for analyzing life or failure time data. However, induced censorship invalidates the use of those standard analytic tools for some survival-type data such as medical costs. In this paper, some valid methods currently available for analyzing censored medical cost data are reviewed. Some cautionary findings under different assumptions are envisioned through application to medical costs from colorectal cancer patients. Cost analysis should be suitably planned and carefully interpreted under various meaningful scenarios even with judiciously selected statistical methods. This approach would be greatly helpful to policy makers who seek to prioritize health care expenditures and to assess the elements of resource use.


Characterization of five different implant surfaces and their effect on osseointegration: a study in dogs.
Chemical modification of implant surface is typically associated with surface topographic alterations that may affect early osseointegration. This study investigates the effects of controlled surface alterations in early osseointegration in an animal model. Five implant surfaces were evaluated: 1) alumina-blasting, 2) biologic blasting, 3) plasma, 4) microblasted resorbable blasting media (microblasted RBM), and 5) alumina-blasting/acid-etched (AB/AE). Surface topography was characterized by scanning electron microscopy and optical interferometry, and chemical assessment by x-ray photoelectron spectroscopy. The implants were placed in the radius of six dogs, remaining 2 and 4 weeks in vivo. After euthanization, specimens were torqued-to-interface failure and non-decalcified-processed for histomorphologic bone-implant contact, and bone area fraction-occupied evaluation. Statistical evaluation was performed by one-way analysis of variance (P <0.05) and post hoc testing by the Tukey test. The alumina-blasting surface presented the highest average surface roughness and mean root square of the surface values, the biologic blasting the lowest, and AB/AE an intermediate value. The remaining surfaces presented intermediate values between the biologic blasting and AB/AE. The x-ray photoelectron spectroscopy spectra revealed calcium and phosphorus for the biologic blasting and microblasted RBM surfaces, and the highest oxygen levels for the plasma, microblasted RBM, and AB/AE surfaces. Significantly higher torque was observed at 2 weeks for the microblasted RBM surface (P <0.04), but no differences existed between surfaces at 4 weeks (P >0.74). No significant differences in bone-implant contact and bone area fraction-occupied values were observed at 2 and 4 weeks. The five surfaces were osteoconductive and resulted in high degrees of osseointegration and biomechanical fixation.


Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages.
Distinguishing dendritic cells (DCs) from other cells of the mononuclear phagocyte system is complicated by the shared expression of cell surface markers such as CD11c. In this study, we identified Zbtb46 (BTBD4) as a transcription factor selectively expressed by classical DCs (cDCs) and their committed progenitors but not by plasmacytoid DCs (pDCs), monocytes, macrophages, or other lymphoid or myeloid lineages. Using homologous recombination, we replaced the first coding exon of Zbtb46 with GFP to inactivate the locus while allowing detection of Zbtb46 expression. GFP expression in Zbtb46(gfp/+) mice recapitulated the cDC-specific expression of the native locus, being restricted to cDC precursors (pre-cDCs) and lymphoid organ- and tissue-resident cDCs. GFP(+) pre-cDCs had restricted developmental potential, generating cDCs but not pDCs, monocytes, or macrophages. Outside the immune system, Zbtb46 was expressed in committed erythroid progenitors and endothelial cell populations. Zbtb46 overexpression in bone marrow progenitor cells inhibited granulocyte potential and promoted cDC development, and although cDCs developed in Zbtb46(gfp/gfp) (Zbtb46 deficient) mice, they maintained expression of granulocyte colony-stimulating factor and leukemia inhibitory factor receptors, which are normally down-regulated in cDCs. Thus, Zbtb46 may help enforce cDC identity by restricting responsiveness to non-DC growth factors and may serve as a useful marker to identify rare cDC progenitors and distinguish between cDCs and other mononuclear phagocyte lineages.


Effect of prenatal exposure to diagnostic ultrasound on the development of mice.
Pregnant Swiss albino mice were exposed to diagnostic ultrasound (3.5 MHz, approximately 65 mW) for 10 min on Day 3.5 (preimplantation period), 6.5 (early organogenesis period), or 11.5 (late organogenesis period) of gestation. Sham-exposed controls were maintained for comparison. Exposed as well as control fetuses were dissected out on the 18th day of gestation, and changes in total mortality, body weight, body length, head length, brain weight, sex ratio, and microphthalmia were recorded. Exposure on Day 3.5 of gestation resulted in a small increase in the resorption rate and a significant reduction in fetal body weight. A low fetal weight and an increase in the number of growth-retarded fetuses were produced by exposure on Day 6.5 postcoitus. A statistically nonsignificant increase in the incidence of microphthalmia was induced in fetuses exposed on Day 6.5 or Day 11.5 of gestation. These results indicate that ultrasound may have some adverse effects on the mouse embryos depending on the developmental stage at which the exposure occurred.


Genetic and environmental correlates of topiramate-induced cognitive impairment.
Topiramate is an antiepileptic drug that has marked treatment-limiting side effects on specific aspects of cognitive performance in both patients and healthy volunteers. Because these severe side effects occur only in certain individuals, identifying genetic or environmental variables that influence cognitive response would be of great utility in determining whether to administer this drug to a patient. We gave an acute 100 mg oral dose of topiramate to 158 healthy volunteers and measured how the drug changed their performance on a diverse battery of cognitive tests. We found a wide range of responses to topiramate, and we demonstrated that not all tests in the battery were equally affected. There was no correlation between the effect of topiramate and either education level or baseline cognitive performance. Of interest, there was an up to 55-fold variation in the topiramate plasma levels of the participants. Our genome-wide association study (GWAS) of cognitive response did not reveal any genome-wide significant associations; the study was powered to find variants explaining at least 25% of the variation in cognitive response. Combining the results of this GWAS with a retrospective study of cognitive complaints in 290 epilepsy patients who received topiramate as part of their treatment also did not result in a significant association. Our results support the need for additional genetic studies of topiramate that use larger sample sizes.


