Whole-body computed tomography: a new point of view in a hospital check-up unit? Our experience in 6516 patients.
There is a growing awareness that prevention and early diagnosis may reduce the high mortality associated with cancer, cardiovascular and other diseases. The role of whole-body computed tomography (WB-CT) in self-referred and asymptomatic patients has been debated. To determine frequency and spectrum of WB-CT findings in average-risk subjects derived from a Medical-Check-Up-Unit, to evaluate recommendations reported and distribution according to sex and age-groups. We retrospectively reviewed 6516 subjects who underwent WB-CT (June 2004/February 2015). All were > 40 years and referred by Medical-Check-Up-Unit of our hospital. The main findings were categorized and classified as normal or not. Its distribution according to sex and age-groups was evaluated using Chi-square test and linear-by-linear association test, respectively. Number of recommendations, type and interval of follow-up were recorded. Descriptive statistics were used. WB-CT performed in 6516 patients (69% men, 31% women, mean age = 58.4 years) revealed chest (81.4%), abdominal (93.06%) and spine (65.39%) abnormalities. Only 1.60% had completely normal exploration. Abnormal WB-CT in men was significantly higher than women (98.64% vs. 97.87%; p = 0.021), with significant increase as age was higher (40-49 years: 95.65%; 50-59 years: 98.33%; 60-69 years: 99.47%; > 69 years: 99.89%) (p < 0.001). Although most findings were benign, we detected 1.47% primary tumors (96, mainly 35 kidneys and 15 lungs). 17.39% of patients received at least one recommendation predominantly in chest (78.19%) and follow-up imaging (69.89%). The most common WB-CT findings in asymptomatic subjects are benign. However, this examination allows identifying an important number of relevant and precocious findings that significantly increase with age, involving changes in lifestyle and precocious treatment.


Design of dual-core optical fibers with NEMS functionality.
An optical fiber with nano-electromechanical functionality is presented. The fiber exhibits a suspended dual-core structure that allows for control of the optical properties via nanometer-range mechanical movements. We investigate electrostatic actuation achieved by applying a voltage to specially designed electrodes integrated in the cladding. Numerical and analytical calculations are preformed to optimize the fiber and electrode design. Based on this geometry an all-fiber optical switch is investigated; we find that optical switching of light between the two cores can be achieved in a 10 cm fiber with an operating voltage of 35 V.


Coexistent thyroid pathologies and high rate of papillary cancer in patients with primary hyperparathyroidism: controversies about minimal invasive parathyroid surgery.
Thyroid carcinoma and benign thyroid diseases associated with primary hyperparathyroidism (PHPT) may cause difficulties in the diagnosis, localization and therapy of PHPT. In this study, we analysed coexistent thyroid pathologies in 51 patients who underwent neck exploration with a diagnosis of PHPT between 1999--2002. Five hundred thirteen patients who underwent thyroidectomy for nodular thyroid disease without a parathyroid pathology in histopathological examination served as controls. In patients with PHPT there were 43 cases (84.3%) of coexistent thyroid pathology. Nine patients (17.6 %) had coexistent papillary thyroid cancer. Nine patients (17.6 %) had lymphocytic thyroiditis, two (3.9%) had benign thyroid adenoma and 24 (47%) had nodular hyperplasia. In one patient (2%), there was intrathyroidal metastasis from a parathyroid cancer. One patient had coexistent lymphocytic thyroiditis and multifocal papillary cancer. One of the two cases with thyroid adenomas was Hürthle cell type. In the control group only 28 patients (5.5%) had thyroid malignancy (27 papillary cancer and one follicular cancer). In conclusion, the coexistent thyroid pathologies are highly prevalent in patients with PHPT and pre- and intra-operative thyroid examination should be performed to avoid overlooking important thyroid pathologies.


Prevalence of Rilpivirine and Etravirine Resistance Mutations in HIV-1 Subtype C-Infected Patients Failing Nevirapine or Efavirenz-Based Combination Antiretroviral Therapy in Botswana.
Rilpivirine (RPV) and Etravirine (ETR) are approved second-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment. There is a cross-resistance HIV mutation profile between first- and second-generation NNRTI drugs. We determined the prevalence of HIV-1 drug resistance mutations (DRMs) to RPV and ETR in Botswana. A total of 168 HIV-1 polymerase gene sequences from participants failing nevirapine (NVP)- or efavirenz (EFV)-containing regimens were analyzed for DRMs using the Stanford University HIV drug resistance database. Forty-one sequences were from an adult antiretroviral therapy (ART) study, the Tshepo study, and 127 from a prevention of mother-to-child transmission (PMTCT) study, the Mashi study, all conducted in Botswana. Prevalence of RPV and ETR highest DRM in the adult ART study (n = 41) were K101E (26.2%), E138A (23.8%), and Y181C (26.2%). The PMTCT cohort's (n = 127) high prevalence mutations were Y181C (15.7%), E138A (15%), and K101E (11%). A total of 42.9% and 3.2% of patients in the adult ART study and PMTCT study, respectively, had three or more NNRTI mutations at virologic failure. We identified HIV-1 mutations conferring resistance to RPV and ETR even though they have not been used in Botswana. Of concern was the high proportion of sequences from the adult ART study that displayed multiple DRMs; as the number of NNRTI mutations increases, the level of cross-resistance increases. It is plausible that patients displaying such profiles maybe at increased risk of failing second-generation NNRTI drugs, hence, calls for genotyping in patients with prior NVP or efavirenz exposure before prescription of RPV- or ETR-containing cART.


Midfrontal-occipital θ-tACS modulates cognitive conflicts related to bodily stimuli.
Neurophysiological studies show that during tasks tapping cognitive control (like the flanker task), midfrontal theta (MFθ) oscillations are associated with conflict and error processing and neural top-down modulation of perceptual processing. What remains unknown is whether perceptual encoding of category-specific stimuli (e.g. body vs letters) used in flanker-like tasks is modulated by theta oscillations. To explore this issue, we delivered transcranial Alternating Current Stimulation (tACS) in the theta frequency band (6 Hz) over the medial frontal cortex (MFC) and the extra-striate body area (EBA), whereas healthy participants performed two variants of the classical flanker task, one with stimuli representing human hands (i.e. hand-flanker) and the other with stimuli representing coloured letters (i.e. letter-flanker). More specifically, we aimed at investigating whether θ-tACS involving a body-related area may modulate the long-range communication between neuronal populations underlying conflict monitoring and visuo-perceptual encoding of hand stimuli without affecting the conflict driven by letter stimuli. Results showed faster correct response times during θ-tACS in the hand-flanker compared with γ-tACS (40 Hz) and sham. Importantly, such an effect did not emerge in the letter-flanker. Our findings show that theta oscillations over midfrontal-occipital areas modulate bodily specific, stimulus content-driven aspects of cognitive control.


Anti-miR21 oligonucleotide enhances chemosensitivity of T98G cell line to doxorubicin by inducing apoptosis.
Various signal transduction pathways seem to be involved in chemoresistance mechanism of glioblastomas (GBMs). miR-21 is an important oncogenic miRNA which modulates drug resistance of tumor cells. We analyzed the expression of 5 miRNAs, previously found to be dysregulated in high grade gliomas, in 9 pediatric (pGBM) and in 5 adult (aGBM) GBMs. miR-21 was over-expressed, with a significant difference between pGBMs and aGBMs represented by a 4 times lower degree of expression in the pediatric compared to the adult series (p = 0.001). Doxorubicin (Dox) seems to be an effective anti-glioma agent with high antitumor activity also against glioblastoma stem cells. We therefore evaluated the chemosensitivity to Dox in 3 GBM cell lines (A172, U87MG and T98G). Dox had a cytotoxic effect after 48 h of treatment in A172 and U87MG, while T98G cells were resistant. TUNEL assay verified that Dox induced apoptosis in A172 and U87MG but not in T98G. miR-21 showed a low basal expression in treated cells and was over-expressed in untreated cells. To validate the possible association of miR-21 with drug resistance of T98G cells, we transfected anti-miR-21 inhibitor into the cells. The expression level of miR-21 was significantly lower in T98G transfected cells (than in the parental control cells). Transfected cells showed a high apoptotic rate compared to control after Dox treatment by TUNEL assay, suggesting that combined Dox and miR-21 inhibitor therapy can sensitize GBM resistant cells to anthracyclines by enhancing apoptosis.


Physiotherapy triage assessment of patients referred for orthopaedic consultation - Long-term follow-up of health-related quality of life, pain-related disability and sick leave.
The literature indicates that physiotherapy triage assessment can be efficient for patients referred for orthopaedic consultation, however long-term follow up of patient reported outcome measures are not available. To report a long-term evaluation of patient-reported health-related quality of life, pain-related disability, and sick leave after a physiotherapy triage assessment of patients referred for orthopaedic consultation compared with standard practice. Patients referred for orthopaedic consultation (n = 208) were randomised to physiotherapy triage assessment or standard practice. The randomised cohort was analysed on an intention-to-treat (ITT) basis. The patient reported outcome measures EuroQol VAS (self-reported health-state), EuroQol 5D-3L (EQ-5D) and Pain Disability Index (PDI) were assessed at baseline and after 3, 6 and 12 months. EQ VAS was analysed using a repeated measure ANOVA. PDI and EQ-5D were analysed using a marginal logistic regression model. Sick leave was analysed for the 12 months following consultation using a Mann-Whitney U-test. The patients rated a significantly better health-state at 3 after physiotherapy triage assessment [mean difference -5.7 (95% CI -11.1; -0.2); p = 0.04]. There were no other statistically significant differences in perceived health-related quality of life or pain related disability between the groups at any of the follow-ups, or sick leave. This study reports that the long-term follow up of the patient related outcome measures health-related quality of life, pain-related disability and sick leave after physiotherapy triage assessment did not differ from standard practice, indicating the possible benefits of implementation of this model of care.


