Aromatase transgenic upregulation modulates basal cardiac performance and the response to ischemic stress in male mice.
Estrogen in females is conventionally considered a cardioprotective influence, but a role for estrogen in male cardioprotection has yet to be defined. Estrogen biosynthesis from testosterone is regulated by aromatase. Aromatase has recently been shown to be expressed in the adult heart, although little is known about its involvement in the regulation of myocardial function and stress responses. The goal of this study was to determine whether upregulation of tissue aromatase expression could improve ischemic resilience in male hearts. Isolated hearts from male transgenic aromatase-overexpressing (AROM(+); high estrogen, low testosterone) mice and wild-type (WT) mice (12 wk) were Langendorff perfused and subjected to ischemia-reperfusion (25 min ischemia and 60 min of reperfusion). Basal systolic function was lower in AROM(+) hearts (dP/dtmax: 4,121 ± 255 vs. 4,992 ± 283 mmHg/s, P < 0.05) and associated with augmented Akt phosphorylation, consistent with a suppressor action of estrogen on contractility. Ischemic contracture was attenuated in AROM(+) hearts (43 ± 3 vs. 55 ± 4 mmHg, P < 0.05), yet AROM(+) hearts were more arrhythmic in early reperfusion. At the end of 60 min of reperfusion, AROM(+) systolic functional recovery was lower (left ventricular developed pressure: 39 ± 6 vs. 56 ± 5 %basal, P < 0.05) and diastolic dysfunction was accentuated (36 ± 4 vs. 24 ± 2 mmHg, P < 0.05). This is the first study to show that in vivo aromatase upregulation modulates basal cardiac performance and the response to ischemic stress. These data suggest that while chronic exposure to enhanced estrogenic influence may have benefits in limiting ischemic contracture severity, acute functional recovery in reperfusion is compromised. A temporally targeted, tissue-specific intervention combining aromatase treatment with inotropic support may offer therapeutic potential for men and women.


The Metastatic Potential and Chemoresistance of Human Pancreatic Cancer Stem Cells.
Cancer stem cells (CSCs) typically have the capacity to evade chemotherapy and may be the principal source of metastases. CSCs for human pancreatic ductal carcinoma (PDAC) have been identified, but neither the metastatic potential nor the chemoresistance of these cells has been adequately evaluated. We have addressed these issues by examining side-population (SP) cells isolated from the Panc-1 and BxPC3 lines of human PDAC cells, the oncogenotypes of which differ. SP cells could be isolated from monolayers of Panc-1, but only from spheroids of BxPC3. Using orthotopic xenografts into the severely immunocompromised NSG mouse, we found that SP cells isolated from both cell lines produced tumors that were highly metastatic, in contrast to previous experience with PDAC cell lines. SP cells derived from both cell lines expressed the ABCG2 transporter, which was demonstrably responsible for the SP phenotype. SP cells gave rise to non-SP (NSP) cells in vitro and in vivo, a transition that was apparently due to posttranslational inhibition of the ABCG2 transporter. Twenty-two other lines of PDAC cells also expressed ABCG2. The sensitivity of PDAC SP cells to the vinca alkaloid vincristine could be greatly increased by verapamil, a general inhibitor of transporters. In contrast, verapamil had no effect on the killing of PDAC cells by gemcitabine, the current first-line therapeutic for PDAC. We conclude that the isolation of SP cells can be a convenient and effective tool for the study of PDAC CSCs; that CSCs may be the principal progenitors of metastasis by human PDAC; that the ABCG2 transporter is responsible for the SP phenotype in human PDAC cells, and may be a ubiquitous source of drug-resistance in PDAC, but does not confer resistance to gemcitabine; and that inhibition of ABCG2 might offer a useful adjunct in a therapeutic attack on the CSCs of PDAC.


Racial and ethnic differences in adjuvant hormonal therapy use.
In the United States, 5-year breast cancer survival is highest among Asian American women, followed by non-Hispanic white, Hispanic, and African American women. Breast cancer treatment disparities may play a role. We examined racial/ethnic differences in adjuvant hormonal therapy use among women aged 18-64 years, diagnosed with hormone receptor-positive breast cancer, using data collected by the Northern California Breast Cancer Family Registry (NC-BCFR), and explored changes in use over time. Odds ratios (OR) comparing self-reported ever-use by race/ethnicity (African American, Hispanic, non-Hispanic white vs. Asian American) were estimated using multivariable adjusted logistic regression. Analyses were stratified by recruitment phase (phase I, diagnosed January 1995-September 1998, phase II, diagnosed October 1998-April 2003) and genetic susceptibility, as cases with increased genetic susceptibility were oversampled. Among 1385 women (731 phase I, 654 phase II), no significant racial/ethnic differences in use were observed among phase I or phase II cases. However, among phase I cases with no susceptibility indicators, African American and non-Hispanic white women were less likely than Asian American women to use hormonal therapy (OR 0.20, 95% confidence interval [CI]0.06-0.60; OR 0.40, CI 0.17-0.94, respectively). No racial/ethnic differences in use were observed among women with 1+ susceptibility indicators from either recruitment phase. Racial/ethnic differences in adjuvant hormonal therapy use were limited to earlier diagnosis years (phase I) and were attenuated over time. Findings should be confirmed in other populations but indicate that in this population, treatment disparities between African American and Asian American women narrowed over time as adjuvant hormonal treatments became more commonly prescribed.


Using short-term concentration measures and intelligence in rehabilitation settings.
Psychological assessment of cognitive functioning among clinical groups that include psychiatric and geriatric patients is a difficult task. This study examines the interrelationship between intelligence and concentrative ability for a group of psychiatric patients. Intellectual and concentrative ability were assessed among a group of 85, predominantly schizophrenic, patients (mean age 32 years) from a Sheltered Workshop (GWN) and neurological-psychiatric institutionalized care units within the Neuss region of North-Rhine Westphalia, Germany. Moderate bivariate relationships were found between all IQ subtests and the concentration performance variables (d2). A substantial overlap in variance was found between "nonverbal" intelligence and the concentration variables (using multiple regression and discrimination analysis). Error rate on the concentration task was significantly negatively correlated with the IQ variables, the magnitude of the correlation coefficient increasing as a function of the time on the task. Future studies would benefit from comparisons in factor structure similarity between abnormal and normal groups as well as between-clinical groups. At a practical level, the relatively easy use (less complex administration) and less obtrusive (hence, low level of personal threat) and inexpensive procedures of the letter cancellation task makes it a useful, albeit "approximate", measure of cognitive functioning.


Artificial light at night advances avian reproductive physiology.
Artificial light at night is a rapidly increasing phenomenon and it is presumed to have global implications. Light at night has been associated with health problems in humans as a consequence of altered biological rhythms. Effects on wild animals have been less investigated, but light at night has often been assumed to affect seasonal cycles of urban dwellers. Using light loggers attached to free-living European blackbirds (Turdus merula), we first measured light intensity at night which forest and city birds are subjected to in the wild. Then we used these measurements to test for the effect of light at night on timing of reproductive physiology. Captive city and forest blackbirds were exposed to either dark nights or very low light intensities at night (0.3 lux). Birds exposed to light at night developed their reproductive system up to one month earlier, and also moulted earlier, than birds kept under dark nights. Furthermore, city birds responded differently than forest individuals to the light at night treatment, suggesting that urbanization can alter the physiological phenotype of songbirds. Our results emphasize the impact of human-induced lighting on the ecology of millions of animals living in cities and call for an understanding of the fitness consequences of light pollution.


Limited evidence of fungicide-driven triazole-resistant Aspergillus fumigatus in Hamilton, Canada.
Aspergillus fumigatus is a ubiquitous opportunistic fungal pathogen that can cause aspergillosis in humans. Over the last decade there have been increasing global reports of treatment failure due to triazole resistance. An emerging hypothesis states that agricultural triazole fungicide use causes clinical triazole resistance. Here we test this hypothesis in Hamilton, Ontario, Canada, by examining a total of 195 agricultural, urban, and clinical isolates using 9 highly polymorphic microsatellite markers. For each isolate, the in vitro susceptibilities to itraconazole and voriconazole, 2 triazole drugs commonly used in the management of patients, were also determined. Our analyses suggested frequent gene flow among the agricultural, urban environmental, and clinical populations of A. fumigatus and found evidence for widespread sexual recombination within and among the different populations. Interestingly, all 195 isolates analyzed in this study were susceptible to both triazoles tested. However, compared with the urban population, agricultural and clinical populations showed significantly reduced susceptibility to itraconazole and voriconazole, consistent with ecological niche-specific selective pressures on A. fumigatus populations in Hamilton. Frequent gene flow and genetic recombination among these populations suggest greater attention should be paid to monitor A. fumigatus populations in Hamilton and other similar jurisdictions.