Protective vaccination and blood-stage malaria modify DNA methylation of gene promoters in the liver of Balb/c mice.
Epigenetic mechanisms such as DNA methylation are increasingly recognized to be critical for vaccination efficacy and outcome of different infectious diseases, but corresponding information is scarcely available for host defense against malaria. In the experimental blood-stage malaria Plasmodium chabaudi, we investigate the possible effects of a blood-stage vaccine on DNA methylation of gene promoters in the liver, known as effector against blood-stage malaria, using DNA methylation microarrays. Naturally susceptible Balb/c mice acquire, by protective vaccination, the potency to survive P. chabaudi malaria and, concomitantly, modifications of constitutive DNA methylation of promoters of numerous genes in the liver; specifically, promoters of 256 genes are hyper(=up)- and 345 genes are hypo(=down)-methylated (p < 0.05). Protective vaccination also leads to changes in promoter DNA methylation upon challenge with P. chabaudi at peak parasitemia on day 8 post infection (p.i.), when 571 and 1013 gene promoters are up- and down-methylated, respectively, in relation to constitutive DNA methylation (p < 0.05). Gene set enrichment analyses reveal that both vaccination and P. chabaudi infections mainly modify promoters of those genes which are most statistically enriched with functions relating to regulation of transcription. Genes with down-methylated promoters encompass those encoding CX3CL1, GP130, and GATA2, known to be involved in monocyte recruitment, IL-6 trans-signaling, and onset of erythropoiesis, respectively. Our data suggest that vaccination may epigenetically improve parts of several effector functions of the liver against blood-stage malaria, as, e.g., recruitment of monocyte/macrophage to the liver accelerated liver regeneration and extramedullary hepatic erythropoiesis, thus leading to self-healing of otherwise lethal P. chabaudi blood-stage malaria.


Kidney function after off-pump or on-pump coronary artery bypass graft surgery: a randomized clinical trial.
Most acute kidney injury observed in the hospital is defined by sudden mild or moderate increases in the serum creatinine concentration, which may persist for several days. Such acute kidney injury is associated with lower long-term kidney function. However, it has not been demonstrated that an intervention that reduces the risk of such acute kidney injury better preserves long-term kidney function. To characterize the risk of acute kidney injury with an intervention in a randomized clinical trial and to determine if there is a difference between the 2 treatment groups in kidney function 1 year later. The Coronary Artery Bypass Grafting Surgery Off- or On-pump Revascularisation Study (CORONARY) enrolled 4752 patients undergoing first isolated coronary artery bypass graft (CABG) surgery at 79 sites in 19 countries. Patients were randomized to receive CABG surgery either with a beating-heart technique (off-pump) or with cardiopulmonary bypass (on-pump). From January 2010 to November 2011, 2932 patients (from 63 sites in 16 countries) from CORONARY were enrolled into a kidney function substudy to record serum creatinine concentrations during the postoperative period and at 1 year. The last 1-year serum creatinine concentration was recorded on January 18, 2013. Acute kidney injury within 30 days of surgery (≥50% increase in serum creatinine concentration from prerandomization concentration) and loss of kidney function at 1 year (≥20% loss in estimated glomerular filtration rate from prerandomization level). Off-pump (n = 1472) vs on-pump (n = 1460) CABG surgery reduced the risk of acute kidney injury (17.5% vs 20.8%, respectively; relative risk, 0.83 [95% CI, 0.72-0.97], P = .01); however, there was no significant difference between the 2 groups in the loss of kidney function at 1 year (17.1% vs 15.3%, respectively; relative risk, 1.10 [95% CI, 0.95-1.29], P = .23). Results were consistent with multiple alternate continuous and categorical definitions of acute kidney injury or kidney function loss, and in the subgroup with baseline chronic kidney disease. Use of off-pump compared with on-pump CABG surgery reduced the risk of postoperative acute kidney injury, without evidence of better preserved kidney function with off-pump CABG surgery at 1 year. In this setting, an intervention that reduced the risk of mild to moderate acute kidney injury did not alter longer-term kidney function. clinicaltrials.gov Identifier: NCT00463294.


Reconstructing Historical VOC Concentrations in Drinking Water for Epidemiological Studies at a U.S. Military Base: Summary of Results.
A U.S. government health agency conducted epidemiological studies to evaluate whether exposures to drinking water contaminated with volatile organic compounds (VOC) at U.S. Marine Corps Base Camp Lejeune, North Carolina, were associated with increased health risks to children and adults. These health studies required knowledge of contaminant concentrations in drinking water-at monthly intervals-delivered to family housing, barracks, and other facilities within the study area. Because concentration data were limited or unavailable during much of the period of contamination (1950s-1985), the historical reconstruction process was used to quantify estimates of monthly mean contaminant-specific concentrations. This paper integrates many efforts, reports, and papers into a synthesis of the overall approach to, and results from, a drinking-water historical reconstruction study. Results show that at the Tarawa Terrace water treatment plant (WTP) reconstructed (simulated) tetrachloroethylene (PCE) concentrations reached a maximum monthly average value of 183 micrograms per liter (μg/L) compared to a one-time maximum measured value of 215 μg/L and exceeded the U.S. Environmental Protection Agency's current maximum contaminant level (MCL) of 5 μg/L during the period November 1957-February 1987. At the Hadnot Point WTP, reconstructed trichloroethylene (TCE) concentrations reached a maximum monthly average value of 783 μg/L compared to a one-time maximum measured value of 1400 μg/L during the period August 1953-December 1984. The Hadnot Point WTP also provided contaminated drinking water to the Holcomb Boulevard housing area continuously prior to June 1972, when the Holcomb Boulevard WTP came on line (maximum reconstructed TCE concentration of 32 μg/L) and intermittently during the period June 1972-February 1985 (maximum reconstructed TCE concentration of 66 μg/L). Applying the historical reconstruction process to quantify contaminant-specific monthly drinking-water concentrations is advantageous for epidemiological studies when compared to using the classical exposed versus unexposed approach.