Knowledge of female genital cutting and experience with women who are circumcised: a survey of nurse-midwives in the United States.
Thousands of women with a history of female genital cutting (FGC) have immigrated to the United States. The purpose of this study was to assess certified nurse-midwives' (CNMs') knowledge of FGC and to explore their experiences caring for African immigrant women with a history of genital cutting. A descriptive survey design was used. A random sample of 600 CNMs from the member list of the American College of Nurse-Midwives was surveyed. Two hundred forty-three CNMs completed a survey of FGC knowledge and provider experience. The respondents exhibited more correct medical knowledge about FGC than knowledge of cultural and legal issues. Differences in correct or incorrect knowledge were statistically significant based on provider experience. Almost 70% of respondents could identify infibulation. Less than 20% knew that both Muslim and Christian women are circumcised. Fifty-seven percent knew that it is illegal in the United States to circumcise women younger than 18 years of age. We found that discussions between CNMs and clients who were circumcised regarding FGC-related concerns and complications were minimal. Women with a history of FGC want female providers. Reinfibulation poses an ethical dilemma for some CNMs. Nurse-midwives in the United States need to learn more about FGC and the cultures of their clients in order to provide culturally competent care.


Differential induction of polyamine oxidase activity in liver and heart of iron-overloaded rats.
The present study was undertaken to investigate the effect of iron dextran treatment on polyamine oxidase (PAO) activity, iron accumulation, and lipid peroxidation in livers and hearts of rats. PAO catalyzes oxidative deamination of polyamines, the cellular aliphatic cations. This reaction produces highly toxic hydrogen peroxide, 3-acetamidopropanal, and precursors of higher polyamines. The rats were given iron dextran daily for 7 d. In iron-dextran-treated rats, a marked increase in the hepatic level of iron was associated with enhanced lipid peroxidation and increased PAO activity. Though iron accumulation and lipid peroxidation in the iron-treated rats increased significantly in the heart, PAO activity remained unchanged. The paraffin sections of livers stained with Perls iron stain showed the presence of iron in macrophages and hepatocytes. The sections of hearts showed iron deposits only in macrophages, while myocytes showed no iron staining. These results show that although iron dextran treatment results in accumulation of iron in both liver and heart, it induces PAO activity only in liver. The significance of increased PAO activity in lipid peroxidation and fibrosis in iron-mediated injury is discussed.


Client-centred empowering partnering in nursing.
This paper explores nurses' experiences 1 year after an organization's commitment to providing a client-centred and client-empowering partnering approach to care. Historically, nurses' approach to providing care in all nursing contexts has been one of doing for clients, and previous studies have focused more on in-hospital care than on home care. However, the isolation inherent in in-home nursing and nurses' limited professional autonomy and power associated with physician control over patients in home care have been reported, as has their difficulty in finding the meaning and satisfaction of human connectedness and mutuality in nurse-client relationships. Overall, research to date does not inform us about how nurses might make a change toward a more client-centred and client-empowering approach to nursing. An interpretive phenomenological design was used to elicit in-depth understanding about Registered Nurses' experiences of providing care using this innovative empowerment model. A purposefully selected sample of eight Registered Nurses participated in in-depth interviews. Data were generated during 2002. Hermeneutic analysis was used to elicit themes and patterns emerging from the data. Caring, client-centredness and the context of in-home care were important in implementing the new partnering approach. Barriers encountered at system, organizational and personal levels distracted nurses from fully comprehending and enacting the approach. After a year, they had begun to contemplate potential strategies for partnering with clients, but had not yet explored the power of their professional autonomy. Nurses are inclined to practise within the expert model of service delivery. They need to work through issues of professional autonomy and rise to the challenge of exercising their autonomy within the current healthcare context if they are to attend more consistently to client-centred empowering partnering. The home care setting offers an excellent environment for achieving these aims.


Characteristics and One Year Outcomes of Melioidosis Patients in Northeastern Thailand: A Prospective, Multicenter Cohort Study.
Melioidosis is a neglected tropical infection caused by the environmental saprophyte Burkholderia pseudomallei. We conducted a prospective, observational study at nine hospitals in northeastern Thailand, a hyperendemic melioidosis zone, to define current characteristics of melioidosis patients and quantify outcomes over one year. 2574 individuals hospitalised with culture-confirmed melioidosis were screened and 1352 patients were analysed. The median age was 55 years, 975 (72%) were male, and 951 (70%) had diabetes. 565 (42%) patients presented with lung infection, 1042 (77%) were bacteremic, 442 (33%) received vasopressors/inotropes and 547 (40%) received mechanical ventilation. 1307 (97%) received an intravenous antibiotic against B. pseudomallei. 335/1345 (25%) patients died within one month and 448/1322 (34%) of patients died within one year. Most patients had risk factors for melioidosis, but patients without identified risk factors did not have a reduced risk of death. Of patients discharged alive, most received oral trimethoprim-sulfamethoxazole, which was associated with decreased risk of post-discharge death; 235/970 (24%) were readmitted, and 874/1015 (86%) survived to one year. Recurrent infection was detected in 17/994 patients (2%). Patients with risk factors other than diabetes had increased risk of death and increased risk of hospital readmission. In northeastern Thailand patients with melioidosis experience high rates of bacteremia, organ failure and death. Most patients discharged alive survive one year although all-cause readmission is common. Recurrent disease is rare. Strategies that emphasize prevention, rapid diagnosis and intensification of early clinical management are likely to have greatest impact in this and other resource-restricted regions. US NIH/NIAID U01AI115520.


Globalization's effects on world agricultural trade, 1960-2050.
Recent globalization has been characterized by a decline in the costs of cross-border trade in farm and other products. It has been driven primarily by the information and communication technology revolution and-in the case of farm products-by reductions in governmental distortions to agricultural production, consumption and trade. Both have boosted economic growth and reduced poverty globally, especially in Asia. The first but maybe not the second of these drivers will continue in coming decades. World food prices will depend also on whether (and if so by how much) farm productivity growth continues to outpace demand growth and to what extent diets in emerging economies move towards livestock and horticultural products at the expense of staples. Demand in turn will be driven not only by population and income growth, but also by crude oil prices if they remain at current historically high levels, since that will affect biofuel demand. Climate change mitigation policies and adaptation, water market developments and market access standards particularly for transgenic foods will add to future production, price and trade uncertainties.


Structural basis for adenylate kinase activity in ABC ATPases.
ATP-binding cassette (ABC) enzymes are involved in diverse biological processes ranging from transmembrane transport to chromosome cohesion and DNA repair. They typically use ATP hydrolysis to conduct energy-dependent biological reactions. However, the cystic fibrosis transmembrane conductance regulator and the DNA repair protein Rad50 can also catalyze the adenylate kinase reaction (ATP+AMP<-->2ADP). To clarify and provide a mechanistic basis for the adenylate kinase activity of ABC enzymes, we report the crystal structure of the nucleotide-binding domain of the Pyrococcus furiosus structural maintenance of chromosome protein (pfSMC(nbd)) in complex with the adenylate kinase inhibitor P(1),P(5)-di(adenosine-5')pentaphosphate. We show that pfSMC(nbd) possesses reverse adenylate kinase activity. Our results suggest that in adenylate kinase reactions, ATP binds to its canonical binding site while AMP binds to the Q-loop glutamine and a hydration water of the Mg(2+) ion. Furthermore, mutational analysis indicates that adenylate kinase reaction occurs in the engaged pfSMC(nbd) dimer and requires the Signature motif for phosphate transfer. Our results explain how ATP hydrolysis and adenylate kinase reactions can be catalyzed by the same functional motifs within the structural framework of ABC enzymes. Thus, adenylate kinase activity is likely to be a latent activity in many ABC enzymes.


Contour length and refolding rate of a small protein controlled by engineered disulfide bonds.
The introduction of disulfide bonds into proteins creates additional mechanical barriers and limits the unfolded contour length (i.e., the maximal extension) measured by single-molecule force spectroscopy. Here, we engineer single disulfide bonds into four different locations of the human cardiac titin module (I27) to control the contour length while keeping the distance to the transition state unchanged. This enables the study of several biologically important parameters. First, we are able to precisely determine the end-to-end length of the transition state before unfolding (53 Angstrom), which is longer than the end-to-end length of the protein obtained from NMR spectroscopy (43 Angstrom). Second, the measured contour length per amino acid from five different methods (4.0 +/- 0.2 Angstrom) is longer than the end-to-end length obtained from the crystal structure (3.6 Angstrom). Our measurement of the contour length takes into account all the internal degrees of freedom of the polypeptide chain, whereas crystallography measures the end-to-end length within the "frozen" protein structure. Furthermore, the control of contour length and therefore the number of amino acids unraveled before reaching the disulfide bond (n) facilitates the test of the chain length dependence on the folding time (tau(F)). We find that both a power law scaling tau(F) lambda n(lambda) with lambda = 4.4, and an exponential scaling with n(0.6) fit the data range, in support of different protein-folding scenarios.


The tachykinins substance P and hemokinin-1 favor the generation of human memory Th17 cells by inducing IL-1β, IL-23, and TNF-like 1A expression by monocytes.
The nervous system influences immune responses through the release of neural factors such as neuropeptides. Among them, the tachykinin substance P (SP) signals via the neurokinin 1 receptor (NK-1R), which is expressed by various immune cells. We thereby analyzed in this paper whether tachykinins may participate in human CD4(+) Th cell polarization. We report that SP and hemokinin-1 (HK-1) upregulate IL-17A and IFN-γ production by human memory CD4(+) T cells without affecting IL-4 and IL-10 production. SP and HK-1 switch non-Th17-committed CD4(+) memory T cells into bona fide Th17 cells and Th1/Th17 cells. In contrast, SP and HK-1 do not modulate the polarization of naive CD4(+) T cells. SP- and HK-1-induced Th17 cell generation is mediated through NK-1R and requires the presence of monocytes. SP and HK-1 trigger IL-1β, IL-6, and TNF-α production, upregulate IL-23 production, and enhance TNF-like 1A expression on monocyte surface. Neutralization experiments demonstrated that IL-1β, IL-23, and TNF-like 1A are involved in the SP- and HK-1-induced Th17 cell. The other members of the tachykinin family, neurokinins A and B, have no effect on the differentiation of naive and memory T cells. These results thereby show that SP and HK-1 are novel Th17 cell-inducing factors that may act locally on memory T cells to amplify inflammatory responses.