Regulation of cardiac autophagy by insulin-like growth factor 1.
Insulin-like growth factor-1 (IGF-1) signaling is a key pathway in the control of cell growth and survival. Three critical nodes in the IGF-1 signaling pathway have been described in cardiomyocytes: protein kinase Akt/mammalian target of rapamycin (mTOR), Ras/Raf/extracellular signal-regulated kinase (ERK), and phospholipase C (PLC)/inositol 1,4,5-triphosphate (InsP3 )/Ca(2+) . The Akt/mTOR and Ras/Raf/ERK signaling arms govern survival in the settings of cardiac stress and hypertrophic growth. By contrast, PLC/InsP3 /Ca(2+) functions to regulate metabolic adaptability and gene transcription. Autophagy is a catabolic process involved in protein degradation, organelle turnover, and nonselective breakdown of cytoplasmic components during nutrient starvation or stress. In the heart, autophagy is observed in a variety of human pathologies, where it can be either adaptive or maladaptive, depending on the context. We proposed the hypothesis that IGF-1 protects the heart by rescuing the mitochondrial metabolism and the energetics state, reducing cell death and controls the potentially exacerbate autophagic response to nutritional stress. In light of the importance of IGF-1 and autophagy in the heart, we review here IGF-1 signaling and autophagy regulation in the context of cardiomyocyte nutritional stress.


Tubulin and neurofilament proteins are transported differently in axons of chicken motoneurons.
1. We previously showed that actin is transported in an unassembled form with its associated proteins actin depolymerizing factor, cofilin, and profilin. Here we examine the specific activities of radioactively labeled tubulin and neurofilament proteins in subcellular fractions of the chicken sciatic nerve following injection of L-[35S]methionine into the lumbar spinal cord. 2. At intervals of 12 and 20 days after injection, nerves were cut into 1-cm segments and separated into Triton X-100-soluble and particulate fractions. Analysis of the fractions by high-resolution two-dimensional gel electrophoresis, immunoblotting, fluorography, and computer densitometry showed that tubulin was transported as a unimodal wave at a slower average rate (2-2.5 mm/day) than actin (4-5 mm/day). Moreover, the specific activity of soluble tubulin was five times that of its particulate form, indicating that tubulin is transported in a dimeric or small oligomeric form and is assembled into stationary microtubules. 3. Neurofilament triplet proteins were detected only in the particulate fractions and transported at a slower average rate (1 mm/day) than either actin or tubulin. 4. Our results indicate that the tubulin was transported in an unpolymerized form and that the neurofilament proteins were transported in an insoluble, presumably polymerized form.


Early clopidogrel versus prasugrel use among contemporary STEMI and NSTEMI patients in the US: insights from the National Cardiovascular Data Registry.
P2Y12 antagonist therapy improves outcomes in acute myocardial infarction (MI) patients. Novel agents in this class are now available in the US. We studied the introduction of prasugrel into contemporary MI practice to understand the appropriateness of its use and assess for changes in antiplatelet management practices. Using ACTION Registry-GWTG (Get-with-the-Guidelines), we evaluated patterns of P2Y12 antagonist use within 24 hours of admission in 100 228 ST elevation myocardial infarction (STEMI) and 158 492 Non-ST elevation myocardial infarction (NSTEMI) patients at 548 hospitals between October 2009 and September 2012. Rates of early P2Y12 antagonist use were approximately 90% among STEMI and 57% among NSTEMI patients. From 2009 to 2012, prasugrel use increased significantly from 3% to 18% (5% to 30% in STEMI; 2% to 10% in NSTEMI; P for trend <0.001 for all). During the same period, we observed a decrease in use of early but not discharge P2Y12 antagonist among NSTEMI patients. Although contraindicated, 3.0% of patients with prior stroke received prasugrel. Prasugrel was used in 1.9% of patients ≥75 years and 4.5% of patients with weight <60 kg. In both STEMI and NSTEMI, prasugrel was most frequently used in patients at the lowest predicted risk for bleeding and mortality. Despite lack of supporting evidence, prasugrel was initiated before cardiac catheterization in 18% of NSTEMI patients. With prasugrel as an antiplatelet treatment option, contemporary practice shows low uptake of prasugrel and delays in P2Y12 antagonist initiation among NSTEMI patients. We also note concerning evidence of inappropriate use of prasugrel, and inadequate targeting of this more potent therapy to maximize the benefit/risk ratio.


Non-Invasive Luciferase Imaging of Type I Interferon Induction in a Transgenic Mouse Model of Biomaterial Associated Bacterial Infections: Microbial Specificity and Inter-Bacterial Species Interactions.
The performance of biomaterials is often compromised by bacterial infections and subsequent inflammation. So far, the conventional analysis of inflammatory processes in vivo involves time-consuming histology and biochemical assays. The present study employed a mouse model where interferon beta (IFN-β) is monitored as a marker for non-invasive rapid detection of inflammation in implant-related infections. The mouse model comprises subcutaneous implantation of morphologically modified titanium, followed by experimental infections with four taxonomically diverse oral bacteria: Streptococcus oralis, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis and Treponema denticola (as mono culture or selected mixed-culture). IFN-β expression increased upon infections depending on the type of pathogen and was prolonged by the presence of the implant. IFN-β expression kinetics reduced with two mixed species infections when compared with the single species. Histological and confocal microscopy confirmed pathogen-specific infiltration of inflammatory cells at the implant-tissue interface. This was observed mainly in the vicinity of infected implants and was, in contrast to interferon expression, higher in infections with dual species. In summary, this non-invasive mouse model can be used to quantify longitudinally host inflammation in real time and suggests that the polymicrobial character of infection, highly relevant to clinical situations, has complex effects on host immunity.


Lizards in 'nuclear families': a novel reptilian social system in Egernia saxatilis (Scincidae).
Recent research has revealed unsuspected complexity in social organization among squamate reptiles. In particular, large Australian scincid lizards of the genus Egernia have been reported to occur in large aggregations of closely related individuals. However, the 'nuclear family' structure found in many other 'social' organisms (especially birds) has not been reported from reptiles. Our field studies on black rock skinks (Egernia saxatilis) in southeastern Australia document exactly this pattern. We quantified group composition using behavioural observations at regular intervals over three field seasons, and took tissue samples for parentage analysis. On the focal rock outcrop 72% of lizards were typically found as part of a stable social grouping, with individuals physically associated with other group members in a third of observations. Eighty-five per cent of juveniles lived in social groups, 65% in family groups with at least one of their parents (including 39% with both parents as revealed by parentage analysis of five microsatellite loci). Broader sampling in surrounding areas revealed similar patterns of group size, composition and relatedness. Overall, of the groups that contained more than one adult, 83% contained a single adult pair. Long-term monogamy and group stability were evident from our genetic data, with up to three annual cohorts of full-sib offspring living with their biological parents. Our data expand the range of social systems known for reptiles, and reveal strong convergence towards 'nuclear family' systems in distantly related vertebrates.


Polyamines are essential for virulence in Salmonella enterica serovar Gallinarum despite evolutionary decay of polyamine biosynthesis genes.
Serovars of Salmonella enterica exhibit different host-specificities where some have broad host-ranges and others, like S. Gallinarum and S. Typhi, are host-specific for poultry and humans, respectively. With the recent availability of whole genome sequences it has been reported that host-specificity coincides with accumulation of pseudogenes, indicating adaptation of host-restricted serovars to their narrow niches. Polyamines are small cationic amines and in Salmonella they can be synthesized through two alternative pathways directly from l-ornithine to putrescine and from l-arginine via agmatine to putrescine. The first pathway is not active in S. Gallinarum and S. Typhi, and this prompted us to investigate the importance of polyamines for virulence in S. Gallinarum. Bioinformatic analysis of all sequenced genomes of Salmonella revealed that pseudogene formation of the speC gene was exclusive for S. Typhi and S. Gallinarum and happened through independent events. The remaining polyamine biosynthesis pathway was found to be essential for oral infection with S. Gallinarum since single and double mutants in speB and speE, encoding the pathways from agmatine to putrescine and from putrescine to spermidine, were attenuated. In contrast, speB was dispensable after intraperitoneal challenge, suggesting that putrescine was less important for the systemic phase of the disease. In support of this hypothesis, a ΔspeE;ΔpotCD mutant, unable to synthesize and import spermidine, but with retained ability to import and synthesize putrescine, was attenuated after intraperitoneal infection. We therefore conclude that polyamines are essential for virulence of S. Gallinarum. Furthermore, our results point to distinct roles for putrescine and spermidine during systemic infection.


Uterine fibroid embolization for symptomatic fibroids: study at a teaching hospital in kenya.
Characterization of magnetic (MRI) features in women undergoing uterine fibroid embolization (UFE) and identification of clinical correlates in an African population. Patients with symptomatic fibroids who are selected to undergo UFE at the hospital formed the study population. The baseline MRI features, baseline symptom score, short-term imaging outcome, and mid-term symptom scores were analyzed for interval changes. Assessment of potential associations between short-term imaging features and mid-term symptom scores was also done. UFE resulted in statistically significant reduction (P < 0.001) of dominant fibroid, uterine volumes, and reduction of symptom severity scores, which were 43.7%, 40.1%, and 37.8%, respectively. Also, 59% of respondents had more than 10 fibroids. The predominant location of the dominant fibroid was intramural. No statistically significant association was found between clinical and radiological outcome. The response of uterine fibroids to embolization in the African population is not different from the findings reported in other studies from the west. The presence of multiple and large fibroids in this study is consistent with the case mix described in other studies of African-American populations. Patient counseling should emphasize the independence of volume reduction and symptom improvement. Though volume changes are of relevance for the radiologist in understanding the evolution of the condition and identifying potential technical treatment failures, it should not be the main basis of evaluation of treatment success.