Local norms of cheating and the cultural evolution of crime and punishment: a study of two urban neighborhoods.
The prevalence of antisocial behavior varies across time and place. The likelihood of committing such behavior is affected by, and also affects, the local social environment. To further our understanding of this dynamic process, we conducted two studies of antisocial behavior, punishment, and social norms. These studies took place in two neighborhoods in Newcastle Upon Tyne, England. According to a previous study, Neighborhood A enjoys relatively low frequencies of antisocial behavior and crime and high levels of social capital. In contrast, Neighborhood B is characterized by relatively high frequencies of antisocial behavior and crime and low levels of social capital. In Study 1, we used an economic game to assess neighborhood differences in theft, third-party punishment (3PP) of theft, and expectation of 3PP. Participants also reported their perceived neighborhood frequency of cooperative norm violation ("cheating"). Participants in Neighborhood B thought that their neighbors commonly cheat but did not condone cheating. They stole more money from their neighbors in the game, and were less punitive of those who did, than the residents of Neighborhood A. Perceived cheating was positively associated with theft, negatively associated with the expectation of 3PP, and central to the neighborhood difference. Lower trust in one's neighbors and a greater subjective value of the monetary cost of punishment contributed to the reduced punishment observed in Neighborhood B. In Study 2, we examined the causality of cooperative norm violation on expectation of 3PP with a norms manipulation. Residents in Neighborhood B who were informed that cheating is locally uncommon were more expectant of 3PP. In sum, our results provide support for three potentially simultaneous positive feedback mechanisms by which the perception that others are behaving antisocially can lead to further antisocial behavior: (1) motivation to avoid being suckered, (2) decreased punishment of antisocial behavior, and (3) decreased expectation of punishment of antisocial behavior. Consideration of these mechanisms and of norm psychology will help us to understand how neighborhoods can descend into an antisocial culture and get stuck there.


Physician-Specific Maximum Acceptable Risk in Personalized Medicine: Implications for Medical Decision Making.
In discrete-choice experiments (DCEs), respondents are presented with a series of scenarios and asked to select their preferred choice. In clinical decision making, DCEs allow one to calculate the maximum acceptable risk (MAR) that a respondent is willing to accept for a one-unit increase in treatment efficacy. Most published studies report the average MAR for the whole sample, without conveying any information about heterogeneity. For a sample of psychiatrists prescribing drugs for a series of hypothetical patients with schizophrenia, this article demonstrates how heterogeneity accounted for in the DCE modeling can be incorporated in the derivation of the MAR. Psychiatrists were given information about a group of patients' responses to treatment on the Positive and Negative Syndrome Scale (PANSS) and the weight gain associated with the treatment observed in a series of 26 vignettes. We estimated a random parameters logit (RPL) model with treatment choice as the dependent variable. Results from the RPL were used to compute the MAR for the overall sample. This was found to be equal to 4%, implying that, overall, psychiatrists were willing to accept a 4% increase in the risk of an adverse event to obtain a one-unit improvement of symptoms - measured on the PANSS. Heterogeneity was then incorporated in the MAR calculation, finding that MARs ranged between 0.5 and 9.5 across the sample of psychiatrists. We provided psychiatrists with hypothetical scenarios, and their MAR may change when making decisions for actual patients. This analysis aimed to show how it is possible to calculate physician-specific MARs and to discuss how MAR heterogeneity could have implications for medical practice.


Labor market and health trajectories during periods of economic recession and expansion in the United States, 1988‒2011.
Objectives We examined associations between labor market and health (LM-H) trajectories in the United States between 1988 and 2011 and whether associations differed across macroeconomic expansion/recession periods. Methods Working-age cohorts, derived from the US Panel Study of Income Dynamics, were followed over time to characterize LM-H trajectories. Poisson regression provided relative risks (RR) with robust 95% confidence intervals (CI) for the association between trajectories, adjusting for demographic and socioeconomic variables. Results LM trajectories ending in unemployment (RR 1.7‒2.5 across periods) or inactivity (RR 2.3-3.2) had a greater risk of worsening health trajectories, compared to stable employment. In contrast, RR for individuals returning to work following an intermediary period of unemployment/inactivity were attenuated across most periods. Stable-employed individuals had the highest probability of remaining in good health, whereas trajectories ending in unemployment or inactivity had the lowest probability. These overall relationships were consistent across macroeconomic periods. Conclusions We found strong and consistent relationships between LM-H trajectories across macroeconomic periods. The attenuated (but not eliminated) risk among individuals returning to work following a period of unemployment/inactivity suggests that health outcomes are not only dependent on the LM end-state, but also on the distinct pattern over time.