The clinical significance of Psoriasin for non-small cell lung cancer patients and its biological impact on lung cancer cell functions.
Psoriasin (S100A7) is a member of the S100 gene family. Alteration of Psoriasin expression has previously been reported to play an important role in cancer aggressive behaviour. The current study sought to investigate the level of Psoriasin expression at the mRNA level in a cohort of patients with non-small cell lung cancer (NSCLC), the association with clinical implication and outcomes, and the molecular and cellular impact of the protein on lung cancer cells. Fresh frozen NSCLC cell carcinoma tissues, along with matched normal tissues were obtained from 83 NSCLC patients who received curative resection from January 2003 to December 2011. The expression of Psoriasin in the NSCLC specimens was assessed using both quantitative real time PCR (QPCR) and immunochemical staining. Knockdown and forced expression of Psoriasin in NSCLC cell lines were carried out using constructed plasmid vectors carrying either ribozyme transgenes targeting human Psoriasin or full-length coding sequence, respectively. The effect of Psoriasin on the functions of NSCLC cells was determined using a variety of in vitro cell function assays. Higher mRNA levels of Psoriasin were observed in tumour tissues when compared to both the paired normal background tissues and none paired normal tissues (p = 0.0251 and 0.0195). The mRNA level of Psoriasin was found to be higher in the squamous carcinoma (P=0.035). Higher Psoriasin expression is associated with poor prognosis. The cell function tests had supportive results to the clinical findings. Over-expression of Posriasin in lung cancer cells (SK-MES-1) resulted in an increase in in vitro growth and invasiveness. In contrast, Psoriasin knockdown suppressed cell growth and invasion (P<0.05), but increased cell adhesion (P<0.05). Psoriasin expression is increased in lung cancer, more specifically in lung squamous carcinoma compared with adenocarcinoma, and is associated with poor prognosis. Psoriasin plays crucial roles in regulating the growth and invasion of lung cancer cells.


Extracellular vesicles from early stage Plasmodium falciparum-infected red blood cells contain PfEMP1 and induce transcriptional changes in human monocytes.
Pathogens can release extracellular vesicles (EVs) for cell-cell communication and host modulation. EVs from Plasmodium falciparum, the deadliest malaria parasite species, can transfer drug resistance genes between parasites. EVs from late-stage parasite-infected RBC (iRBC-EVs) are immunostimulatory and affect endothelial cell permeability, but little is known about EVs from early stage iRBC. We detected the parasite virulence factor PfEMP1, which is responsible for iRBC adherence and a major contributor to disease severity, in EVs, only up to 12-hr post-RBC invasion. Furthermore, using PfEMP1 transport knockout parasites, we determined that EVs originated from inside the iRBC rather than the iRBC surface. Proteomic analysis detected 101 parasite and 178 human proteins in iRBC-EVs. Primary human monocytes stimulated with iRBC-EVs released low levels of inflammatory cytokines and showed transcriptomic changes. Stimulation with iRBC-EVs from PfEMP1 knockout parasites induced more gene expression changes and affected pathways involved in defence response, stress response, and response to cytokines, suggesting a novel function of PfEMP1 when present in EVs. We show for the first time the presence of PfEMP1 in early stage P. falciparum iRBC-EVs and the effects of these EVs on primary human monocytes, uncovering a new mechanism of potential parasite pathogenesis and host interaction.


Simplification and Saving.
The daunting complexity of important financial decisions can lead to procrastination. We evaluate a low-cost intervention that substantially simplifies the retirement savings plan participation decision. Individuals received an opportunity to enroll in a retirement savings plan at a pre-selected contribution rate and asset allocation, allowing them to collapse a multidimensional problem into a binary choice between the status quo and the pre-selected alternative. The intervention increases plan enrollment rates by 10 to 20 percentage points. We find that a similar intervention can be used to increase contribution rates among employees who are already participating in a savings plan.


The XTH family of enzymes involved in xyloglucan endotransglucosylation and endohydrolysis: current perspectives and a new unifying nomenclature.
The polysaccharide xyloglucan is thought to play an important structural role in the primary cell wall of dicotyledons. Accordingly, there is considerable interest in understanding the biochemical basis and regulation of xyloglucan metabolism, and research over the last 16 years has identified a large family of cell wall proteins that specifically catalyze xyloglucan endohydrolysis and/or endotransglucosylation. However, a confusing and contradictory series of nomenclatures has emerged in the literature, of which xyloglucan endotransglycosylases (XETs) and endoxyloglucan transferases (EXGTs) are just two examples, to describe members of essentially the same class of genes/proteins. The completion of the first plant genome sequencing projects has revealed the full extent of this gene family and so this is an opportune time to resolve the many discrepancies in the database that include different names being assigned to the same gene. Following consultation with members of the scientific community involved in plant cell wall research, we propose a new unifying nomenclature that conveys an accurate description of the spectrum of biochemical activities that cumulative research has shown are catalyzed by these enzymes. Thus, a member of this class of genes/proteins will be referred to as a xyloglucan endotransglucosylase/hydrolase (XTH). The two known activities of XTH proteins are referred to enzymologically as xyloglucan endotransglucosylase (XET, which is hereby re-defined) activity and xyloglucan endohydrolase (XEH) activity. This review provides a summary of the biochemical and functional diversity of XTHs, including an overview of the structure and organization of the Arabidopsis XTH gene family, and highlights the potentially important roles that XTHs appear to play in numerous examples of plant growth and development.


Physicians for the 21st century. Challenges facing medical education in the United States.
Since the 1980s, the American medical educational system has come under attack for its failure to train and prepare physicians for the challenges created by the changing health care market. The medical schools have been criticized for producing too many specialists and for not providing sufficient training in ethics and moral reasoning, care of the terminally ill, health care economics, alternative medicine, and the role of spiritual and religious values in healing. This study attempts to ascertain the extent to which medical schools have responded to these criticisms by changing their curriculum. The study is based on a survey of deans of medical schools in the United States. The study finds that medical schools have indeed responded to some of the criticisms by incorporating training in ethics, communication, primary and preventive care, and care of the terminally ill in their curriculum. However, the study concludes that more changes are needed to train physicians for the 21st century.


Functional regulatory T cells produced by inhibiting cyclic nucleotide phosphodiesterase type 3 prevent allograft rejection.
Regulatory T cells (T(regs)) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring T(regs), an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen-presenting cells (APCs) under conditions that lead to the generation or expansion of donor-reactive, adaptive T(regs). Here we demonstrate that stimulation of mouse CD4(+) T cells by immature allogeneic dendritic cells combined with pharmacological inhibition of phosphodiesterase 3 (PDE) resulted in a functional enrichment of Foxp3(+) T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4(+) effectors or donor-reactive CD8(+) T cell receptor transgenic T cells and inhibited both effector cell proliferation and T cell priming for interferon-γ production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3(+) CD4(+) T cells driven by allogeneic APCs. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and, moreover, attenuated the development of vasculopathy mediated by autologous peripheral blood mononuclear cells in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft-reactive, functional mouse and human T(regs) that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for T(reg)-based therapies.


Impact of Reducing Complement Inhibitor Binding on the Immunogenicity of Native Neisseria meningitidis Outer Membrane Vesicles.
Neisseria meningitidis recruits host human complement inhibitors to its surface to down-regulate complement activation and enhance survival in blood. We have investigated whether such complement inhibitor binding occurs after vaccination with native outer membrane vesicles (nOMVs), and limits immunogenicity of such vaccines. To this end, nOMVs reactogenic lipopolysaccharide was detoxified by deletion of the lpxl1 gene (nOMVlpxl1). nOMVs unable to bind human complement factor H (hfH) were generated by additional deletions of the genes encoding factor H binding protein (fHbp) and neisserial surface protein A (NspA) (nOMVdis). Antibody responses elicited in mice with nOMVdis were compared to those elicited with nOMVlpxl1 in the presence of hfH. Results demonstrate that the administration of human fH to mice immunized with fHbp containing OMVlpxl1 decreased immunogenicity against fHbp (but not against the OMV as a whole). The majority of the OMV-induced bactericidal immune response (OMVlpxl1 or OMVdis) was versus PorA. Despite a considerable reduction of hfH binding to nOMVdis, and the absence of the vaccine antigen fHbp, immunogenicity in mice was not different from nOMVlpxl1, in the absence or presence of hfH (serum bactericidal titers of 1:64 vs 1:128 after one dose in the nOMVdis and nOMVlpxl1-immunized groups respectively). Therefore, partial inhibition of fH binding did not enhance immunity in this model.


Liposome entrapment enhances the hypocalcemic action of parenterally administered calcitonin.
The hypocalcemic effect of liposomal-entrapped calcitonin (CT) was evaluated in rats. Salmon CT and human CT were entrapped in liposomes composed of egg phosphatidylcholine with or without an equimolar amount of cholesterol. The liposomes were separated by Sepharose 4B chromatography into fractions consisting of large multilamellar vesicles and small unilamellar vesicles. The incorporation of CT was monitored by counting [125I]CT and by specific RIA. Liposomal entrapment enhanced the hypocalcemic potency of parenterally administered salmon CT and human CT. After iv administration, the large multilamellar vesicles were more potent than small unilamellar vesicles in their hypocalcemic effect; cholesterol inclusion in the MLV liposome preparation prolonged the hypocalcemia. However, with im administration, the cholesterol-free liposomes were more potent than their cholesterol-containing counterparts regardless of size. These studies demonstrate that liposomal entrapment can be used to enhance the hypocalcemic potency of CT. It appears that both the size and composition of the liposome preparation are important in this effect, as is the route of administration. It may be possible to produce liposome-CT preparations with advantageous pharmacological characteristics.