Electron and Proton Flux for Carbon Dioxide Reduction in Methanosarcina barkeri During Direct Interspecies Electron Transfer.
Direct interspecies electron transfer (DIET) is important in diverse methanogenic environments, but how methanogens participate in DIET is poorly understood. Therefore, the transcriptome of Methanosarcina barkeri grown via DIET in co-culture with Geobacter metallireducens was compared with its transcriptome when grown via H2 interspecies transfer (HIT) with Pelobacter carbinolicus. Notably, transcripts for the F420H2 dehydrogenase, Fpo, and the heterodisulfide reductase, HdrABC, were more abundant during growth on DIET. A model for CO2 reduction was developed from these results in which electrons delivered to methanophenazine in the cell membrane are transferred to Fpo. The external proton gradient necessary to drive the otherwise thermodynamically unfavorable reverse electron transport for Fpo-catalyzed F420 reduction is derived from protons released from G. metallireducens metabolism. Reduced F420 is a direct electron donor in the carbon dioxide reduction pathway and also serves as the electron donor for the proposed HdrABC-catalyzed electron bifurcation reaction in which reduced ferredoxin (also required for carbon dioxide reduction) is generated with simultaneous reduction of CoM-S-S-CoB. Expression of genes for putative redox-active proteins predicted to be localized on the outer cell surface was higher during growth on DIET, but further analysis will be required to identify the electron transfer route to methanophenazine. The results indicate that the pathways for electron and proton flux for CO2 reduction during DIET are substantially different than for HIT and suggest that gene expression patterns may also be useful for determining whether Methanosarcina are directly accepting electrons from other extracellular electron donors, such as corroding metals or electrodes.


Completely transparent conducting oxide-free and flexible dye-sensitized solar cells fabricated on plastic substrates.
To achieve commercialization and widespread application of next-generation photovoltaics, it is important to develop flexible and cost-effective devices. Given this, the elimination of expensive transparent conducting oxides (TCO) and replacement of conventional glass substrates with flexible plastic substrates presents a viable strategy to realize extremely low-cost photovoltaics with a potentially wide applicability. To this end, we report a completely TCO-free and flexible dye-sensitized solar cell (DSSC) fabricated on a plastic substrate using a unique transfer method and back-contact architecture. By adopting unique transfer techniques, the working and counter electrodes were fabricated by transferring high-temperature-annealed TiO2 and Pt/carbon films, respectively, onto flexible plastic substrates without any exfoliation. The fabricated working electrode with the conventional counter electrode exhibited a record efficiency for flexible DSSCs of 8.10%, despite its TCO-free structure. In addition, the completely TCO-free and flexible DSSC exhibited a remarkable efficiency of 7.27%. Furthermore, by using an organic hole-transporting material (spiro-MeOTAD) with the same transfer method, solid-state flexible TCO-free DSSCs were also successfully fabricated, yielding a promising efficiency of 3.36%.


Differential effects of professional leaders on health care teams in chronic disease management groups.
Leadership by health care professionals is likely to vary because of differences in the social contexts within which they are situated, socialization processes and societal expectations, education and training, and the way their professions define and operationalize key concepts such as teamwork, collaboration, and partnership. This research examines the effect of the nurse and physician leaders on interdependence and encounter preparedness in chronic disease management practice groups. The aim of this study was to examine the effect of complementary leadership by nurses and physicians involved in jointly producing a health care service on care team functioning. The design is a retrospective observational study based on survey data. The unit of analysis is heart failure care groups in U.S. Veterans Health Administration medical centers. Survey and administrative data were collected in 2009 from 68 Veterans Health Administration medical centers. Key variables include nurse and physician leadership, interdependence, psychological safety, coordination, and encounter preparedness. Reliability and validity of survey measures were assessed with exploratory factor analysis and Cronbach alphas. Multivariate analyses tested hypotheses. Professional leadership by nurses and physicians is related to encounter preparedness by different paths. Nurse leadership is associated with greater team interdependence, and interdependence is positively associated with respect. Physician leadership is positively associated with greater psychological safety, respect, and shared goals but is not associated with interdependence. Respect is associated with involvement in learning activities, and shared goals are associated with coordination. Coordination and involvement in learning activities are positively associated with encounter preparedness. By focusing on increasing interdependence and a constructive climate, nurse and physician leaders have the opportunity to increase care coordination and involvement in learning activities.


Brain-stem auditory-evoked potentials during lidocaine infusion in humans.
Auditory brain-stem responses (ABR) were recorded in six healthy male volunteers during intravenous infusion of lidocaine that achieved systemic blood levels similar to those seen with conduction anesthesia and antiarrhythmic therapy. Following an initial loading dose of lidocaine (1 mg/kg), subjects noted prominent tinnitus, perioral numbness, and drowsiness. All of these symptoms except drowsiness abated during continued infusion as blood concentrations reached equilibrium. All subjects noted that the click stimuli used to elicit ABR varied markedly in intensity and character throughout the lidocaine infusion. Although waves I and III were unaffected by lidocaine, wave V exhibited significant decreases in amplitude and increases in latency. Therefore, the more central components of the auditory system seem to be the prominent site of lidocaine's central nervous system effects.


Escherichia coli interactions with Acanthamoeba: a symbiosis with environmental and clinical implications.
The ability of Acanthamoeba to feed on Gram-negative bacteria, as well as to harbour potential pathogens, such as Legionella pneumophila, Coxiella burnetii, Pseudomonas aeruginosa, Vibrio cholerae, Helicobacter pylori, Listeria monocytogenes and Mycobacterium avium, suggest that both amoebae and bacteria are involved in complex interactions, which may play important roles in the environment and in human health. In this study, Acanthamoeba castellanii (a keratitis isolate belonging to the T4 genotype) was used and its interactions with Escherichia coli (strain K1, a cerebrospinal fluid isolate from a meningitis patient, O18 : K1 : H7, and a K-12 laboratory strain, HB101) were studied. The invasive K1 isolate exhibited a significantly higher association with A. castellanii than the non-invasive K-12 isolate. Similarly, K1 showed significantly increased invasion and/or uptake by A. castellanii in gentamicin protection assays than the non-invasive K-12. Using several mutants derived from K1, it was observed that outer-membrane protein A (OmpA) and LPS were crucial bacterial determinants responsible for E. coli K1 interactions with A. castellanii. Once inside the cell, E. coli K1 remained viable and multiplied within A. castellanii, while E. coli K-12 was killed. Again, OmpA and LPS were crucial for E. coli K1 intracellular survival in A. castellanii. In conclusion, these findings suggest that E. coli K1 interactions with A. castellanii are carefully regulated by the virulence of E. coli.


Accumulation of human apolipoprotein-E in rat plasma after in vivo intramuscular injection of naked DNA.
Naked DNA was found to be incorporated and consistently expressed after in vivo direct injection into striated muscle. In addition to the local expression of muscle-related or exogenous proteins, intramuscular direct gene transfer may be a useful tool to deliver recombinant proteins into the blood stream. However, no direct demonstration of recombinant protein secretion from muscle to the circulation has been reported thus far. We have injected a naked plasmid DNA containing the human receptor-binding defective apo-E2 cDNA, under the control of CMV promoter, into the quadriceps of Yoshida rats, affected by hereditary hypercholesterolemia and altered LDL-receptor activity. Plasma accumulation of human apo-E2 was demonstrated for at least 45 days after injection. On the contrary, the expression of the normal human apo-E3, injected into the muscle of normal Wistar rats, was demonstrated only in the area of muscular injection and not in the blood plasma. Endogenous rat apo-E expression was not affected by the exogenous human apo-E2 production. Our results demonstrate the availability of intramuscular direct gene transfer as a safe and simple method for the chronic systemic delivery of recombinant proteins to the circulation, although further improvements are needed in order to enhance the efficiency and stability of expression.


Biorefinery of Dunaliella salina: Sustainable recovery of carotenoids, polar lipids and glycerol.
Dunaliella salina is well-known for its high content in carotenoids and glycerol. Nevertheless, Dunaliella salina has also a high content in lipids, including polar lipids, which are suitable for nutraceutical/cosmeceutical applications. This work proposes a sustainable process to maximise the potential of Dunaliella salina for the production of distinct fractions of carotenoids, glycerol, polar lipids and proteins, which may contribute to improve the revenues of the microalgae industry. In this work, extraction with non-hazardous solvents and organic solvent nanofiltration are integrated, in order to obtain added-value products and glycerol. Also, aiming to separate carotenoids from glycerides, a saponification process is proposed. High overall recoveries were obtained for carotenoids (85%), glycerol (86%), polar lipids (94%) and proteins (95%). In order to evaluate the profitability of the proposed biorefinery, an economic assessment was accomplished. Both CAPEX and OPEX (Capital and Operating expenditure) were calculated, likewise the Return of Investment (ROI).