Large-scale mapping of cortical alterations in 22q11.2 deletion syndrome: Convergence with idiopathic psychosis and effects of deletion size.
The 22q11.2 deletion (22q11DS) is a common chromosomal microdeletion and a potent risk factor for psychotic illness. Prior studies reported widespread cortical changes in 22q11DS, but were generally underpowered to characterize neuroanatomic abnormalities associated with psychosis in 22q11DS, and/or neuroanatomic effects of variability in deletion size. To address these issues, we developed the ENIGMA (Enhancing Neuro Imaging Genetics Through Meta-Analysis) 22q11.2 Working Group, representing the largest analysis of brain structural alterations in 22q11DS to date. The imaging data were collected from 10 centers worldwide, including 474 subjects with 22q11DS (age = 18.2 ± 8.6; 46.9% female) and 315 typically developing, matched controls (age = 18.0 ± 9.2; 45.9% female). Compared to controls, 22q11DS individuals showed thicker cortical gray matter overall (left/right hemispheres: Cohen's d = 0.61/0.65), but focal thickness reduction in temporal and cingulate cortex. Cortical surface area (SA), however, showed pervasive reductions in 22q11DS (left/right hemispheres: d = -1.01/-1.02). 22q11DS cases vs. controls were classified with 93.8% accuracy based on these neuroanatomic patterns. Comparison of 22q11DS-psychosis to idiopathic schizophrenia (ENIGMA-Schizophrenia Working Group) revealed significant convergence of affected brain regions, particularly in fronto-temporal cortex. Finally, cortical SA was significantly greater in 22q11DS cases with smaller 1.5 Mb deletions, relative to those with typical 3 Mb deletions. We found a robust neuroanatomic signature of 22q11DS, and the first evidence that deletion size impacts brain structure. Psychotic illness in this highly penetrant deletion was associated with similar neuroanatomic abnormalities to idiopathic schizophrenia. These consistent cross-site findings highlight the homogeneity of this single genetic etiology, and support the suitability of 22q11DS as a biological model of schizophrenia.


Compatibility of Cats With Children in the Family.
Although studies involving pet dogs and cats, and human adults and children, have been reported, the specific interactions between cats and children have not. This study sought information from parents about the cat's role in families that have at least one child 3-12 years of age and at least one cat. Demographic data on cat source, breed, gender/neuter status, was sought as well as information on adults and children in the families and on affectionate, aggressive, fearful, and playful responses of the cats to children. A convenience sample was recruited via listservs for pet owners and parents. Using a pilot tested web survey, descriptive statistics were based on 865 respondents. Multi-variate statistical analyses were conducted on data from 665 respondents with complete responses for all items, including respondents' locations and whether cats were adopted as kittens. Multi-variate analyses included consideration of demographic data, geographic region of respondents, behavioral characteristics of the cats, and responses of the children to the cats. From descriptive statistics, cats' affection was more typical with adults than young children. Neuter status or gender was unrelated to cats' aggression or affection. Being the family's only cat was associated with heightened aggression and reduced affection. Younger cats were more likely to be affectionate. Multivariate analysis revealed three primary factors accounting for children's compatibility with the specified cat: positive interactions of the cat, aggression/fearfulness of cat, and the cat's playfulness and children's reaction to the cats. Positive child-cat relationships were more typical with two or more adults and multiple cats in the home. Old cats were the least satisfactory. A breeder or shelter was a better source than as a feral, from a newspaper ad, or another source. European respondents rated their cats' interactions with children more favorably than in U.S./Canada. This difference may reflect the European adoptions more frequently being of kittens, often purebred, assuring more early handling within the family. A noteworthy finding was that all family participants, humans, and pets alike, affect the cat-child relationship, and these results reveal that many variables can play a role in achieving a desirable relationship for a cat and child.


Long-term follow-up of bilateral hypothalamic stimulation for intractable cluster headache.
We provide a detailed case history of the first patient to receive bilateral hypothalamic stimulation to control severe bilateral chronic intractable cluster headaches initially occurring mostly on the left. These attacks were accompanied by life-threatening hypertensive crises and a grave deterioration in the patient's psychological state. Destructive surgery to the left trigeminal was absolutely contraindicated. Electrode implantation and continuous stimulation of the left posterior inferior hypothalamus resolved the left attacks. After four destructive operations on the right trigeminal, right side attacks recurred. Electrode implantation (with continuous stimulation) to the right resulted in immediate resolution of the right side pain and the hypertensive crises. On several occasions, both known and unknown to the patient, the stimulators were turned off: in all cases, crises reappeared and in all instances disappeared relatively quickly after turning stimulation back on. Pain crises have never reappeared when ipsilateral stimulation is ongoing. The only side effects were observed during long-term bilateral stimulation, consisting of transient vertigo and bradycardia. After 42 months (left) and 31 months (right) of follow-up, the patient remains crisis free without the need for pharmacological prophylaxis.


Manipulating the crystal structure of a conjugated polymer for efficient sequentially processed organic solar cells.
Recently, the sequential (Sq) process, which forms nanoscale network structures from quasi-solid-state inter-diffusion through swelling and annealing, is considered to be one of the most efficient methods for fabricating organic solar cells and blend films. Here, we examined the effect of the crystallinity and orientation of poly(3-hexylthiophene) (P3HT) molecules on the formation of the nanostructure by carrying out a Sq process using various solvents with different boiling points. We showed that the moderate crystallinity promoted suitable inter-diffusion between the donor (P3HT) and acceptor ([6,6]-pentadeuterophenyl C61 butyric acid methyl ester, PC60BM), and hence was important for achieving high-performance solar cells using Sq processing. Nanostructure formation by inter-diffusion was investigated and visualized by taking a combination of grazing-incidence wide-angle X-ray scattering (GIWAXS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS) measurements. In addition, our Sq-processed solar cell yielded a device efficiency as high as 3.25%, and was also impressive because it was made with an eco-friendly solvent and using a short-duration annealing process, in contrast to the conventional BHJ process. The present findings provided advanced insight into the Sq process, and we anticipate this efficacious sequential process to contribute not only to the development of higher-efficiency organic solar cells but also to the fabrication of functional blend films.