Critical body residues, Michaelis-Menten analysis of bioaccumulation, lethality and behaviour as endpoints of waterborne Ni toxicity in two teleosts.
Traditionally, water quality guidelines/criteria are based on lethality tests where results are expressed as a function of waterborne concentrations (e.g. LC50). However, there is growing interest in the use of uptake and binding relationships, such as biotic ligand models (BLM), and in bioaccumulation parameters, such as critical body residue values (e.g. CBR50), to predict metal toxicity in aquatic organisms. Nevertheless, all these approaches only protect species against physiological death (e.g. mortality, failed recruitment), and do not consider ecological death which can occur at much lower concentrations when the animal cannot perform normal behaviours essential for survival. Therefore, we investigated acute (96 h) Ni toxicity in two freshwater fish species, the round goby (Neogobius melanostomus) and rainbow trout (Oncorhynchus mykiss) and compared LC, BLM, and CBR parameters for various organs, as well as behavioural responses (spontaneous activity). In general, round goby were more sensitive. Ni bioaccumulation displayed Michaelis-Menten kinetics in most tissues, and round goby gills had lower Kd (higher binding affinity) but similar Bmax (binding site density) values relative to rainbow trout gills. Round goby also accumulated more Ni than did trout in most tissues at a given exposure concentration. Organ-specific 96 h acute CBR values tended to be higher in round goby but 96 h acute CBR50 and CBR10 values in the gills were very similar in the two species. In contrast, LC50 and LC10 values were significantly higher in rainbow trout. With respect to BLM parameters, gill log KNiBL values for bioaccumulation were higher by 0.4-0.8 log units than the log KNiBL values for toxicity in both species, and both values were higher in goby (more sensitive). Round goby were also more sensitive with respect to the behavioural response, exhibiting a significant decline of 63-75 % in movements per minute at Ni concentrations at and above only 8 % of the LC50 value; trout exhibited no clear behavioural response. Across species, diverse behavioral responses may be more closely related to tissue Ni burdens than to waterborne Ni concentrations. To our knowledge, this is the first study to link Ni bioaccumulation with behavioural endpoints. In future it would be beneficial to expand these analyses to a wider range of species to determine whether Ni bioaccumulation, specifically in the gills, gut and whole fish, may be a good predictor of behavioural changes from metal exposure; which in the wild can lead to ecological death.


Reduction of IL-12 p40 production in activated monocytes after exposure to diesel exhaust particles.
A reduction of IL-12 production by lung macrophages may partly explain the presumed adjuvant effect of diesel exhaust particles (DEP) in allergy and asthma. IL-12 stimulates T helper type 1 (Th1) lymphocytes, which inhibit Th2 cells via Th1-specific cytokines. The aim of this study was to investigate the influence of DEP on the production of IL-12 p40 in lipopolysaccharide (LPS)-activated monocytes. The human monocytic cell line Mono-Mac-6 was stimulated with LPS (200 ng/ml) and grown with DEP (0-200 microg/ml) for 0, 6 or 24 h. IL-12 p40 and the pro-inflammatory cytokine TNF were analysed in the cell supernatants by ELISA and a cell assay, respectively. Levels of IL-12 p40 correlated inversely with the DEP exposure concentrations, whereas TNF increased in parallel to the DEP concentrations. At a DEP concentration of 200 microg/ml, the amount of IL-12 p40 was 35% of that observed without DEP. The corresponding TNF value was 230% of the control. Reduced viability, binding of cytokines to DEP or endotoxin in the DEP samples cannot fully explain the changes in the concentrations of these two cytokines. DEP seem to inhibit the production of IL-12 p40 and stimulate that of TNF in activated monocytes. This may partly explain the presumed adjuvant effect of DEP in atopy; by altering the Th1/Th2 balance via down-regulation of IL-12, the Th2 response characteristic of allergy and asthma may be favoured.


Analgesic drug use and risk of ovarian cancer.
Previous epidemiologic research suggests that analgesic use may reduce the risk of ovarian cancer, although results are not consistent. In a population-based, case-control study, we analyzed data from 586 ovarian cancer cases and 627 matched controls in North Carolina for the relationship between analgesic use and ovarian cancer risk. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for potential confounders. Use of any nonsteroidal antiinflammatory drugs, including aspirin, within 5 years of diagnosis/interview was found to be associated with a reduction in the risk of ovarian cancer (adjusted OR = 0.72; 95% CI = 0.56-0.92). For use of acetaminophen, the OR was 0.78 (95% CI = 0.56-1.08). These data support an inverse relationship between the use of both nonsteroidal antiinflammatory drugs and acetaminophen and the risk of ovarian cancer.


Real science at the petascale.
We describe computational science research that uses petascale resources to achieve scientific results at unprecedented scales and resolution. The applications span a wide range of domains, from investigation of fundamental problems in turbulence through computational materials science research to biomedical applications at the forefront of HIV/AIDS research and cerebrovascular haemodynamics. This work was mainly performed on the US TeraGrid 'petascale' resource, Ranger, at Texas Advanced Computing Center, in the first half of 2008 when it was the largest computing system in the world available for open scientific research. We have sought to use this petascale supercomputer optimally across application domains and scales, exploiting the excellent parallel scaling performance found on up to at least 32 768 cores for certain of our codes in the so-called 'capability computing' category as well as high-throughput intermediate-scale jobs for ensemble simulations in the 32-512 core range. Furthermore, this activity provides evidence that conventional parallel programming with MPI should be successful at the petascale in the short to medium term. We also report on the parallel performance of some of our codes on up to 65 636 cores on the IBM Blue Gene/P system at the Argonne Leadership Computing Facility, which has recently been named the fastest supercomputer in the world for open science.


A novel method of transcriptional response analysis to facilitate drug repositioning for cancer therapy.
Little research has been done to address the huge opportunities that may exist to reposition existing approved or generic drugs for alternate uses in cancer therapy. In addition, there has been little work on strategies to reposition experimental cancer agents for testing in alternate settings that could shorten their clinical development time. Progress in each area has lagged, in part, because of the lack of systematic methods to define drug off-target effects (OTE) that might affect important cancer cell signaling pathways. In this study, we addressed this critical gap by developing an OTE-based method to repurpose drugs for cancer therapeutics, based on transcriptional responses made in cells before and after drug treatment. Specifically, we defined a new network component called cancer-signaling bridges (CSB) and integrated it with a Bayesian factor regression model (BFRM) to form a new hybrid method termed CSB-BFRM. Proof-of-concept studies were conducted in breast and prostate cancer cells and in promyelocytic leukemia cells. In each system, CSB-BFRM analysis could accurately predict clinical responses to more than 90% of drugs approved by the U.S. Food and Drug Administration and more than 75% of experimental clinical drugs that were tested. Mechanistic investigation of OTEs for several high-ranking drug-dose pairs suggested repositioning opportunities for cancer therapy, based on the ability to enforce retinoblastoma-dependent repression of important E2F-dependent cell-cycle genes. Together, our findings establish new methods to identify opportunities for drug repositioning or to elucidate the mechanisms of action of repositioned drugs.


Inhibition of protein-tyrosine phosphatases by mild oxidative stresses is dependent on S-nitrosylation.
Previous studies have shown that a Ca(2+)-dependent nitric-oxide synthase (NOS) is activated as part of a cellular response to low doses of ionizing radiation. Genetic and pharmacological inhibitor studies linked this NO signaling to the radiation-induced activation of ERK1/2. Herein, a mechanism for the radiation-induced activation of Tyr phosphorylation-dependent pathways (e.g. ERK1/2) involving the inhibition of protein-Tyr phosphatases (PTPs) by S-nitrosylation is tested. The basis for this mechanism resides in the redox-sensitive active site Cys in PTPs. These studies also examined oxidative stress induced by low concentrations of H(2)O(2). S-Nitrosylation of total cellular PTP and immunopurified SHP-1 and SHP-2 was detected as protection of PTP enzymatic activity from alkylation by N-ethylmaleimide and reversal by ascorbate. Both radiation and H(2)O(2) protected PTP activity from alkylation by a mechanism reversible by ascorbate and inhibited by NOS inhibitors or expression of a dominant negative mutant of NOS-1. Radiation and H(2)O(2) stimulated a transient increase in cytoplasmic free [Ca(2+)]. Radiation, H(2)O(2), and the Ca(2+) ionophore, ionomycin, also stimulated NOS activity, and this was associated with an enhanced S-nitrosylation of the active site Cys(453) determined by isolation of S-nitrosylated wild type but not active site Cys(453) --> Ser SHP-1 mutant by the "biotin-switch" method. Thus, one consequence of oxidative stimulation of NO generation is S-nitrosylation and inhibition of PTPs critical in cellular signal transduction pathways. These results support the conclusion that a mild oxidative signal is converted to a nitrosative one due to the better redox signaling properties of NO.


A potent specific pure antiestrogen with clinical potential.
Previous studies from this laboratory have described a series of 7 alpha-alkylamide analogues of estradiol with pure antiestrogenic activity, exemplified by ICI 164,384. A new compound, 7 alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)nonyl]estra-1,3,5(10 )- triene-3,17 beta-diol (ICI 182,780) has now been identified which has significantly increased antiestrogenic potency and retains pure estrogen antagonist activity. The antiuterotrophic potency of ICI 182,780 in the immature rat was more than 10-fold greater than that of ICI 164,384 (50% effective doses of 0.06 and 0.9 mg/kg, respectively). This order of magnitude increase of in vivo potency was also reflected, in part, by intrinsic activity at the estrogen receptor. The relative binding affinities of ICI 182,780 and ICI 164,384 were 0.89 and 0.19, respectively, compared with that of estradiol (1.0). Similarly, the in vitro growth-inhibitory potency of ICI 182,780 exceeded that of ICI 164,384 in MCF-7 human breast cancer cells, where 50% inhibitory concentrations of 0.29 and 1.3 nM, respectively, were recorded. ICI 182,780 was a more effective inhibitor of MCF-7 growth than 4'-hydroxytamoxifen, producing an 80% reduction of cell number under conditions where 4'-hydroxytamoxifen achieved a maximum of 50% inhibition. This increased efficacy was reflected by a greater reduction of the proportion of cells engaged in DNA synthesis in ICI 182,780-treated cell cultures compared with tamoxifen-treated cells. Sustained antiestrogenic effects, following a single parenteral dose of ICI 182,780 in oil suspension, were apparent in both rats and pigtail monkeys. In vivo, antitumor activity of ICI 182,780 was demonstrated with xenografts of MCF-7 and Br10 human breast cancers in nude mice. A single injection of ICI 182,780 provided antitumor efficacy equivalent to that of daily tamoxifen treatment for at least 4 weeks. The properties of ICI 182,780 identify this pure antiestrogen as a prime candidate with which to evaluate the potential therapeutic benefits of complete estrogen withdrawal in endocrine-responsive human breast cancer.