PET Imaging of Phosphodiesterase-4 Identifies Affected Dysplastic Bone in McCune-Albright Syndrome, a Genetic Mosaic Disorder.
McCune-Albright syndrome (MAS) is a mosaic disorder arising from gain-of-function mutations in the GNAS gene, which encodes the 3',5'-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gsα. Clinical manifestations of MAS in a given individual, including fibrous dysplasia, are determined by the timing and location of the GNAS mutation during embryogenesis, the tissues involved, and the role of Gsα in the affected tissues. The Gsα mutation results in dysregulation of the cAMP signaling cascade, leading to upregulation of phosphodiesterase type 4 (PDE4), which catalyzes the hydrolysis of cAMP. Increased cAMP levels have been found in vitro in both animal models of fibrous dysplasia and in cultured cells from individuals with MAS but not in humans with fibrous dysplasia. PET imaging of PDE4 with 11C-(R)-rolipram has been used successfully to study the in vivo activity of the cAMP cascade. To date, it remains unknown whether fibrous dysplasia and other symptoms of MAS, including neuropsychiatric impairments, are associated with increased PDE4 activity in humans. Methods:11C-(R)-rolipram whole-body and brain PET scans were performed on 6 individuals with MAS (3 for brain scans and 6 for whole-body scans) and 9 healthy controls (7 for brain scans and 6 for whole-body scans). Results:11C-(R)-rolipram binding correlated with known locations of fibrous dysplasia in the periphery of individuals with MAS; no uptake was observed in the bones of healthy controls. In peripheral organs and the brain, no difference in 11C-(R)-rolipram uptake was noted between participants with MAS and healthy controls. Conclusion: This study is the first to find evidence for increased cAMP activity in areas of fibrous dysplasia in vivo. No differences in brain uptake between MAS participants and controls were detected-a finding that could be due to several reasons, including the limited anatomic resolution of PET. Nevertheless, the results confirm the usefulness of PET scans with 11C-(R)-rolipram to indirectly measure increased cAMP pathway activation in human disease.


Efficacy and Safety of High-Dose Controlled-Release Oxycodone in the Treatment of Moderate to Severe Pain in Patients with Advanced Cancer: A Retrospective Study.
BACKGROUND Opioid analgesics are used to relieve pain in patients with cancer and can improve their quality of life. This study aimed to investigate the efficacy and tolerability of high-dose (>150 mg/day) controlled-release oxycodone for the control of pain in patients with advanced solid malignant tumors. MATERIAL AND METHODS A retrospective clinical study was undertaken to include patients with advanced cancer treated at the Zhejiang Cancer Hospital who had treatment that included high-dose controlled-release oxycodone. The subjective numeric rating scale (NRS) for assessment of pain intensity (scores between 0-10) was used in all cases. RESULTS The study included 131 patients with advanced solid tumors with moderate to severe cancer pain. The mean NRS score before commencing high-dose controlled-release oxycodone was 7.10. The effective rate of relief pain was achieved in 90.1% (118/131) of patients, with an average effective dose of controlled-release oxycodone of 177.18±11.71 mg/day, resulting in a mean NRS of 2.15. There were 51 patients who achieved pain relief with mean treatment duration of 49.98±11.71 days. Combination therapy was required in 79 patients. Additional drugs included gabapentin (43 patients), pregabalin (10 patients) and non-steroidal anti-inflammatory drugs (NSAIDS) (26 patients). The main side effects of high-dose controlled-release oxycodone included constipation, nausea, vomiting, dysuria, dizziness, and drowsiness, but no patients discontinued treatment because of these. CONCLUSIONS This study showed that high-dose controlled-release oxycodone could effectively relieve moderate to severe cancer pain, without side effects that were severe enough to result in discontinuation of treatment.


Acyl-coenzyme A-binding protein regulates Beta-oxidation required for growth and survival of non-small cell lung cancer.
We identified acyl-coenzyme A-binding protein (ACBP) as part of a proteomic signature predicting the risk of having lung cancer. Because ACBP is known to regulate β-oxidation, which in turn controls cellular proliferation, we hypothesized that ACBP contributes to regulation of cellular proliferation and survival of non-small cell lung cancer (NSCLC) by modulating β-oxidation. We used matrix-assisted laser desorption/ionization-imaging mass spectrometry (MALDI-IMS) and immunohistochemistry (IHC) to confirm the tissue localization of ABCP in pre-invasive and invasive NSCLCs. We correlated ACBP gene expression levels in NSCLCs with clinical outcomes. In loss-of-function studies, we tested the effect of the downregulation of ACBP on cellular proliferation and apoptosis in normal bronchial and NSCLC cell lines. Using tritiated-palmitate ((3)H-palmitate), we measured β-oxidation levels and tested the effect of etomoxir, a β-oxidation inhibitor, on proliferation and apoptosis. MALDI-IMS and IHC analysis confirmed that ACBP is overexpressed in pre-invasive and invasive lung cancers. High ACBP gene expression levels in NSCLCs correlated with worse survival (HR = 1.73). We observed a 40% decrease in β-oxidation and concordant decreases in proliferation and increases in apoptosis in ACBP-depleted NSCLC cells as compared with bronchial airway epithelial cells. Inhibition of β-oxidation by etomoxir in ACBP-overexpressing cells produced dose-dependent decrease in proliferation and increase in apoptosis (P = 0.01 and P < 0.001, respectively). These data suggest a role for ACBP in controlling lung cancer progression by regulating β-oxidation.


The dynamics of injection drug users' personal networks and HIV risk behaviors.
While studies of the social networks of injection drug users (IDUs) have provided insight into how the structures of interpersonal relationships among IDUs affect HIV risk behaviors, the majority of these studies have been cross-sectional. The present study examined the dynamics of IDUs' social networks and HIV risk behaviors over time. Using data from a longitudinal HIV-intervention study conducted in Baltimore, MD, this study assessed changes in the composition of the personal networks of 409 IDUs. We used a multi-nomial logistic regression analysis to assess the association between changes in network composition and simultaneous changes in levels of injection HIV risk behaviors. Using the regression parameters generated by the multi-nomial model, we estimated the predicted probability of being in each of four HIV risk behavior change groups. Compared to the base case, individuals who reported an entirely new set of drug-using network contacts at follow-up were more than three times as likely to be in the increasing risk group. In contrast, reporting all new non-drug-using contacts at follow-up increased the likelihood of being in the stable low-risk group by almost 50% and decreased the probability of being in the consistently high-risk group by more than 70%. The findings from this study show that, over and above IDUs' baseline characteristics, changes in their personal networks are associated with changes in individuals' risky injection behaviors. They also suggest that interventions aimed at reducing HIV risk among IDUs might benefit from increasing IDUs' social contacts with individuals who are not drug users.


Alcohol Elicits Functional and Structural Plasticity Selectively in Dopamine D1 Receptor-Expressing Neurons of the Dorsomedial Striatum.
Addiction is thought to be a maladaptive form of learning and memory caused by drug-evoked aberrant synaptic plasticity. We previously showed that alcohol facilitates synaptic plasticity in the dorsomedial striatum (DMS), a brain region that drives goal-directed behaviors. The majority of DMS cells are medium spiny neurons (MSNs) that express dopamine D1 receptors (D1Rs) or D2 receptors (D2Rs), which drive "Go" or "No-Go" behaviors, respectively. Here, we report that alcohol induces cell type-specific synaptic and structural plasticity in the DMS. Using mice that express a fluorescence marker to visualize D1R or D2R MSNs, we show that repeated cycles of systemic administration of alcohol or alcohol consumption induces a long-lasting increase in AMPAR activity specifically in DMS D1R but not in D2R MSNs. Importantly, we report that alcohol consumption increases the complexity of dendritic branching and the density of mature mushroom-shaped spines selectively in DMS D1R MSNs. Finally, we found that blockade of D1R but not D2R activity in the DMS attenuates alcohol consumption. Together, these data suggest that alcohol intake produces profound functional and structural plasticity events in a subpopulation of neurons in the DMS that control reinforcement-related learning. Alcohol addiction is considered maladaptive learning and memory processes. Here we unraveled a long-lasting cellular mechanism that may contribute to the memory of alcohol-seeking behaviors. Specifically, we found that alcohol consumption produces a long-lasting enhancement of channel activity and persistent alterations of neuronal morphology in a part of the brain (DMS) that controls alcohol-drinking behaviors. Furthermore, we show that these alterations occur only in a subpopulation of neurons that positively control reward and reinforcement of drugs of abuse. Finally, we report that blocking the activity of this neuronal population reduces alcohol intake. As such synaptic and structural changes are the cellular hallmarks of learning and memory, and these neuroadaptations may drive the development of pathological heavy alcohol consumption.