Structure of alkyne monolayers on hydrogen-terminated Si(100) surfaces investigated by external reflection infrared spectroscopy.
Monolayers of terminal alkynes with long hydrocarbon chains C(n)H(2n+1)C≡CH (n = 10, 13, 16) were prepared on Si(100) substrates via thermally induced hydrosilylation and the surface orientation of the hydrocarbon chains was investigated by external reflection infrared spectroscopy. It was found that under rigorous exclusion of oxygen in the monolayer preparation process, all three compounds yield highly characteristic IR reflection spectra, consisting of upward-pointing ν(CH(2)) absorptions and downward-pointing ν(CH(3)) absorptions, indicative of a highly ordered anisotropic film structure. Via spectral simulations it was found that the methylene backbones (CH(2))(n) in these films adopt a uniform, all-trans conformation with a tilt angle of about 30° toward the surface normal, whereas the chain termini are disordered and give an isotropic film surface composed of randomly oriented CH(3) groups. Lower quality films, which are hardly distinguishable from highly ordered films by other methods, but have been shown to exhibit inferior electrical properties, are clearly identified in their infrared (IR) spectra as partly disordered structures. External reflection IR therefore proves to be an exceptionally sensitive tool to detect structural defects in these monolayers.


Visualization of mRNA translation in living cells.
The role of mRNA localization is presumably to effect cell asymmetry by synthesizing proteins in specific cellular compartments. However, protein synthesis has never been directly demonstrated at the sites of mRNA localization. To address this, we developed a live cell method for imaging translation of beta-actin mRNA. Constructs coding for beta-actin, containing tetracysteine motifs, were transfected into C2C12 cells, and sites of nascent polypeptide chains were detected using the biarsenial dyes FlAsH and ReAsH, a technique we call translation site imaging. These sites colocalized with beta-actin mRNA at the leading edge of motile myoblasts, confirming that they were translating. beta-Actin mRNA lacking the sequence (zipcode) that localizes the mRNA to the cell periphery, eliminated the translation there. A pulse-chase experiment on living cells showed that the recently synthesized protein correlated spatially with the sites of its translation. Additionally, localization of beta-actin mRNA and translation activity was enhanced at cell contacts and facilitated the formation of intercellular junctions.


Validation of a plasma metabolomics model that allows anticipation of the occurrence of cytomegalovirus DNAaemia in allogeneic stem cell transplant recipients.
A plasma metabolomic model obtained by means of untargeted 1H nuclear magnetic resonance, to which taurine, choline, methylamine, total glutathione, trimethylamine N-oxide, lactate, lysine, isoleucine, total fatty acids and unsaturated fatty acids contributed, was validated for the prediction of first episodes of cytomegalovirus (CMV) DNAaemia in a cohort of 79 allogeneic stem haematopoietic stem cell transplant (allo-HSCT) recipients. The predictive success rate was nearly 65 % for patients at both low and high risk of CMV-related complications according to their baseline characteristics. Plasma metabolomics profiling shortly after engraftment (day 21 after transplantation) allowed the anticipation of the occurrence of CMV DNAaemia in 71 % of patients. Plasma metabolomics analyses may be ancillary for identifying allo-HSCT patients at the highest risk of CMV DNAaemia who may benefit from early targeted antiviral prophylaxis.


PET/CT Imaging of Chemokine Receptors in Inflammatory Atherosclerosis Using Targeted Nanoparticles.
Atherosclerosis is inherently an inflammatory process that is strongly affected by the chemokine-chemokine receptor axes regulating the trafficking of inflammatory cells at all stages of the disease. Of the chemokine receptor family, some specifically upregulated on macrophages play a critical role in plaque development and may have the potential to track plaque progression. However, the diagnostic potential of these chemokine receptors has not been fully realized. On the basis of our previous work using a broad-spectrum peptide antagonist imaging 8 chemokine receptors together, the purpose of this study was to develop a targeted nanoparticle for sensitive and specific detection of these chemokine receptors in both a mouse vascular injury model and a spontaneously developed mouse atherosclerosis model. The viral macrophage inflammatory protein-II (vMIP-II) was conjugated to a biocompatible poly(methyl methacrylate)-core/polyethylene glycol-shell amphiphilic comblike nanoparticle through controlled conjugation and polymerization before radiolabeling with (64)Cu for PET imaging in an apolipoprotein E-deficient (ApoE(-/-)) mouse vascular injury model and a spontaneous ApoE(-/-) mouse atherosclerosis model. Histology, immunohistochemistry, and real-time reverse transcription polymerase chain reaction were performed to assess the plaque progression and upregulation of chemokine receptors. The chemokine receptor-targeted (64)Cu-vMIP-II-comb showed extended blood retention and improved biodistribution. PET imaging showed specific tracer accumulation at plaques in ApoE(-/-) mice, confirmed by competitive receptor blocking studies and assessment in wild-type mice. Histopathologic characterization showed the progression of plaque including size and macrophage population, corresponding to the elevated concentration of chemokine receptors and more importantly increased PET signals. This work provides a useful nanoplatform for sensitive and specific detection of chemokine receptors to assess plaque progression in mouse atherosclerosis models.