Adaptive evolution and effective population size in wild house mice.
Estimates of the proportion of amino acid substitutions that have been fixed by selection (α) vary widely among taxa, ranging from zero in humans to over 50% in Drosophila. This wide range may reflect differences in the efficacy of selection due to differences in the effective population size (N(e)). However, most comparisons have been made among distantly related organisms that differ not only in N(e) but also in many other aspects of their biology. Here, we estimate α in three closely related lineages of house mice that have a similar ecology but differ widely in N(e): Mus musculus musculus (N(e) ∼ 25,000-120,000), M. m. domesticus (N(e) ∼ 58,000-200,000), and M. m. castaneus (N(e) ∼ 200,000-733,000). Mice were genotyped using a high-density single nucleotide polymorphism array, and the proportions of replacement and silent mutations within subspecies were compared with those fixed between each subspecies and an outgroup, Mus spretus. There was significant evidence of positive selection in M. m. castaneus, the lineage with the largest N(e), with α estimated to be approximately 40%. In contrast, estimates of α for M. m. domesticus (α = 13%) and for M. m. musculus (α = 12 %) were much smaller. Interestingly, the higher estimate of α for M. m. castaneus appears to reflect not only more adaptive fixations but also more effective purifying selection. These results support the hypothesis that differences in N(e) contribute to differences among species in the efficacy of selection.


Exciton polaritons confined in a ZnO nanowire cavity.
Semiconductor nanowires of high purity and crystallinity hold promise as building blocks for miniaturized optoelectrical devices. Using scanning-excitation single-wire emission spectroscopy, with either a laser or an electron beam as a spatially resolved excitation source, we observe standing-wave exciton polaritons in ZnO nanowires at room temperature. The Rabi splitting between the polariton branches is more than 100 meV. The dispersion curve of the modes in the nanowire is substantially modified due to light-matter interaction. This finding forms a key aspect in understanding subwavelength guiding in these nanowires.


Forearm endurance training attenuates sympathetic nerve response to isometric handgrip in normal humans.
Recent evidence indicates that muscle ischemia and activation of the muscle chemoreflex are the principal stimuli to sympathetic nerve activity (SNA) during isometric exercise. We postulated that physical training would decrease muscle chemoreflex stimulation during isometric exercise and thereby attenuate the SNA response to exercise. We investigated the effects of 6 wk of unilateral handgrip endurance training on the responses to isometric handgrip (IHG: 33% of maximal voluntary contraction maintained for 2 min). In eight normal subjects the right arm underwent exercise training and the left arm sham training. We measured muscle SNA (peroneal nerve), heart rate, and blood pressure during IHG before vs. after endurance training (right arm) and sham training (left arm). Maximum work to fatigue (an index of training efficacy) was increased by 1,146% in the endurance-trained arm and by only 40% in the sham-trained arm. During isometric exercise of the right arm, SNA increased by 111 +/- 27% (SE) before training and by only 38 +/- 9% after training (P less than 0.05). Endurance training did not significantly affect the heart rate and blood pressure responses to IHG. We also measured the SNA response to 2 min of forearm ischemia after IHG in five subjects. Endurance training also attenuated the SNA response to postexercise forearm ischemia (P = 0.057). Sham training did not significantly affect the SNA responses to IHG or forearm ischemia. We conclude that endurance training decreases muscle chemoreflex stimulation during isometric exercise and thereby attenuates the sympathetic nerve response to IHG.


Nerve growth factor induces rapid increases in functional cell surface low density lipoprotein receptor-related protein.
The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that binds multiple ligands and is highly expressed in neurons. Several LRP ligands, including apolipoprotein E/lipoproteins and amyloid precursor protein, have been shown to participate either in Alzheimer's disease pathogenesis or pathology. However, factors that regulate LRP expression in neurons are unknown. In the current study, we analyzed the effects of nerve growth factor (NGF) treatment on LRP expression, distribution, and function within neurons in two neuronal cell lines. Our results show that NGF induces a rapid increase of cell surface LRP expression in a central nervous system-derived neuronal cell line, GT1-1 Trk, which was seen within 10 min and reached a maximum at about 1 h of NGF treatment. This increase of cell surface LRP expression is concomitant with an increase in the endocytic activity of LRP as measured via ligand uptake and degradation assays. We also found that the cytoplasmic tail of LRP is phosphorylated and that NGF rapidly increases the amount of phosphorylation. Furthermore, we detected a significant increase of LRP expression at the messenger RNA level following 24 h of NGF treatment. Both rapid and long term induction of LRP expression were also detected in peripheral nervous system-derived PC12 cells following NGF treatment. Taken together, our results demonstrate that NGF regulates LRP expression in neuronal cells.


Affective medicine: technology with emotional intelligence.
For a long time people have kept emotions out of the deliberate tools of medicine and science; scientists, physicians, and patients have often felt and sometimes expressed emotion, but no tools could sense, measure, and respond to their affective information. A series of recent studies indicates that emotions, particularly stress, anger, and depression, are important factors with serious and significant implications for health. This paper highlights research at the MIT Media Lab aimed at giving computers the ability to comfortably sense, recognize, and respond to certain aspects of human emotion, especially affective states such as frustration, confusion, interest, stress, anger, and joy. Examples of recently developed systems are shown, including computer systems that are wearable and computers that respond to people with a kind of active listening, empathy, and sympathy. Results are reported for computer recognition of emotion, for teaching affective skills to autistics, and for having computers help users manage emotions such as frustration.


Idiopathic chronic ulcerative enteritis with perforation and recurrent bleeding: a case report.
Idiopathic chronic ulcerative enteritis (ICUE) is a distinct entity without a defined etiology and is rarely seen in the clinic. Patients with ICUE mainly present with insidious abdominal symptoms such as chronic abdominal pain and intermittent gastrointestinal hemorrhage and symptoms of malnourishment in the early stages of the disease. ICUE is always difficult to diagnose. However, as the disease progresses, patients have a variety of acute abdominal complications such as hemorrhage, perforation, or ileus. Surgical intervention is always needed, and the condition can recur and require repeat laparotomy. When diffuse ulceration of the small bowel is present in the absence of recognizable causes, it is classified as nonspecific or idiopathic. The histological examination always demonstrates an acute, chronic inflammatory infiltration without giant cells, granulomas, or villous atrophy. The etiology of ICUE has not been identified, and its pathogenesis is poorly understood; therefore, radical surgical resection is considered the best available treatment. Here, we report a case of ICUE characterized by nonspecific, multiple, small intestinal ulcers resulting in perforation and recurrent bleeding. The differential diagnosis and the treatment are also discussed.


Preclinical evaluation of ultrasound-augmented needle navigation for laparoscopic liver ablation.
For laparoscopic ablation to be successful, accurate placement of the needle to the tumor is essential. Laparoscopic ultrasound is an essential tool to guide needle placement, but the ultrasound image is generally presented separately from the laparoscopic image. We aim to evaluate an augmented reality (AR) system which combines laparoscopic ultrasound image, laparoscope video, and the needle trajectory in a unified view. We created a tissue phantom made of gelatin. Artificial tumors represented by plastic spheres were secured in the gelatin at various depths. The top point of the sphere surface was our target, and its 3D coordinates were known. The participants were invited to perform needle placement with and without AR guidance. Once the participant reported that the needle tip had reached the target, the needle tip location was recorded and compared to the ground truth location of the target, and the difference was the target localization error (TLE). The time of the needle placement was also recorded. We further tested the technical feasibility of the AR system in vivo on a 40-kg swine. The AR guidance system was evaluated by two experienced surgeons and two surgical fellows. The users performed needle placement on a total of 26 targets, 13 with AR and 13 without (i.e., the conventional approach). The average TLE for the conventional and the AR approaches was 14.9 mm and 11.1 mm, respectively. The average needle placement time needed for the conventional and AR approaches was 59.4 s and 22.9 s, respectively. For the animal study, ultrasound image and needle trajectory were successfully fused with the laparoscopic video in real time and presented on a single screen for the surgeons. By providing projected needle trajectory, we believe our AR system can assist the surgeon with more efficient and precise needle placement.


Cerebral function revealed by transcranial magnetic stimulation.
Although transcranial magnetic stimulation (TMS) has been introduced only recently, it is safe and provides a painless, inexpensive noninvasive method for the evaluation of brain function. Determining central motor conduction time (CMCT) permits assessment of the corticospinal pathways. Mapping the central representation of muscles provides a method for investigating the cortical reorganization that follows training, amputation and injury to the central nervous system. Such studies of human plasticity may have important implications for neurorehabilitation. TMS also provides a method whereby cortical excitability can be noninvasively evaluated, which is likely to have important implications in the study of epilepsy, movement disorders and related conditions. TMS is useful in tracking the flow of information from one brain region to another and in investigations of cognition and functional localization, thereby complementing information obtained using functional imaging techniques, which have superior spatial but inferior temporal resolution. Finally, TMS is currently being investigated as a method for establishing cerebral dominance and as a therapeutic tool in the treatment of depression. Investigations for treatment of other neurologic and psychiatric conditions are likely to be undertaken.


Judgments of pain in the neonatal intensive care setting: a survey of direct care staffs' perceptions of pain in infants at risk for neurological impairment.
To determine whether healthcare professionals believe the pain of infants at risk for neurologic impairment differs from that of typical infants. Neonatal intensive care units at 2 tertiary pediatric centers in Canada. Ninety-nine healthcare professionals who practice in the neonatal intensive care unit (51 nurses, 19 physicians, 18 respiratory therapists, 11 other). MAJOR MEASURES: Participants completed the Pain Opinion Questionnaire. It elicits beliefs regarding the similarity of the pain experienced by infants at mild, moderate, and severe risk for neurologic impairment relative to those without risk for neurologic impairment along 5 pain facets (ie, sensation, emotional reaction, behavioral reaction, communication, incidence). Pain Opinion Questionnaire scores varied by level of risk of neurologic impairment (mild, moderate, severe) and pain facet. Respondents believed infants with risk were overall less likely to experience pain similar to infants without risk as the level of risk increased [F(2,97) = 66.0, P < 0.001] and were more likely to have a reduced pain experience relative to infants without risk as the level of risk increased [F(2,97) = 62.2, P < 0.001]. Pain Opinion Questionnaire scores did not vary due to profession, experience, gender, or age. Professionals expressed the belief that neurologically impaired infants' pain experience is reduced, relative to infants without impairment, as their level of risk for neurologic impairment increases. This belief did not vary due to professional experience or personal factors. Future studies should investigate the source of these beliefs and their impact on the pain management provided to infants with risk for neurologic impairment.