Challenges of maintaining research protocol fidelity in a clinical care setting: a qualitative study of the experiences and views of patients and staff participating in a randomized controlled trial.
Trial research has predominantly focused on patient and staff understandings of trial concepts and/or motivations for taking part, rather than why treatment recommendations may or may not be followed during trial delivery. This study sought to understand why there was limited attainment of the glycaemic target (HbA(1c) ≤6.5%) among patients who participated in the Treating to Target in Type 2 Diabetes Trial (4-T). The objective was to inform interpretation of trial outcomes and provide recommendations for future trial delivery. In-depth interviews were conducted with 45 patients and 21 health professionals recruited from 11 of 58 trial centres in the UK. Patients were broadly representative of those in the main trial in terms of treatment allocation, demographics and glycaemic control. Both physicians and research nurses were interviewed. Most patients were committed to taking insulin as recommended by 4-T staff. To avoid hypoglycaemia, patients occasionally altered or skipped insulin doses, normally in consultation with staff. Patients were usually unaware of the trial's glycaemic target. Positive staff feedback could lead patients to believe they had been 'successful' trial participants even when their HbA(1c) exceeded 6.5%. While some staff felt that the 4-T automated insulin dose adjustment algorithm had increased their confidence to prescribe larger insulin doses than in routine clinical practice, all described situations where they had not followed its recommendations. Staff regarded the application of a 'one size fits all' glycaemic target during the trial as contradicting routine clinical practice where they would tailor treatments to individuals. Staff also expressed concerns that 'tight' glycaemic control might impose an unacceptably high risk of hypoglycaemia, thus compromising trust and safety, especially amongst older patients. To address these concerns, staff tended to adapt the trial protocol to align it with their clinical practices and experiences. To understand trial findings, foster attainment of endpoints, and promote protocol fidelity, it may be necessary to look beyond individual patient characteristics and experiences. Specifically, the context of trial delivery, the impact of staff involvement, and the difficulties staff may encounter in balancing competing 'clinical' and 'research' roles and responsibilities may need to be considered and addressed.


Gathering and exploring scientific knowledge in pharmacovigilance.
Pharmacovigilance plays a key role in the healthcare domain through the assessment, monitoring and discovery of interactions amongst drugs and their effects in the human organism. However, technological advances in this field have been slowing down over the last decade due to miscellaneous legal, ethical and methodological constraints. Pharmaceutical companies started to realize that collaborative and integrative approaches boost current drug research and development processes. Hence, new strategies are required to connect researchers, datasets, biomedical knowledge and analysis algorithms, allowing them to fully exploit the true value behind state-of-the-art pharmacovigilance efforts. This manuscript introduces a new platform directed towards pharmacovigilance knowledge providers. This system, based on a service-oriented architecture, adopts a plugin-based approach to solve fundamental pharmacovigilance software challenges. With the wealth of collected clinical and pharmaceutical data, it is now possible to connect knowledge providers' analysis and exploration algorithms with real data. As a result, new strategies allow a faster identification of high-risk interactions between marketed drugs and adverse events, and enable the automated uncovering of scientific evidence behind them. With this architecture, the pharmacovigilance field has a new platform to coordinate large-scale drug evaluation efforts in a unique ecosystem, publicly available at http://bioinformatics.ua.pt/euadr/.


Differences in sensitivity to cold in Japanese men and postmenopausal women aged > or =50 years.
Sensitivity to cold is associated with several factors, such as aging, sex, and body composition. However, no previous studies have examined the differences in sensitivity to cold in men and women or the association of hormonal levels with sensitivity to cold. The aim of the present study was to clarify both the change in sensitivity to cold with aging and the difference in sensitivity to cold between men and women. Associations were also examined between circulating hormonal concentrations and the changes with aging and differences in sensitivity. This population-based cohort study enrolled healthy Japanese men and women aged > or = 50 years. A standardized 210-item health questionnaire was used to obtain information on symptoms of sensitivity to cold. Serum concentrations of luteinizing hormone, follicle-stimulating hormone (FSH), estradiol, testosterone, dehydroepiandrosterone sulfate, and sex hormone-binding globulin (SHBG) were measured. Of the 154 men and 180 women enrolled in this study, more women than men had sensitivity to cold. Whereas the percentage of men who had sensitivity to cold significantly increased with aging (P < 0.05), the percentage of women who had sensitivity to cold was already high (23.7%) at 50 to 60 years of age and did not change with aging. In men, advancing age and low body mass index (BMI) were significantly associated with sensitivity to cold (P < 0.05); however, age and BMI in women were not similarly associated. In addition, the effect of sex after adjustment for age was significant (P < 0.05), and there was also a numeric but nonsignificant effect of sex after adjustment for BMI. In men, low serum levels of the gonadal hormone FSH were significantly associated with sensitivity to cold in logistic analysis, but this association was nonsignificant after multivariate analysis. Serum concentrations of gonadal hormones and SHBG in women were not associated with sensitivity to col. The association of age with sensitivity to cold was different in men and women; the association of BMI with sensitivity to cold might be different in men and women. In addition, these changes in sensitivity to cold were not associated with circulating hormonal concentrations.


Genome Instability Is Promoted by the Chromatin-Binding Protein Spn1 in Saccharomyces cerevisiae.
Cells expend a large amount of energy to maintain their DNA sequence. DNA repair pathways, cell cycle checkpoint activation, proofreading polymerases, and chromatin structure are ways in which the cell minimizes changes to the genome. During replication, the DNA-damage tolerance pathway allows the replication forks to bypass damage on the template strand. This avoids prolonged replication fork stalling, which can contribute to genome instability. The DNA-damage tolerance pathway includes two subpathways: translesion synthesis and template switch. Post-translational modification of PCNA and the histone tails, cell cycle phase, and local DNA structure have all been shown to influence subpathway choice. Chromatin architecture contributes to maintaining genome stability by providing physical protection of the DNA and by regulating DNA-processing pathways. As such, chromatin-binding factors have been implicated in maintaining genome stability. Using Saccharomyces cerevisiae, we examined the role of Spn1 (Suppresses postrecruitment gene number 1), a chromatin-binding and transcription elongation factor, in DNA-damage tolerance. Expression of a mutant allele of SPN1 results in increased resistance to the DNA-damaging agent methyl methanesulfonate, lower spontaneous and damage-induced mutation rates, along with increased chronological life span. We attribute these effects to an increased usage of the template switch branch of the DNA-damage tolerance pathway in the spn1 strain. This provides evidence for a role of wild-type Spn1 in promoting genome instability, as well as having ties to overcoming replication stress and contributing to chronological aging.


Mx mRNA expression and RFLP analysis of rainbow trout Oncorhynchus mykiss genetic crosses selected for susceptibility or resistance to IHNV.
Three interferon-inducible Mx genes have been identified in rainbow trout Oncorhynchus mykiss and their roles in virus resistance have yet to be determined. In mice, expression of the Mx1 protein is associated with resistance to influenza virus. We report a study to determine whether there was a correlation between the expression of Mx in rainbow trout and resistance to a fish rhabdovirus, infectious hematopoietic necrosis virus (IHNV). A comparison of Mx mRNA expression was made between different families of cultured rainbow trout selected for resistance or for susceptibility to IHNV. A trout-specific Mx cDNA gene probe was used to determine whether there was a correlation between Mx mRNA expression and resistance to the lethal effects of IHNV infection. Approximately 99% of trout injected with a highly virulent strain of the fish rhabdovirus, IHNV, were able to express full length Mx mRNA at 48 h post infection. This is markedly different from the expression of truncated, non-functional Mx mRNA found in most laboratory strains of mice, and the ability of only 25% of wild mice to express functional Mx protein. A restriction fragment length polymorphism (RFLP) assay was developed to compare the Mx locus between individual fish and between rainbow trout genetic crosses bred for IHNV resistance or susceptibility. The assay was able to discriminate 7 distinct RFLP patterns in the rainbow trout crosses. One cross was identified that showed a correlation between homozygosity at the Mx locus and greater susceptibility to IHN-caused mortality.


Patient perspectives of dabigatran: analysis of online discussion forums.
In 2010 the US FDA approved dabigatran, the first new anticoagulant for stroke prevention in non-valvular atrial fibrillation (AF) since 1954. To date there is little data that reflects the experiences and perceptions of real-world patients with dabigatran. The abundance of Internet-based discussion forums and support groups related to AF or anticoagulation may provide a low-cost resource for assessing patient experiences. The aim of this study was to determine patient experiences and perceptions regarding dabigatran through qualitative thematic content analysis of comments posted on publicly accessible virtual discussion forums and Internet support groups. Comments posted between January 2011 and September 2012 were downloaded from websites focusing on support of patients with AF or on anticoagulation therapy. Comments were analyzed for thematic content. Five broad thematic categories emerged from the posted comments: general concerns about safety and efficacy, questions about indications and contraindications, questions about proper use and storage, questions about diet and drug restrictions, and experiences with perceived side effects. Our data revealed that a primary concern for patients taking dabigatran is the lack of antidote to reverse the effects of dabigatran if bleeding occurs. Several questions pertaining to the use of dabigatran with other medications or medical conditions were noted, and multiple patients expressed confusion about instructions for using dabigatran before and after medical procedures. An unexpected finding included several criticisms of the medication packaging, which many patients found inconvenient or difficult to open. Finally, several perceived side effects were noted, including some not reported in clinical trials. Online communities may provide information about topics that are a concern to patients and that may not be discernible in clinical trials, such as medication side effects, proper use, and safety. Our data also highlighted potential topics that may not be a priority to researchers but are nevertheless important to patients (e.g. medication convenience or packaging). Despite the growing use of online health-related communities, very little research makes use of this low-cost resource for identifying patient interests regarding therapeutic treatments to guide patient-oriented research.