gamma-Hydroxybutyric acid increases intracellular Ca2+ concentration and nuclear cyclic AMP-responsive element- and activator protein 1 DNA-binding activities through GABAB receptor in cultured cerebellar granule cells.
In primary cultures of mouse cerebellar granule cells, a brief stimulation by gamma-hydroxybutyric acid (GHB, 0.1-3 mM) significantly increased the intracellular Ca2+ concentration ([Ca2+]i) in a concentration-dependent manner. In addition, gel mobility assay showed that exposure of the cells to GHB also increased nuclear DNA-binding activity specific for the cyclic AMP-responsive element (CRE) and activator protein 1 (AP-1) transcriptional element in a concentration-dependent manner. The concentration range of GHB that increased the DNA-binding activity was essentially the same as the concentration range that elicited the increase in [Ca2+]i. The GHB-induced increases in [Ca2+]i and nuclear DNA-binding activity were antagonized by specific GABAB antagonists such as p-[3-aminopropyl]-p-diethoxymethylphosphinic acid (CGP 35 348) and 3-N-[1-(S)-(3,4-dichlorobenzyl)ethanol-2-(S)-hydroxy-P-benzylphosphin ic acid (CGP 55 845). In addition, the GHB-induced increase in [Ca2+]i was abolished by pretreatment of the cells with islet-activating protein. Furthermore, treatment of the cells with 1,2-bis(2'-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM) and thapsigargin blocked the GHB-induced increase in nuclear DNA-binding activity. GHB inhibited [3H]baclofen binding to cultured cerebellar granule cells and mouse cerebellar membranes. These results suggest that stimulation of GABAB receptors by GHB activates intracellular Ca2+ stores and that the increased [Ca2+]i resulting from release of stored Ca2+ plays an important role in increasing the CRE- and AP-1 DNA-binding activities in cultured cerebellar granule cells.


Characterization of clinical study populations by race and ethnicity in biomedical literature.
The importance of race and ethnicity in biomedical research has long been a subject of debate, recently heightened by data revealed by the completion of the sequencing of the human genome and the mapping of human genetic variation. We aimed to determine whether and how the reporting of race has changed over the last three decades and how the practice may differ given study location, where the journal of publication is based, and decade of publication. We analyzed a sample of studies published in the Journal of the American Medical Association, The Lancet, and the Canadian Medical Association Journal from 1980 to 2009. The number of articles that reported race by journal and decade and the descriptors used. Of 1867 articles analyzed, 17.30% reported race. The reporting of race and number of populations reported increased over time for all three journals. In addition, the diversity of race/ethnicity descriptors increased, with increased use of race/ethnicity combinations and nationality of research subjects. Though it has increased over the past few decades, the reporting of race/ethnicity of study populations is relatively low, ambiguous and inconsistent, likely influenced by the uncertain relevance of these variables to the study's outcomes, study location, researcher views, and the policies of journals and funding agencies. Thus, due to the inconsistent and ambiguous practice of reporting race/ethnicity, comparison of study outcomes can result in misleading conclusions. Improvements in standardization of terms and new approaches to characterize research participants related to race/ethnicity are imperative.


Human fronto-mesolimbic networks guide decisions about charitable donation.
Humans often sacrifice material benefits to endorse or to oppose societal causes based on moral beliefs. Charitable donation behavior, which has been the target of recent experimental economics studies, is an outstanding contemporary manifestation of this ability. Yet the neural bases of this unique aspect of human altruism, which extends beyond interpersonal interactions, remain obscure. In this article, we use functional magnetic resonance imaging while participants anonymously donated to or opposed real charitable organizations related to major societal causes. We show that the mesolimbic reward system is engaged by donations in the same way as when monetary rewards are obtained. Furthermore, medial orbitofrontal-subgenual and lateral orbitofrontal areas, which also play key roles in more primitive mechanisms of social attachment and aversion, specifically mediate decisions to donate or to oppose societal causes. Remarkably, more anterior sectors of the prefrontal cortex are distinctively recruited when altruistic choices prevail over selfish material interests.


The regulation of abscission by multi-protein complexes.
The terminal stage of cytokinesis - a process termed abscission - is the severing of the thin intercellular bridge that connects the two daughter cells. Recent work provides new insight into the mechanism by which this microtubule-dense membrane bridge is resolved, and highlights important roles for multi-protein assemblies in different facets of abscission. These include the endosomal sorting complex required for transport (ESCRT), which appears to have a decisive role in the final scission event, and vesicle tethering complexes, which potentially act at an earlier stage, and might serve to prepare the abscission site. Here, we review recent studies of the structure, function and regulation of these complexes as related to abscission. We focus largely on studies of cytokinesis in mammalian cells. However, cell division in other systems, such as plants and Archae, is also considered, reflecting the mechanistic conservation of membrane-scission processes during cell division.


Therapeutic outcomes of low-level laser therapy for closed bone fracture in the human wrist and hand.
The therapeutic outcomes of low-level laser therapy (LLLT) on closed bone fractures (CBFs) in the wrist and hand were investigated in this controlled study. Animal research has confirmed that LLLT increases osteocyte quantity; however, little research has been conducted to determine the effect of LLLT on the treatment of human bone fractures. In this study, the therapeutic outcomes of administering 830 nm LLLT to treat CBFs in the wrist or hand were examined. Fifty patients with CBFs in the wrist and hand, who had not received surgical treatment, were recruited and randomly assigned to two groups. The laser group underwent a treatment program in which 830 nm LLLT (average power 60 mW, peak power 8 W, 10 Hz, 600 sec, and 9.7 J/cm(2) per fracture site) was administered five times per week for 2 weeks. Participants in a placebo group received sham laser treatment. The pain, functional disability, grip strength, and radiographic parameters of the participants were evaluated before and after treatment and at a 2-week follow-up. After treatment and at the follow-up, the laser group exhibited significant changes in all of the parameters compared with the baseline (p<0.05). The results of comparing the two groups after treatment and at the follow-up indicated significant between-group differences among all of the parameters (p<0.05). LLLT can relieve pain and improve the healing process of CBFs in the human wrist and hand.