Branched-chain amino acid enriched supplements as therapy for liver disease.
Altered amino acid metabolism is a hallmark of liver disease, characterized by low levels of circulating BCAAs and elevated levels of circulating aromatic amino acids, and methionine. Although overwhelming evidence indicates that the incidence of complications of liver disease increases with malnutrition, the reported impact of nutritional therapy, specifically BCAA supplementation, on outcomes in patients with liver disease has varied with the indication. Multiple small studies report the beneficial effects of BCAA supplementation, including improved metabolic profiles, as measured by protein sparing and/or normalization of respiratory quotients and clinical improvement of hepatic encephalopathy. Other studies have failed to show a clinical benefit of BCAA supplementation. The data concerning the impact of BCAA supplementation in prophylaxis of long-term morbidity and mortality in patients with cirrhosis is more promising and has been the subject of 2, large randomized controlled trials. In a study of 174 patients with advanced cirrhosis, who were randomized to either BCAA or 1 of 2 control arms, the combined event rates were seen to be significantly reduced in the BCAA supplementation arm, although this was not true for individual complications. In a more recent, larger, randomized controlled trial (n = 646) using a more palatable formulation, investigators demonstrated that long-term BCAA supplementation is associated with decreased frequency of hepatic failure and overall complication frequency. Both studies found improved nutritional status associated with BCAA supplementation. On balance, BCAA supplementation appears to be associated with decreased frequency of complications of cirrhosis and improved nutritional status when prescribed as maintenance therapy. Cost and palatability may limit the potential applicability of this treatment modality.


Flood-deposited wood debris and its contribution to heterogeneity and regeneration in a semi-arid riparian landscape.
We investigated whether large woody debris (LWD) piles create nodes of environmental resources that contribute to the recovery of riparian vegetation and that also augment the heterogeneity and resilience of the riverine system. River and riparian systems are typified by a large degree of heterogeneity and complex interactions between abiotic and biotic elements. Disturbance such as floods re-distribute the resources, such as LWD, and thereby add greater complexity to the system. We examined this issue on a semi-arid savanna river where approximately a 100-year return interval flood in 2000 uprooted vegetation and deposited substantial LWD. We investigated the micro-environment within the newly established LWD piles and compared this with conditions at adjacent reference sites containing no LWD. We found soil nutrient concentrations to be significantly higher in LWD piles compared with the reference plots (total N +19%, available P +51%, and total C +36%). Environmental variables within LWD piles and reference sites varied with landscape position in the river-riparian landscape and with LWD pile characteristics. Observed differences were generally between piles located in the terrestrial and riparian areas as compared to piles located on the macro-channel floor. After 3 years the number and cover of woody species were significantly higher when associated with LWD piles, regardless of landscape position or pile type. We conclude that LWD piles formed after large floods act as resource nodes by accumulating fine sediments and by retaining soil nutrients and soil moisture. The subsequent influence of LWD deposition on riparian heterogeneity is discerned at several spatial scales including within and between LWD piles, across landscape positions and between channel types. LWD piles substantially influence the initial developmental of riparian vegetation as the system regenerates following large destructive floods.


Bivariate whole-genome linkage scan for bone geometry and total body fat mass.
To quantify the genetic correlations between total body fat mass (TBFM) and femoral neck geometric parameters (FNGPs) and, if possible, to detect the specific genomic regions shared by them, bivariate genetic analysis and bivariate whole-genome linkage scan were carried out in a large Caucasian population. All the phenotypes studied were significantly controlled by genetic factors (P < 0.001) with the heritabilities ranging from 0.45 to 0.68. Significantly genetic correlations were found between TBFM and CSA (cross-section area), W (sub-periosteal diameter), Z (section modulus) and CT (cortical thickness) except between TBFM and BR (buckling ratio). The peak bivariate LOD scores were 3.23 (20q12), 2.47 (20p11), 3.19 (6q27), 1.68 (20p12), and 2.47 (7q11) for the five pairs of TBFM and BR, CSA, CT, W, and Z in the entire sample, respectively. Gender-specific bivariate linkage evidences were also found for the five pairs. 6p25 had complete pleiotropic effects on the variations of TBFM & Z in the female sub-population, and 6q27 and 17q11 had coincident linkages for TBFM & CSA and TBFM & Z in the entire population. We identified moderate genetic correlations and several shared genomic regions between TBFM and FNGPs in a large Caucasian population.


Host mediated inflammatory influence on glioblastoma multiforme recurrence following high-dose ionizing radiation.
Despite optimal clinical treatment, glioblastoma multiforme (GBM) inevitably recurs. Standard treatment of GBM, exposes patients to radiation which kills tumor cells, but also modulates the molecular fingerprint of any surviving tumor cells and the cross-talk between those cells and the host. Considerable investigation of short-term (hours to days) post-irradiation tumor cell response has been undertaken, yet long-term responses (weeks to months) which are potentially even more informative of recurrence, have been largely overlooked. To better understand the potential of these processes to reshape tumor regrowth, molecular studies in conjunction with in silico modeling were used to examine short- and long-term growth dynamics. Despite survival of 2.55% and 0.009% following 8 or 16Gy, GBM cell populations in vitro showed a robust escape from cellular extinction and a return to pre-irradiated growth rates with no changes in long-term population doublings. In contrast, these same irradiated GBM cell populations injected in vivo elicited tumors which displayed significantly suppressed growth rates compared to their pre-irradiated counterparts. Transcriptome analysis days to weeks after irradiation revealed, 281 differentially expressed genes with a robust increase for cytokines, histones and C-C or C-X-C motif chemokines in irradiated cells. Strikingly, this same inflammatory signature in vivo for IL1A, CXCL1, IL6 and IL8 was increased in xenografts months after irradiation. Computational modeling of tumor cell dynamics indicated a host-mediated negative pressure on the surviving cells was a source of inhibition consistent with the findings resulting in suppressed tumor growth. Thus, tumor cells surviving irradiation may shift the landscape of population doubling through inflammatory mediators interacting with the host in a way that impacts tumor recurrence and affects the efficacy of subsequent therapies. Clues to more effective therapies may lie in the development and use of pre-clinical models of post-treatment response to target the source of inflammatory mediators that significantly alter cellular dynamics and molecular pathways in the early stages of tumor recurrence.


GlycoMob: an ion mobility-mass spectrometry collision cross section database for glycomics.
Ion mobility mass spectrometry (IM-MS) is a promising analytical technique for glycomics that separates glycan ions based on their collision cross section (CCS) and provides glycan precursor and fragment masses. It has been shown that isomeric oligosaccharide species can be separated by IM and identified on basis of their CCS and fragmentation. These results indicate that adding CCSs information for glycans and glycan fragments to searchable databases and analysis pipelines will increase identification confidence and accuracy. We have developed a freely accessible database, GlycoMob ( http://www.glycomob.org ), containing over 900 CCSs values of glycans, oligosaccharide standards and their fragments that will be continually updated. We have measured the absolute CCSs of calibration standards, biologically derived and synthetic N-glycans ionized with various adducts in positive and negative mode or as protonated (positive ion) and deprotonated (negative ion) ions.


Chemical basis for minimal cognition.
We have developed a simple chemical system capable of self-movement in order to study the physicochemical origins of movement. We propose how this system may be useful in the study of minimal perception and cognition. The system consists simply of an oil droplet in an aqueous environment. A chemical reaction within the oil droplet induces an instability, the symmetry of the oil droplet breaks, and the droplet begins to move through the aqueous phase. The complement of physical phenomena that is then generated indicates the presence of feedback cycles that, as will be argued, form the basis for self-regulation, homeostasis, and perhaps an extended form of autopoiesis. We discuss the result that simple chemical systems are capable of sensory-motor coupling and possess a homeodynamic state from which cognitive processes may emerge.


Categorical Colormap Optimization with Visualization Case Studies.
Mapping a set of categorical values to different colors is an elementary technique in data visualization. Users of visualization software routinely rely on the default colormaps provided by a system, or colormaps suggested by software such as ColorBrewer. In practice, users often have to select a set of colors in a semantically meaningful way (e.g., based on conventions, color metaphors, and logological associations), and consequently would like to ensure their perceptual differentiation is optimized. In this paper, we present an algorithmic approach for maximizing the perceptual distances among a set of given colors. We address two technical problems in optimization, i.e., (i) the phenomena of local maxima that halt the optimization too soon, and (ii) the arbitrary reassignment of colors that leads to the loss of the original semantic association. We paid particular attention to different types of constraints that users may wish to impose during the optimization process. To demonstrate the effectiveness of this work, we tested this technique in two case studies. To reach out to a wider range of users, we also developed a web application called Colourmap Hospital.


Cloning and functional expression of dendrotoxin K from black mamba, a K+ channel blocker.
Mamba dendrotoxins, 7K M(r) polypeptides with three disulfide bonds, selectively inhibit certain fast-activating, voltage-sensitive neuronal K+ channels and have been instrumental in their identification, localization, and purification. However, derivatives with more refined specificity are essential to define the structural and functional properties of the multiple subtypes known to reside in the nervous system. Hence, utilizing a constructed cDNA library from the venom glands of the black mamba (Dendroaspis polylepis), the gene encoding dendrotoxin K was isolated, amplified, and expressed as a maltose-binding fusion protein in the periplasmic space of Escherichia coli. After cleavage of the chaperone from the affinity-purified product, a recombinant protein was isolated and shown to be identical to native dendrotoxin K in its N-terminal sequence, chromatographic behavior, convulsive-inducing activity, and binding to voltage-activated K+ channels in bovine synaptic membranes. This successful expression of refolded active toxin, in adequate yield, makes possible for the first time the preparation of mutants with specificity tailored for each K+ channel subtype, based both on the recently derived three-dimensional structure of alpha-dendrotoxin and the identified binding site on cloned K+ channels.


Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report.
Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. Finally, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.