The human exosome: an autoantigenic complex of exoribonucleases in myositis and scleroderma.
The anti-PM/Scl autoantibodies are known to characterize a subset of autoimmune patients with myositis, scleroderma (Scl), and the PM/Scl overlap syndrome. The major autoantigens that are recognized by anti-PM/Scl autoantibodies are designated PM/Scl-100 and PM/Scl-75. These autoantigens have been reported to associate into a large complex consisting of 11 to 16 proteins and to play a role in ribosome synthesis. Recently, it was discovered that the PM/Scl complex is the human counterpart of the yeast (Saccharomyces cerevisiae) exosome, which is an RNA-processing complex consisting of 11 3' --> 5' exoribonucleases. To date, 10 human exosome components have been identified, although only some of these were studied in more detail. In this review, we discuss some recent advances in the characterization of the PM/Scl complex.


The nonserotypeable pneumococcus: phenotypic dynamics in the era of anticapsular vaccines.
Nonserotypeable pneumococci (NSP) are commonly carried by Australian Indigenous children in remote communities. The purpose of this study was to characterize carriage isolates of NSP from Indigenous children vaccinated with the seven-valent pneumococcal conjugate vaccine (PCV7) and to use these data to guide decisions on reporting of NSP. A total of 182 NSP were characterized by BOX typing, antibiogram analysis, and multilocus sequence typing (MLST) of common BOX types. NSP positive for the wzg capsule gene were analyzed by a multiplex PCR-based reverse line blot hybridization assay (mPCR/RLB-H) targeting capsule genes to determine the serotype. Among 182 NSP, 49 BOX types were identified. MLST of 10 representative isolates found 7 STs, including ST448 (which accounted for 11% of NSP). Non-penicillin susceptibility was evident in 51% of the isolates. Pneumococcal wzg sequences were detected in only 23 (13%) NSP, including 10 that contained an approximately 1.2-kb insert in the region. mPCR/RLB-H identified serotype 14 wzy sequences in all 10 NSP, and 1 also contained a serotype 3-specific wze sequence. Among the remaining 13 wzg-positive NSP, few belonged to the serotypes represented in PCV7. It appears that most NSP identified in Australian Indigenous children are from a true nonencapsulated lineage. Few NSP represented serotypes in PCV7 that suppress capsular expression. High rates of carriage and penicillin resistance and the occasional presence of capsule genes suggest a role for NSP in the maintenance and survival of capsulated pneumococci. To avoid the inflation of pneumococcal carriage and antibiotic resistance rates, in clinical trials, we recommend separate reporting of rates of capsular strains and NSP and the exclusion of data for NSP from primary analyses.


Assessment of TD-DFT and LF-DFT for study of d - d transitions in first row transition metal hexaaqua complexes.
Herein, we present the systematic, comparative computational study of the d - d transitions in a series of first row transition metal hexaaqua complexes, [M(H2O)6](n+) (M(2+/3+) = V (2+/3+), Cr(2+/3+), Mn(2+/3+), Fe(2+/3+), Co(2+/3+), Ni(2+)) by the means of Time-dependent Density Functional Theory (TD-DFT) and Ligand Field Density Functional Theory (LF-DFT). Influence of various exchange-correlation (XC) approximations have been studied, and results have been compared to the experimental transition energies, as well as, to the previous high-level ab initio calculations. TD-DFT gives satisfactory results in the cases of d(2), d(4), and low-spin d(6) complexes, but fails in the cases when transitions depend only on the ligand field splitting, and for states with strong character of double excitation. LF-DFT, as a non-empirical approach to the ligand field theory, takes into account in a balanced way both dynamic and non-dynamic correlation effects and hence accurately describes the multiplets of transition metal complexes, even in difficult cases such as sextet-quartet splitting in d(5) complexes. Use of the XC functionals designed for the accurate description of the spin-state splitting, e.g., OPBE, OPBE0, or SSB-D, is found to be crucial for proper prediction of the spin-forbidden excitations by LF-DFT. It is shown that LF-DFT is a valuable alternative to both TD-DFT and ab initio methods.


Acupuncture for anxiety and anxiety disorders--a systematic literature review.
The aim of this study was to evaluate the evidence for the efficacy of acupuncture in the treatment of anxiety and anxiety disorders by systematic review of the relevant research. Searches of the major biomedical databases (MEDLINE, EMBASE, ClNAHL, PsycINFO, Cochrane Library) were conducted between February and July 2004. Specialist complementary medicine databases were also searched and efforts made to identify unpublished research. No language restrictions were imposed and translations were obtained where necessary. Study methodology was appraised and clinical commentaries obtained for studies reporting clinical outcomes. Twelve controlled trials were located, of which 10 were randomised controlled trials (RCTs). Four RCTs focused on acupuncture in generalised anxiety disorder or anxiety neurosis, while six focused on anxiety in the perioperative period. No studies were located on the use of acupuncture specifically for panic disorder, phobias or obsessive-compulsive disorder. In generalised anxiety disorder or anxiety neurosis, it is difficult to interpret the findings of the studies of acupuncture because of the range of interventions against which acupuncture was compared. All trials reported positive findings but the reports lacked many basic methodological details. Reporting of the studies of perioperative anxiety was generally better and the initial indications are that acupuncture, specifically auricular acupuncture, is more effective than acupuncture at sham points and may be as effective as drug therapy in this situation. The results were, however, based on subjective measures and blinding could not be guaranteed. Positive findings are reported for acupuncture in the treatment of generalised anxiety disorder or anxiety neurosis but there is currently insufficient research evidence for firm conclusions to be drawn. No trials of acupuncture for other anxiety disorders were located. There is some limited evidence in favour of auricular acupuncture in perioperative anxiety. Overall, the promising findings indicate that further research is warranted in the form of well designed, adequately powered studies.


Comparing clinical outcomes of piperacillin-tazobactam administration and dosage strategies in critically ill adult patients: a systematic review and meta-analysis.
Recently, continuous administration of piperacillin-tazobactam has been proposed as a valuable alternative to traditional intermittent administration especially in critically ill patients. However, antibiotic dosing remains a challenge for clinicians as antibiotic dosing regimens are usually determined in non-critically ill hospitalized adult patients. The aim was to conduct a systematic review to identify and highlight studies comparing clinical outcomes of piperacillin tazobactam dosing regimens, continuous/prolonged infusion vs intermittent infusion in critically ill patients. Meta-analyses were performed to assess the overall effect of dosing regimen on clinical efficacy. Studies were identified systematically through searches of PubMed and Science Direct, in compliance with PRISMA guidelines. Following the systematic literature review, meta-analyses were performed using Review Manager. Twenty-three studies were included in the analysis involving 3828 critically ill adult participants in total (continuous/prolonged infusion = 2197 and intermittent infusion = 1631) from geographically diverse regions. Continuous/prolonged resulted in significantly: higher clinical cure rates (Odds Ratio 1.56, 95% Confidence Interval 1.28-1.90, P = 0 .0001), lower mortality rates (Odds Ratio 0.68, 95% Confidence Interval 0.55-0.84, P = 0 .0003), higher microbiological success rates (Odds Ratio 1.52, 95% Confidence Interval 1.10-2.11, P = 0.01) and decreasing the length of hospital stay (Mean Difference - 1.27, 95% Confidence Interval - 2.45-0.08, P = 0.04) in critically ill patients. Results from this study show that there is a significant level of evidence that clinical outcome in critically ill patients is improved in patients receiving piperacillin-tazobactam via continuous/prolonged infusion. However, more rigorous scientific studies in critically ill patients are warranted to reach a sufficient level of evidence and promote further implementation of C/PI as a dosing strategy.


The demonstration of a theory-based approach to the design of localized patient safety interventions.
There is evidence of unsafe care in healthcare systems globally. Interventions to implement recommended practice often have modest and variable effects. Ideally, selecting and adapting interventions according to local contexts should enhance effects. However, the means by which this can happen is seldom systematic, based on theory, or made transparent. This work aimed to demonstrate the applicability, feasibility, and acceptability of a theoretical domains framework implementation (TDFI) approach for co-designing patient safety interventions. We worked with three hospitals to support the implementation of evidence-based guidance to reduce the risk of feeding into misplaced nasogastric feeding tubes. Our stepped process, informed by the TDF and key principles from implementation literature, entailed: involving stakeholders; identifying target behaviors; identifying local factors (barriers and levers) affecting behavior change using a TDF-based questionnaire; working with stakeholders to generate specific local strategies to address key barriers; and supporting stakeholders to implement strategies. Exit interviews and audit data collection were undertaken to assess the feasibility and acceptability of this approach. Following audit and discussion, implementation teams for each Trust identified the process of checking the positioning of nasogastric tubes prior to feeding as the key behavior to target. Questionnaire results indicated differences in key barriers between organizations. Focus groups generated innovative, generalizable, and adaptable strategies for overcoming barriers, such as awareness events, screensavers, equipment modifications, and interactive learning resources. Exit interviews identified themes relating to the benefits, challenges, and sustainability of this approach. Time trend audit data were collected for 301 patients over an 18-month period for one Trust, suggesting clinically significant improved use of pH and documentation of practice following the intervention. The TDF is a feasible and acceptable framework to guide the implementation of patient safety interventions. The stepped TDFI approach engages healthcare professionals and facilitates contextualization in identifying the target behavior, eliciting local barriers, and selecting strategies to address those barriers. This approach may be of use to implementation teams and policy makers, although our promising findings confirm the need for a more rigorous evaluation; a balanced block evaluation is currently underway.