Detecting the Significant Flux Backbone of Escherichia coli metabolism.
The heterogeneity of computationally predicted reaction fluxes in metabolic networks within a single flux state can be exploited to detect their significant flux backbone. Here, we disclose the backbone of Escherichia coli, and compare it with the backbones of other bacteria. We find that, in general, the core of the backbones is mainly composed of reactions in energy metabolism corresponding to ancient pathways. In E. coli, the synthesis of nucleotides and the metabolism of lipids form smaller cores which rely critically on energy metabolism. Moreover, the consideration of different media leads to the identification of pathways sensitive to environmental changes. The metabolic backbone of an organism is thus useful to trace simultaneously both its evolution and adaptation fingerprints.


Evaluation of selected publications on reference values for lead in blood.
As a part of the global Tracy project, whose aim is to define metal concentrations in tissues and body fluids of reference populations, more than 1000 papers published from 1980 to 1994 were scrutinized that presented tentative reference values for lead in blood in occupationally unexposed adult populations. Ten studies exemplifying criteria for proper sampling, analysis and data treatment are presented and discussed. Levels of lead in blood are influenced by numerous factors. Accordingly, a wide variation in blood lead concentrations was observed. As an example, in a global study in 1983 of nonsmoking female schoolteachers, the geometric mean value for lead in blood varied from 52 micrograms. l-1 in Tokyo, Japan, up to 193 micrograms. l-1 in Mexico City. The Tracy survey demonstrates the importance of factors such as age, gender, ethnicity, food, drinking and smoking habits, hobbies, season and year of sampling, residential area, and geographic location. Lead in blood was shown to be both time and area specific. Thus it was not possible to establish a general reference value for lead in blood.


Using density based indexes to characterize excited states evolution.
With the aim of offering new computational tools helping in the description of photochemical reactions and phenomena occurring at the excited state, we present in this work the capability of a density based index (Π) in locating decay channels from higher to lower excited states. The Π index, previously applied to disclose non-radiative decay channels from the first excited state to the ground state, is very simple in its formulation and can be evaluated, practically with no extra computational cost, and coupled to any quantum method able to provide excited states densities. Indeed, this index relies only on the knowledge of energetics and electron densities of the different electronic states involved in the decay. In the present work, we show the proficiency of the Π index in the general case of decay between excited states by applying it to two model systems well characterized both theoretically and experimentally. In both cases, this descriptor was successful in spotting the regions where excited states are more likely to decay, thus suggesting its potential interest for further application in the design of new compounds. © 2018 Wiley Periodicals, Inc.


Managing ethical issues in sexual violence research using a pilot study.
Conducting research in the area of sexual violence has complex ethical and practical challenges for the researcher. Managing ethical issues in sexual violence is important and can be achieved through the use of pilot studies. The primary purpose of the pilot study was to identify and manage potential ethical and practical problems that could jeopardise the main study or violate the ethical and human rights of participants in the main study on women's journey of recovery from sexual assault. The secondary purpose was to collect preliminary data in order to determine the human, financial and time resources needed for a planned study. The methods and processes used in conducting the pilot study in the study on women's journey of recovery are discussed according to each of the objectives of the pilot study, methods used to achieve the objective, observations or findings made during the pilot study, and implications for the main study. This article aims to demonstrate how a pilot study was used to manage identified potential ethical and practical research issues during the recruitment of participants and data collection for the research that was conducted by the first author to investigate women's journey of recovery from sexual assault trauma within the first week following sexual assault.


An Evaluation of the Healthiness of the Indian Packaged Food and Beverage Supply.
Availability of less-healthy packaged food and beverage products has been implicated as an important driver of obesity and diet-related disease. An increasing number of packaged foods and beverages are sold in India. Our objective was to evaluate the healthiness of packaged foods sold by India's largest manufacturers. Healthiness was assessed using the Australian Health Star Rating (HSR) system and the World Health Organization's European Regional Office (WHO Euro) Nutrient Profile Model. Sales-value-weighted mean healthiness and the proportions of "healthy" products (using a validated HSR cut-off of ≥3.5, and products meeting WHO Euro criteria as healthy enough to market to children) were calculated overall, by company and by food category. Nutrient information for 943 products sold by the 11 largest Indian manufacturers was obtained from nutrient labels, company websites or directly from the manufacturer. Healthiness was low overall (mean HSR 1.8 out of 5.0 stars) with a low proportion defined as "healthy" by both HSR (17%) and also by WHO Euro criteria (8%). There were marked differences in the healthiness of similar products within food categories. Substantial variation between companies (minimum sales-value-weighted mean HSR 0.5 for Company G, versus maximum HSR 3.0 for Company F) was a result of differences in the types of products sold and the nutritional composition of individual products. There are clear opportunities for India's largest food companies to improve both the nutritional quality of individual products and to improve their product mix to include a greater proportion of healthy products.