A transcranial direct current stimulation over the sensorimotor cortex modulates the itch sensation induced by histamine.
Itching can be suppressed by scratching. However, scratching may aggravate itch symptoms by damaging the skin. Therefore, identifying an alternative approach to suppress itching is of clinical importance. The aim of the present study was to determine whether a transcranial direct current stimulation (tDCS) was useful for itch relief. The present study was performed on a double-blind, Sham-controlled, and cross-over experimental design. A histamine-induced itch was evoked on the left dorsal forearms of healthy participants, who were asked to report the subjective sensation of itching every 30s for 23 min. tDCS was applied over the sensorimotor cortex (SMC) according to a bi-hemispheric stimulation protocol during the itch stimuli; one electrode was placed over the right SMC, while the other was placed over the left SMC. The peak and lasting sensations of itching were compared between R-A/L-C (anodal electrode placed over the right and cathodal electrode over the left), L-A/R-C (anodal electrode placed over the left and cathodal electrode over the right), and Sham interventions. The peak and lasting itch sensation were significantly suppressed during the R-A/L-C intervention than during the Sham intervention. On the other hand, the L-A/R-C intervention suppressed the peak itch sensation, but the effects did not last for more than a few minutes. These results suggest that a bi-hemispheric tDCS intervention, especially when the anodal electrode was placed over the SMC of the contralateral side, was a potentially useful method for relieving lasting itch sensations. The present study demonstrated that a tDCS intervention may be an alternative approach for suppressing unpleasant itch sensations in healthy participants. Since tDCS has some advantages, namely, its easy application and safety in a clinical setting, it may become a useful method for the treatment of itching.


Differential expression of the topoisomerase II alpha and beta genes in human breast cancers.
Topoisomerase II is a key target for several anti-cancer drugs used for breast cancer therapy, including doxorubicin, epirubicin and mitoxantrone. Two isoforms of topoisomerase II (alpha and beta) have been described in human cells which differ in their subcellular localisation, biochemical properties and susceptibility to inhibition by anti-cancer drugs. The relative level of expression of the alpha and beta isoforms may contribute to the degree of tumour responsiveness to different chemotherapeutic agents. To assess the relationship between expression of topoisomerase II isoforms and established prognostic factors and pathological variables, 56 primary breast tumour samples were studied. The expression of the two topoisomerase II genes was apparently not co-ordinately regulated in these tissue samples. There was no relationship between any of the commonly used pathological variables [tumour size, lymph node status, S-phase fraction (SPF)] and the level of expression of topoisomerase II beta mRNA. However, high topoisomerase II alpha gene expression was significantly associated with a high SPF (sign-rank test; P = 0.01). Moreover, the ratio of mRNA levels for topoisomerase II alpha and beta showed a stronger relationship to SPF (median raito 0.62 for tumours with SPF < 10, and 1.64 for SPF > 10; P = 0.0021, sign-rank test). As expected from previous studies, an SPF > 10 was associated with poor overall survival (P = 0.01). Immunohistochemical analysis revealed that topoisomerase II beta was widely distributed ( > 90% positive tumour cells), but that topoisomerase II alpha expression was less widely expressed, with a pattern of expression similar to that of the proliferation-dependent antigen recognised by Ki67. Because topoisomerase II gene expression showed a log-normal distribution, log-transformed data were used in multivariate analysis of relapse-free survival. This showed that lymph node status and topoisomerase II beta mRNA expression were the only significant survival factors (P = 0.001 and 0.05, respectively, with relative risks of 1.3 and 1.8). These results indicate that topoisomerase II alpha, but not beta, expression is dependent upon cellular proliferation status, but that the more widely expressed topoisomerase II beta protein may play a significant role as a target for anti-tumour therapy.


Proteomic profiling of exosomes leads to the identification of novel biomarkers for prostate cancer.
Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, the complexity of body fluids often hampers biomarker discovery. An attractive alternative approach is the isolation of small vesicles, i.e. exosomes, ∼100 nm, which contain proteins that are specific to the tissue from which they are derived and therefore can be considered as treasure chests for disease-specific biomarker discovery. Exosomes were isolated from 2 immortalized primary prostate epithelial cells (PNT2C2 and RWPE-1) and 2 PCa cell lines (PC346C and VCaP) by ultracentrifugation. After tryptic digestion, proteomic analyses utilized a nanoLC coupled with an LTQ-Orbitrap operated in tandem MS (MS/MS) mode. Accurate Mass and Time (AMT) tag approach was employed for peptide identification and quantitation. Candidate biomarkers were validated by Western blotting and Immunohistochemistry. Proteomic characterization resulted in the identification of 248, 233, 169, and 216 proteins by at least 2 peptides in exosomes from PNT2C2, RWPE-1, PC346C, and VCaP, respectively. Statistical analyses revealed 52 proteins differently abundant between PCa and control cells, 9 of which were more abundant in PCa. Validation by Western blotting confirmed a higher abundance of FASN, XPO1 and PDCD6IP (ALIX) in PCa exosomes. Identification of exosomal proteins using high performance LC-FTMS resulted in the discovery of PDCD6IP, FASN, XPO1 and ENO1 as new candidate biomarkers for prostate cancer.


Degradation of arouser by endosomal microautophagy is essential for adaptation to starvation in Drosophila.
Hunger drives food-seeking behaviour and controls adaptation of organisms to nutrient availability and energy stores. Lipids constitute an essential source of energy in the cell that can be mobilised during fasting by autophagy. Selective degradation of proteins by autophagy is made possible essentially by the presence of LIR and KFERQ-like motifs. Using in silico screening of Drosophila proteins that contain KFERQ-like motifs, we identified and characterized the adaptor protein Arouser, which functions to regulate fat storage and mobilisation and is essential during periods of food deprivation. We show that hypomorphic arouser mutants are not satiated, are more sensitive to food deprivation, and are more aggressive, suggesting an essential role for Arouser in the coordination of metabolism and food-related behaviour. Our analysis shows that Arouser functions in the fat body through nutrient-related signalling pathways and is degraded by endosomal microautophagy. Arouser degradation occurs during feeding conditions, whereas its stabilisation during non-feeding periods is essential for resistance to starvation and survival. In summary, our data describe a novel role for endosomal microautophagy in energy homeostasis, by the degradation of the signalling regulatory protein Arouser.


Lower-Limb Muscle-Activation Patterns During Off-Axis Elliptical Compared With Conventional Gluteal-Muscle-Strengthening Exercises.
Gluteal-muscle strength has been identified as an important component of injury prevention and rehabilitation in several common knee injuries. However, many conventionally prescribed gluteal-strengthening exercises are not performed during dynamic weight-bearing activities, which is when most injuries occur. To compare lower-limb muscle-activation patterns between conventional gluteal-strengthening exercises and off-axis elliptical exercises with motorized foot-plate perturbations designed to activate gluteal muscles during dynamic exercise. Twelve healthy volunteers (26.1 ± 4.7 y) participated in the study. They performed 3 conventional exercises (single-leg squat, forward lunge, and clamshell) and 3 elliptical exercises (regular, while resisting an adduction force, and while resisting an internal-rotation torque). Gluteus medius (GMed) and maximus (GMax), quadriceps, hamstrings, and gastrocnemius muscle activations during each exercise were recorded using surface electromyography (EMG) and normalized to maximal voluntary isometric contraction (MVIC). Normalized GMed EMG was the highest during the adduction-resistance elliptical exercise (22.4% ± 14.8% MVIC), significantly greater than forward lunge (8.2% ± 3.8% MVIC) and regular elliptical (6.4% ± 2.5% MVIC) and similar to clamshell (19.1% ± 8.8% MVIC) and single-leg squat (18.4% ± 7.9% MVIC). Normalized GMax EMG during adduction-resistance (11.1% ± 7.6% MVIC) and internal-rotation-resistance elliptical (7.4% ± 3.8% MVIC) was significantly greater than regular elliptical (4.4% ± 2.4% MVIC) and was similar to conventional exercises. The single-leg squat required more muscle activation from the quadriceps and gastrocnemius than the elliptical exercises. Off-axis elliptical exercise while resisting an adduction force or internal-rotation torque activates gluteal muscles dynamically while avoiding excessive quadriceps activation during a functional weight-bearing activity compared with conventional gluteal-strengthening exercises.


Total elbow arthroplasty as primary treatment for distal humeral fractures in elderly patients.
We retrospectively reviewed the results of primary total elbow arthroplasty for the treatment of an acute fracture of the distal aspect of the humerus in twenty consecutive patients (twenty-one elbows) who had a mean age of seventy-two years (range, forty-eight to ninety-two years) at the time of the injury. The patients were managed between November 1982 and October 1992. The presence of rheumatoid arthritis in nine patients (ten elbows) influenced the choice of treatment. The mean interval between the injury and the total elbow arthroplasty was seven days (range, one to twenty-five days). The mean duration of postoperative hospitalization was seven days (range, four to thirteen days). The mean duration of follow-up was 3.3 years (range, three months to 10.5 years). All patients were followed for a minimum of two years or until the time of death; the duration of follow-up was less than two years for three patients who died. None of the patients were lost to follow-up. Twenty implants were intact at the latest follow-up examination. One patient had a revision total elbow arthroplasty twenty months after the index procedure because of a fracture of the ulnar component sustained in a fall on the outstretched arm. On the basis of the Mayo elbow performance score, fifteen elbows had an excellent result and five had a good result; there were inadequate data for one elbow. There were no fair or poor results. The mean arc of flexion was 25 to 130 degrees. There was no evidence of loosening on the radiographs. Postoperative complications included fracture of the ulnar component in one patient, ulnar neurapraxia in three, and reflex sympathetic dystrophy in one. The results suggest that total elbow arthroplasty can be an alternative form of treatment of a severely comminuted fracture of the distal aspect of the humerus in older patients even in the presence of rheumatoid arthritis. This procedure is not an alternative to osteosynthesis in younger patients.