G-quadruplex conformation and dynamics are determined by loop length and sequence.
The quadruplex forming G-rich sequences are unevenly distributed throughout the human genome. Their enrichment in oncogenic promoters and telomeres has generated interest in targeting G-quadruplex (GQ) for an anticancer therapy. Here, we present a quantitative analysis on the conformations and dynamics of GQ forming sequences measured by single molecule fluorescence. Additionally, we relate these properties to GQ targeting ligands and G4 resolvase 1 (G4R1) protein binding. Our result shows that both the loop (non-G components) length and sequence contribute to the conformation of the GQ. Real time single molecule traces reveal that the folding dynamics also depend on the loop composition. We demonstrate that GQ-stabilizing small molecules, N-methyl mesoporphyrin IX (NMM), its analog, NMP and the G4R1 protein bind selectively to the parallel GQ conformation. Our findings point to the complexity of GQ folding governed by the loop length and sequence and how the GQ conformation determines the small molecule and protein binding propensity.


Distinct Neuroanatomical Correlates of Neuropsychiatric Symptoms in the Three Main Forms of Genetic Frontotemporal Dementia in the GENFI Cohort.
The overlap between frontotemporal dementia (FTD) and primary psychiatric disorders has been brought to light by reports of prominent neuropsychiatric symptoms (NPS) in FTD-related genetic mutations, particularly among C9orf72 and GRN carriers. It has been recently demonstrated that early neuroanatomical changes in genetic FTD may be different across the major disease-causing mutations. We aimed to identify whether NPS could be driven by distinct structural correlates. One hundred and sixty-seven mutation carriers (75 GRN, 60 C9orf72, and 32 MAPT) were included from the Genetic FTD Initiative (GENFI) study, a large international cohort of genetic FTD. Neuropsychiatric symptoms including delusions, hallucinations (visual, auditory, and tactile), depression, and anxiety were investigated using a structured interview. Voxel-based morphometry was performed to identify neuroanatomical correlates of NPS. Psychotic symptoms correlated mainly with grey matter (GM) atrophy in the anterior insula, left thalamus, cerebellum, and cortical regions including frontal, parietal, and occipital lobes in GRN mutations carriers. GM atrophy in posterior structures of the default-mode network was associated with anxiety in the GRN group. Delusions in C9orf72 expansion carriers were mainly associated with left frontal cortical atrophy. Cerebellar atrophy was found to be correlated only with anxiety in C9orf72 carriers. NPS in the MAPT group were mainly associated with volume loss in the temporal lobe. Neuroanatomical correlates of NPS appear to be distinct across the main forms of genetic FTD. Overall, our findings support overlapping brain structural changes between FTD and primary psychiatric disorders.


Enhancing the usefulness of the Mini-BESTest for measuring dynamic balance: a Rasch validation study.
Recently, a new balance scale, the Mini-BESTest, was introduced. This scale can be administered in about 15 min, and focuses on "dynamic balance". In spite of the recently increased use of this scale, further psychometric studies seem called for to enhance confidence in its use in different fields of clinical practice and research. To re-examine through Rasch analysis the metric properties of the Mini-BESTest and provide a nomogram that allow to quickly transform raw scores of the scale into linear estimates of dynamic balance. Observational cross-sectional study. Rehabilitation hospital. A total of 234 patients were consecutively admitted with a variety of neurological diseases causing balance impairment. Internal construct validity was assessed by determining how well data fit the Rasch model. Reliability was estimated for both persons and items. Scale unidimensionality and local independence of items were analysed performing a principal component analysis (PCA) on the standardized residuals. Also, a differential item functioning (DIF) analysis was run to assess the stability of item calibration across subsamples of patients. All 14 items of Mini-BESTest fitted the "dynamic balance" construct, i.e., the mean of the squared residuals for both the infit and outfit was between 0.8 and 1.2. The person abilities-item difficulty matching was very good. The reliability indices of the Mini-BESTest were as follows: person separation index=3.24 and person reliability=0.91; item separation index=12.00 and item reliability=0.99. The PCA of standardized residuals showed that the variance attributable to the Rasch factor was good (68%) and the eigenvalue of the unexplained variance in the first contrast was just 1.9, thus confirming the unidimensionality of the scale. No DIF was found across gender and age groups. The reliability indexes confirmed their high values, giving a high degree of confidence in the consistency of both person-ability and item-difficulty estimates. Results allowed to transform the ordinal summed raw scores of the Mini-BESTest into interval-level measurements using a nomogram. Since no significant local dependence between items was found, this means that each Mini-BESTest item is appropriate for measuring the variable of interest (dynamic balance) and not redundant. DIF analysis showed the stability of item hierarchy and difficulty among subsamples of patients of different gender and age. This study further increases confidence in use of the Mini-BESTest for clinical assessment of dynamic balance in patients undergoing rehabilitation.


An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study.
A new strain of a novel infectious disease affecting millions of people, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been declared as a pandemic by the World Health Organization (WHO). Currently, several clinical trials are underway to identify specific drugs for the treatment of this novel virus. The inhibition of the SARS-CoV-2 main protease is necessary for the blockage of the viral replication. Here, in this study, we have utilized a blind molecular docking approach to identify the possible inhibitors of the SARS-CoV-2 main protease, by screening a total of 33 molecules which includes natural products, anti-virals, anti-fungals, anti-nematodes and anti-protozoals. All the studied molecules could bind to the active site of the SARS-CoV-2 protease (PDB: 6Y84), out of which rutin (a natural compound) has the highest inhibitor efficiency among the 33 molecules studied, followed by ritonavir (control drug), emetine (anti-protozoal), hesperidin (a natural compound), lopinavir (control drug) and indinavir (anti-viral drug). All the molecules, studied out here could bind near the crucial catalytic residues, HIS41 and CYS145 of the main protease, and the molecules were surrounded by other active site residues like MET49, GLY143, HIS163, HIS164, GLU166, PRO168, and GLN189. As this study is based on molecular docking, hence being particular about the results obtained, requires extensive wet-lab experimentation and clinical trials under in vitro as well as in vivo conditions.Communicated by Ramaswamy H. Sarma.


The Relationship Between Number of Comorbidities and Age of Colorectal Cancer Diagnosis in US Male Veteran Population: A Single-Center Experience.
Comorbidities of tobacco and alcohol abuse and obesity are major risk factors for colon carcinogenesis. These risk factors are considered the most prevalent modifiable risk factors linked to malignancies including colorectal cancer (CRC) in both high- and low-income countries. The aim of this study was to investigate the relationship between number of comorbidities and age of CRC diagnosis in US male veteran population. A retrospective single-center study using chart review and the International Classification of Diseases, Ninth Revision (ICD-9) codes to identify patients with a diagnosis of CRC and comorbidities of tobacco abuse, alcohol abuse, hypertension (HTN), diabetes mellitus (DM) and chronic kidney disease (CKD). The primary aim was to study effect of these comorbidities on age of CRC diagnosis. Univariable and then multivariable logistic regression models were fit to age at diagnosis for each patient variable. A total of 362 patients were included in the study. The mean age of CRC diagnosis was 66.8. Eighty percent were Caucasians, and 20% were African Americans. African Americans were diagnosed with CRC 3.8 years younger compared to Caucasians (P = 0.01). Controlling for other variables in the multivariable model, age at CRC diagnosis was significantly lower for African Americans and for patients with higher total counts for tobacco and alcohol abuse and obesity. HTN, DM and CKD were not associated with a lower age of CRC diagnosis. Tobacco and alcohol abuse and obesity have negative cumulative effect on age of CRC diagnosis in US male veteran population. Patients with increasing number of these comorbidities are associated with significantly lower age of CRC diagnosis. It is important to identify veterans with these comorbidities and encourage CRC screening.


Genetically encoded chloride indicator with improved sensitivity.
Chloride (Cl) is the most abundant physiological anion. Abnormalities in Cl regulation are instrumental in the development of several important diseases including motor disorders and epilepsy. Because of difficulties in the spectroscopic measurement of Cl in live tissues there is little knowledge available regarding the mechanisms of regulation of intracellular Cl concentration. Several years ago, a CFP-YFP based ratiometric Cl indicator (Clomeleon) was introduced [Kuner, T., Augustine, G.J. A genetically encoded ratiometric indicator for chloride: capturing chloride transients in cultured hippocampal neurons. Neuron 2000; 27: 447-59]. This construct with relatively low sensitivity to Cl (K(app) approximately 160 mM) allows ratiometric monitoring of Cl using fluorescence emission ratio. Here, we propose a new CFP-YFP-based construct (Cl-sensor) with relatively high sensitivity to Cl (K(app) approximately 30 mM) due to triple YFP mutant. The construct also exhibits good pH sensitivity with pK(alpha) ranging from 7.1 to 8.0 pH units at different Cl concentrations. Using Cl-sensor we determined non-invasively the distribution of [Cl](i) in cultured CHO cells, in neurons of primary hippocampal cultures and in photoreceptors of rat retina. This genetically encoded indicator offers a means for monitoring Cl and pH under different physiological conditions and high-throughput screening of pharmacological agents.