Phosphorylated epidermal growth factor receptor and cyclooxygenase-2 expression in localized non-small cell lung cancer.
The prognostic significance of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) expression remains unestablished, although EGFR and COX-2 are frequently overexpressed in non-small cell lung cancer (NSCLC). Considering the importance of EGFR activation after ligand binding, however, the expression of phosphorylated EGFR (p-EGFR) may have more significance in predicting tumor aggressiveness in NSCLC than either EGFR or COX-2 expression. We studied the relationships between p-EGFR, EGFR, and COX-2 overexpression and examined their association with prognosis in localized NSCLC. The expression of p-EGFR, EGFR, and COX-2 was studied by immunohistochemistry in 77 surgically-resected stage I/II NSCLC cases. EGFR mutational status was determined by sequencing exons 18-21. Correlation of expression with clinical outcome and other biomarkers, including Ki-67 and microvessel density (MVD), was also examined. Out of the 77 patients, EGFR overexpression was observed in 37 (48.1%), p-EGFR expression was found in 22 (28.6%), and COX-2 overexpression was seen in 45 (58.4%). Expression of p-EGFR was associated with COX-2 overexpression (P = 0.047), but not EGFR overexpression or high Ki-67 (P = 0.087 and P = 0.092, respectively). COX-2 overexpression was significantly associated with high Ki-67 (P = 0.011). Expression of p-EGFR correlated with lower disease-free survival (P = 0.045), but not overall survival. Neither EGFR nor COX-2 overexpression was associated with prognosis. p-EGFR appears to be a better indicator for lower disease-free survival than EGFR overexpression itself in localized NSCLC. Pathways other than EGFR activation may influence COX-2 overexpression.


The asymmetric distribution of enzymic activity between the six subunits of bovine liver glutamate dehydrogenase. Use of D- and L-glutamyl alpha-chloromethyl ketones (4-amino-6-chloro-5-oxohexanoic acid.
A method for the preparation of D- and L-glutamyl alpha-chloromethyl ketones (4-amino-6-chloro-5-oxohexanoic acid) is described. These chloromethyl ketones irreversibly inactivated bovine glutamate dehydrogenase, whereas several other related compounds had no adverse effect on the activity of the enzyme. The inactivation process was shown to be due to the modification of lysine-126. The time-courses for the inactivation and the incorporation of radioactivity from tritiated L-glutamyl alpha-chloromethyl ketone into the glutamate dehydrogenase were biphasic. The results were interpreted to suggest the involvement of 'negative co-operative' interactions in the reactivity of lysine-126. From the cumulative evidence it is argued that the first subunit of the enzyme, which takes part in catalysis, makes the largest, and the last the smallest, contribution to the overall catalysis. It is emphasized that three of the six subunits of the enzyme may possess as much as 80% of the total activity of bovine glutamate dehydrogenase.


Cytotoxic T-cells as imaging probes for detecting glioma.
Tumor vaccination using tumor-associated antigen-primed dendritic cells (DCs) is in clinical trials. Investigators are using patients' own immune systems to activate T-cells against recurrent or metastatic tumors. Following vaccination of DCs or attenuated tumor cells, clinical as well as radiological improvements have been noted due to migration and accumulation of cytotoxic T-cells (CTLs). CTLs mediated tumor cell killing resulted in extended survival in clinical trails and in preclinical models. Besides administration of primed DCs or attenuated or killed tumors cells to initiate the generation of CTLs, investigators have started making genetically altered T-cells (CTLs) to target specific tumors and showed in vivo migration and accumulation in the implanted or recurrent tumors using different imaging modalities. Our groups have also showed the utilization of both in vivo and in vitro techniques to make CTLs against glioma and used them as imaging probes to determine the sites of tumors. In this short review, the current status of vaccination therapy against glioma and utilization of CTLs as in vivo imaging probes to determine the sites of tumors and differentiate recurrent glioma from radiation necrosis will be discussed.


Minimizing photobleaching during confocal microscopy of fluorescent probes bound to chromatin: role of anoxia and photon flux.
Exposure to light can destroy the ability of a molecule to fluoresce. Such photobleaching limits the use of fluorescence and confocal microscopy in biological studies. Loss of fluorescence decreases the signal-to-noise ratio and so image resolution; it also prevents the acquisition of meaningful data late during repeated scanning (e.g. when collecting three-dimensional images). The aim of this work was to investigate the role of oxygen in the photobleaching of fluorophores bound to DNA in fixed cells, and to explore whether anoxia could minimize such bleaching. Anoxia significantly reduced bleaching rates and changed the order of reaction of both propidium iodide (an intercalator) and chromomycin A3 (a minor-groove binder) bound to DNA; it afforded the greatest protection at low photon fluxes. However, it had no effect on the bleaching of the green fluorescent protein (GFP) covalently attached to a histone and so bound to DNA, probably because the protein shielded the chromophore from oxygen. Bleaching of all three fluorophores depended on photon flux. Practical ways of minimizing bleaching were examined, and examples of three-dimensional images of DNA marked by propidium and GFP (collected under standard and optimized conditions) are presented.


SU-E-T-186: An Automated Quality Assurance Tool for HDR Treatment Planning.
Treatment planning for high dose rate (HDR) brachytherapy requires many user inputs, all of which are potential sources of error. The goal of quality assurance (QA) is to ensure that errors are not made. In this study, we developed a software program to analyze the treatment printout from the HDR treatment planning computer and flag any suspected errors. The treatment printout from the HDR planning computer is imported by the software. The software then performs the following checks: (1) verifies that the correct source was chosen (we have multiple in our database), (2) performs an independent decay of the Ir-192 source, (3) verifies source step size, (4) verifies the offsets and indexer lengths in the catheter definitions based upon expected values for the applicator used, (4) performs an independent 2nd check of dose to a cloud of dose points surrounding the treatment region, (5) verifies that the dose per fraction and the number of fractions were entered correctly in the planning computer, and (6) verifies that the dose volume histogram (DVH) metrics were within acceptable tolerances. The software then prints this information to a PDF file, which is appended to the original treatment printout and placed in the patient's medical record. This QA tool has now been implemented for six months in our clinic, and is a critical QA tool in our HDR program. Although each plan is checked by an independent 2nd physicist, this tool provides an additional independent check on the treatment plan. A simple series of automatic 2nd checks helps reduce the risk of errors occurring in the treatment planning portion of HDR brachytherapy and can easily be implemented.