Impact of chronic kidney disease on the incidence of peri-procedural myocardial injury in patients undergoing elective stent implantation.
It is well known that chronic kidney disease is a strong independent predictor of adverse outcomes after percutaneous coronary intervention in patients with ischemic heart disease. Recently, peri-procedural myocardial injury has been associated with adverse cardiac events. The aim of this study was to investigate the relationship between renal function and peri-procedural myocardial injury in patients undergoing elective stent implantation. This study comprised 273 consecutive patients who underwent elective stent implantation. They were divided into two groups: estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m(2) and eGFR ≥60 mL/min/1.73m(2). Peri-procedural TnT levels higher than three times the normal limit were defined as peri-procedural myocardial injury. Patients with eGFR <60 mL/min/1.73m(2) showed a higher incidence of peri-procedural myocardial injury compared to patients with eGFR ≥60 mL/min/1.73m(2) (4.3 versus 20.9%, P < 0.0001). Even after a multivariate adjustment, the eGFR level predicted peri-procedural myocardial injury [odds ratio 0.92, 95% confidence interval (CI): 0.89-0.95, P < 0.0001]. Total stent length was also an independent predictor of peri-procedural myocardial injury (odds ratio 1.09, 95% CI: 1.02-1.16, P = 0.009). Using a receiver-operating curve analysis, eGFR level of 62.1 mL/min/1.73m(2) (sensitivity 93.3%, specificity 57.2%) was the best value (area under the curve = 0.803) to maximize the power of eGFR levels in predicting peri-procedural myocardial injury. Patients with eGFR <60 mL/min/1.73m(2) were strongly associated with peri-procedural myocardial injury after elective stent implantation. Therefore, eGFR may be a simple and convenient predictor of peri-procedural myocardial injury.


Pleasure, prophylaxis and procreation: a qualitative analysis of intermittent contraceptive use and unintended pregnancy.
Although pregnancy ambivalence is consistently associated with poorer contraceptive use, little is known about the sexual, social and emotional dynamics at work in pregnancy ambivalence. During in-depth sexual and reproductive history interviews conducted in 2003, 36 women and men were asked about the relational and emotional circumstances surrounding each pregnancy, as well as their thoughts about conceiving a baby with both current and previous partners. An ethnographic, inductive approach was used to analyze the data. Half of respondents had experienced at least one unintended pregnancy. Respondents described three categories of pleasure related to pregnancy ambivalence: active eroticization of risk, in which pregnancy fantasies heightened the charge of the sexual encounter; passive romanticization of pregnancy, in which people neither actively sought nor prevented conception; and an escapist pleasure in imagining that a pregnancy would sweep one away from hardship. All three categories were associated with misuse or nonuse of coitus-dependent methods. For some individuals, the perceived emotional and sexual benefits of conception may outweigh the goal of averting conception, even when a child is not wholly intended. Future behavioral studies should collect more nuanced data on pregnancy-related pleasure. Clinicians and patients would benefit from clearer guidelines for assessing ambivalence and for linking ambivalent clients with longer-acting methods that are not coitus-dependent.


The role of left and right hemispheres in the comprehension of idiomatic language: an electrical neuroimaging study.
The specific role of the two cerebral hemispheres in processing idiomatic language is highly debated. While some studies show the involvement of the left inferior frontal gyrus (LIFG), other data support the crucial role of right-hemispheric regions, and particularly of the middle/superior temporal area. Time-course and neural bases of literal vs. idiomatic language processing were compared. Fifteen volunteers silently read 360 idiomatic and literal Italian sentences and decided whether they were semantically related or unrelated to a following target word, while their EEGs were recorded from 128 electrodes. Word length, abstractness and frequency of use, sentence comprehensibility, familiarity and cloze probability were matched across classes. Participants responded more quickly to literal than to idiomatic sentences, probably indicating a difference in task difficulty. Occipito/temporal N2 component had a greater amplitude in response to idioms between 250-300 ms. Related swLORETA source reconstruction revealed a difference in the activation of the left fusiform gyrus (FG, BA19) and medial frontal gyri for the contrast idiomatic-minus-literal. Centroparietal N400 was much larger to idiomatic than to literal phrases (360-550 ms). The intra-cortical generators of this effect included the left and right FG, the left cingulate gyrus, the right limbic area, the right MTG (BA21) and the left middle frontal gyrus (BA46). Finally, an anterior late positivity (600-800 ms) was larger to idiomatic than literal phrases. ERPs also showed a larger right centro-parietal N400 to associated than non-associated targets (not differing as a function of sentence type), and a greater right frontal P600 to idiomatic than literal associated targets. The data indicate bilateral involvement of both hemispheres in idiom comprehension, including the right MTG after 350 ms and the right medial frontal gyrus in the time windows 270-300 and 500-780 ms. In addition, the activation of left and right limbic regions (400-450 ms) suggests that they have a role in the emotional connotation of colourful idiomatic language. The data support the view that there is direct access to the idiomatic meaning of figurative language, not dependent on the suppression of its literal meaning, for which the LIFG was previously thought to be responsible.


Terahertz transmission vs reflection imaging and model-based characterization for excised breast carcinomas.
This work presents experimental and analytical comparison of terahertz transmission and reflection imaging modes for assessing breast carcinoma in excised paraffin-embedded human breast tissue. Modeling for both transmission and reflection imaging is developed. The refractive index and absorption coefficient of the tissue samples are obtained. The reflection measurements taken at the system's fixed oblique angle of 30° are shown to be a hybridization of TE and TM modes. The models are validated with transmission spectroscopy at fixed points on fresh bovine muscle and fat tissues. Images based on the calculated absorption coefficient and index of refraction of bovine tissue are successfully compared with the terahertz magnitude and phase measured in the reflection mode. The validated techniques are extended to 20 and 30 μm slices of fixed human lobular carcinoma and infiltrating ductal carcinoma mounted on polystyrene microscope slides in order to investigate the terahertz differentiation of the carcinoma with non-cancerous tissue. Both transmission and reflection imaging show clear differentiation in carcinoma versus healthy tissue. However, when using the reflection mode, in the calculation of the thin tissue properties, the absorption is shown to be sensitive to small phase variations that arise due to deviations in slide and tissue thickness and non-ideal tissue adhesion. On the other hand, the results show that the transmission mode is much less sensitive to these phase variations. The results also demonstrate that reflection imaging provides higher resolution and more clear margins between cancerous and fibroglandular regions, cancerous and fatty regions, and fibroglandular and fatty tissue regions. In addition, more features consistent with high power pathology images are exhibited in the reflection mode images.


Reducing surgical site infections in low-income and middle-income countries (FALCON): a pragmatic, multicentre, stratified, randomised controlled trial.
Surgical site infection (SSI) is the most common postoperative complication worldwide. WHO guidelines to prevent SSI recommend alcoholic chlorhexidine skin preparation and fascial closure using triclosan-coated sutures, but called for assessment of both interventions in low-resource settings. This study aimed to test both interventions in low-income and middle-income countries. FALCON was a 2 × 2 factorial, randomised controlled trial stratified by whether surgery was clean-contaminated, or contaminated or dirty, including patients undergoing abdominal surgery with a skin incision of 5 cm or greater. This trial was undertaken in 54 hospitals in seven countries (Benin, Ghana, India, Mexico, Nigeria, Rwanda, and South Africa). Patients were computer randomised 1:1:1:1 to: (1) 2% alcoholic chlorhexidine and non-coated suture, (2) 2% alcoholic chlorhexidine and triclosan-coated suture, (3) 10% aqueous povidone-iodine and non-coated suture, or (4) 10% aqueous povidone-iodine and triclosan-coated suture. Patients and outcome assessors were masked to intervention allocation. The primary outcome was SSI, reported by trained outcome assessors, and presented using adjusted relative risks and 95% CIs. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT03700749. Between Dec 10, 2018, and Sept 7, 2020, 5788 patients (3091 in clean-contaminated stratum, 2697 in contaminated or dirty stratum) were randomised (1446 to alcoholic chlorhexidine and non-coated suture, 1446 to alcoholic chlorhexidine and triclosan-coated suture, 1447 to aqueous povidone-iodine and non-coated suture, and 1449 to aqueous povidone-iodine and triclosan-coated suture). 14·0% (810/5788) of patients were children and 66·9% (3873/5788) had emergency surgery. The overall SSI rate was 22·0% (1163/5284; clean-contaminated stratum 15·5% [454/2923], contaminated or dirty stratum 30·0% [709/2361]). For both strata, there was no evidence of a difference in the risk of SSI with alcoholic chlorhexidine versus povidone-iodine (clean-contaminated stratum 15·3% [223/1455] vs 15·7% [231/1468], relative risk 0·97 [95% CI 0·82-1·14]; contaminated or dirty stratum 28·3% [338/1194] vs 31·8% [371/1167], relative risk 0·91 [95% CI 0·81-1·02]), or with triclosan-coated sutures versus non-coated sutures (clean-contaminated stratum 14·7% [215/1459] vs 16·3% [239/1464], relative risk 0·90 [95% CI 0·77-1·06]; contaminated or dirty stratum 29·4% [347/1181] vs 30·7% [362/1180], relative risk 0·98 [95% CI 0·87-1·10]). With both strata combined, there were no differences using alcoholic chlorhexidine or triclosan-coated sutures. This trial did not show benefit from 2% alcoholic chlorhexidine skin preparation compared with povidone-iodine, or with triclosan-coated sutures compared with non-coated sutures, in preventing SSI in clean-contaminated or contaminated or dirty surgical wounds. Both interventions are more expensive than alternatives, and these findings do not support recommendations for routine use. National Institute for Health Research (NIHR) Global Health Research Unit Grant, BD.


Rapid optimization of drug combinations for the optimal angiostatic treatment of cancer.
Drug combinations can improve angiostatic cancer treatment efficacy and enable the reduction of side effects and drug resistance. Combining drugs is non-trivial due to the high number of possibilities. We applied a feedback system control (FSC) technique with a population-based stochastic search algorithm to navigate through the large parametric space of nine angiostatic drugs at four concentrations to identify optimal low-dose drug combinations. This implied an iterative approach of in vitro testing of endothelial cell viability and algorithm-based analysis. The optimal synergistic drug combination, containing erlotinib, BEZ-235 and RAPTA-C, was reached in a small number of iterations. Final drug combinations showed enhanced endothelial cell specificity and synergistically inhibited proliferation (p < 0.001), but not migration of endothelial cells, and forced enhanced numbers of endothelial cells to undergo apoptosis (p < 0.01). Successful translation of this drug combination was achieved in two preclinical in vivo tumor models. Tumor growth was inhibited synergistically and significantly (p < 0.05 and p < 0.01, respectively) using reduced drug doses as compared to optimal single-drug concentrations. At the applied conditions, single-drug monotherapies had no or negligible activity in these models. We suggest that FSC can be used for rapid identification of effective, reduced dose, multi-drug combinations for the treatment of cancer and other diseases.