Inflammatory cell infiltrates in advanced metastatic uveal melanoma.
Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival. Immunotherapy trials for mUM are few and to date have demonstrated only marginal success. High densities of tumor-associated macrophages (TAMs) and infiltrating T lymphocytes (TILs) in primary UM are associated with poor prognosis. Little is known about the immune microenvironment of mUM. Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver. Whole-tissue sections of liver mUM (n=35) were examined by immunohistochemistry. For TAMs, monoclonal antibodies against CD68 and CD163 were used. Macrophage density and morphology were scored using previous established systems. Density and spatial distribution of TILs were highlighted using antibodies against CD3 (pan-lymphocyte marker), CD4 (T-helper cells), and CD8 (T-cytotoxic cells). CD68+ and CD163+ TAMs were seen within the tumor in all 35 specimens; their density was "moderate" in 50% of cases and "few" in 43%, and the majority showed an "indeterminate" phenotype. CD3+ TILs were noted both within mUMs and surrounding the tumor. Of these, CD8+ TILs were "few" in number within mUM but were predominantly seen peritumorally at the tumor/normal liver interface, whereas CD4+ TILs showed a high perivascular density within mUM. CD68+ and CD163+ TAMs of "indeterminate" morphology were observed in mUM, suggesting a tendency toward the protumorigenic M2 phenotype. CD4+ TILs were seen within the mUM, whereas CD8+ TILs tended to be peritumoral. The biological and functional roles of inflammatory cells in mUM require further investigation to determine if they represent potential targets for future therapies in mUM.


Conducting cancer control and survivorship research via cooperative groups: a report from the American Society of Preventive Oncology.
As the number of cancer survivors expands, the need for cancer control and survivorship research becomes increasingly important. The National Cancer Institute (NCI) Cooperative Groups may offer a viable platform to perform such research. Observational, preventive, and behavioral research can often be performed within the cooperative group setting, especially if resources needed for evaluation are fairly simple, if protocols are easily implemented within the typical clinical setting, and if interventions are well standardized. Some protocols are better suited to cooperative groups than are others, and there are advantages and disadvantages to conducting survivorship research within the cooperative group setting. Behavioral researchers currently involved in cooperative groups, as well as program staff within the NCI, can serve as sources of information for those wishing to pursue symptom management and survivorship studies within the clinical trial setting. The structure of the cooperative groups is currently changing, but going forward, survivorship is bound to be a topic of interest and one that perhaps may be more easily addressed using the proposed more centralized structure.


Importance of anorectal manometry after definitive surgery for Hirschsprung's disease in children.
The purpose of this investigation is to evaluate anorectal function after definitive surgery for Hirschsprung's disease (HD) by anorectal manometry. We evaluated the anorectal manometric assessment of 18 children who were operated for HD. Functional outcomes were determined by a questionnaire. Rectoanal inhibitory reflex (RAIR) and maximum anal resting pressure (MARP) were monitored. The results were compared between obstructive patients and asymptomatic patients. The median age at definitive operation was 19 months (range 12-72 months). Anorectal manometry was performed in 14 male and 4 female patients. All the cases underwent three staged procedure for HD and modified Duhamel procedure was performed as definitive procedure for all the patients. Mean age was 4.3 months (range 25 days to 5 years) at time of diagnosis. Post-operative enterocolitis or severe constipation was observed in seven patients (38.8%). There were no patients with incontinence. Eighteen patients underwent anorectal manometry meanly 2 years after definitive operation. RAIR was absent in 14 (77.7%) patients and abnormal in 4 (22.2%). There were no significant differences in the MARP values between symptomatic and asymptomatic patients. The results of our study showed that the majority of the patients have impaired anorectal motility. There were no significant differences in the results of the functional studies for the seven patients with symptoms of obstruction or constipation when compared with asymptomatic patients after surgery for HD.


Mie scattering in the time domain. Part II. The role of diffraction.
The p=0 term of the Mie-Debye scattering amplitude contains the effects of external reflection and diffraction. We computed the reflected intensity in the time domain as a function of the scattering angle and delay time for a short electromagnetic pulse incident on a spherical particle and compared it to the predicted behavior in the forward-focusing region, the specular reflection region, and the glory region. We examined the physical consequences of three different approaches to the exact diffraction amplitude, and determined the signature of diffraction in the time domain. The external reflection surface wave amplitude gradually replaces the diffraction amplitude in the angular transition region between forward-focusing and the region of specular reflection. The details of this replacement were studied in the time domain.


Medical screening of 1500 patients in a dental surgery: a prospective study.
Communication between medical and dental practitioners about patients they have in common enhances total patient care, but such communication rarely occurs. This may be due to lack of appreciation by doctors of the medical risks to certain patients undergoing dental treatment. To ascertain a relevant medical history, prospective medical screening was performed on 1500 new patients attending a general dental practice using a standard health questionnaire followed by an interview between the patient and dentist. There were 382 (25.5%) patients with a current or past medical history of relevance to dentistry, 90 (6.0%) were taking medication of potential importance and 105 (7.0%) considered they had an intolerance to certain drugs. The screening provided a patient data base for medical and medico-legal purposes. A total of 376 (25.1%) questionnaires were filled out incorrectly and 63 of these (16.8%) had major misinformation about medical history. A small but important group deliberately misled the dentist either from fear of refusal of treatment or embarrassment about their medical history. Therefore interviews are an essential adjunct to written health questionnaires in eliciting accurate information. Formal screening of new patients is essential in general dental practice. Furthermore, general medical practitioners need to become aware of the common risks to patients undergoing dentistry. Better formal and informal communication between general medical and dental practitioners is recommended for the benefit of their mutual patients.


On a New Species of Parasitic Barnacle (Crustacea: Rhizocephala), Sacculina shiinoi sp. nov., Parasitizing Japanese Mud Shrimps Upogebia spp. (Decapoda: Thalassinidea: Upogebiidae), Including a Description of a Novel Morphological Structure in the Rhizocephala.
The rhizocephalan Sacculina shiinoi sp. nov. parasitizes three species of Upogebia in Japan. It is described morphologically and compared with another Upogebia parasite, Sacculina upogebiae Shiino, 1943 from Japan and Korea. These two species are the only sacculinids that parasitize mud shrimps. DNA analyses clearly show the two species to be separate and not closely related. The cuticle differs in being provided with close-set, branched, and spiny excrescences in S. shiinoi, while it lacks excrescences, but forms small scales in S. upogebiae. In S. upogebiae, the bulbous sperm-producing part and the narrow receptacle duct are separated by a compartmentalized mid portion, which is missing in S. shiinoi. A ridge, having a thickened, fluffy cuticle with a U-shaped course, passes across the visceral mass between the two receptacle openings in S. shiinoi. Such a structure has never been described in other rhizocephalans, and its function is uncertain.


Animal models for genetic neuromuscular diseases.
The neuromuscular disorders are a heterogeneous group of genetic diseases, caused by mutations in genes coding sarcolemmal, sarcomeric, and citosolic muscle proteins. Deficiencies or loss of function of these proteins leads to variable degree of progressive loss of motor ability. Several animal models, manifesting phenotypes observed in neuromuscular diseases, have been identified in nature or generated in laboratory. These models generally present physiological alterations observed in human patients and can be used as important tools for genetic, clinic, and histopathological studies. The mdx mouse is the most widely used animal model for Duchenne muscular dystrophy (DMD). Although it is a good genetic and biochemical model, presenting total deficiency of the protein dystrophin in the muscle, this mouse is not useful for clinical trials because of its very mild phenotype. The canine golden retriever MD model represents a more clinically similar model of DMD due to its larger size and significant muscle weakness. Autosomal recessive limb-girdle MD forms models include the SJL/J mice, which develop a spontaneous myopathy resulting from a mutation in the Dysferlin gene, being a model for LGMD2B. For the human sarcoglycanopahties (SG), the BIO14.6 hamster is the spontaneous animal model for delta-SG deficiency, whereas some canine models with deficiency of SG proteins have also been identified. More recently, using the homologous recombination technique in embryonic stem cell, several mouse models have been developed with null mutations in each one of the four SG genes. All sarcoglycan-null animals display a progressive muscular dystrophy of variable severity and share the property of a significant secondary reduction in the expression of the other members of the sarcoglycan subcomplex and other components of the Dystrophin-glycoprotein complex. Mouse models for congenital MD include the dy/dy (dystrophia-muscularis) mouse and the allelic mutant dy(2J)/dy(2J) mouse, both presenting significant reduction of alpha2-laminin in the muscle and a severe phenotype. The myodystrophy mouse (Large(myd)) harbors a mutation in the glycosyltransferase Large, which leads to altered glycosylation of alpha-DG, and also a severe phenotype. Other informative models for muscle proteins include the knockout mouse for myostatin, which demonstrated that this protein is a negative regulator of muscle growth. Additionally, the stress syndrome in pigs, caused by mutations in the porcine RYR1 gene, helped to localize the gene causing malignant hypertermia and Central Core myopathy in humans. The study of animal models for genetic diseases, in spite of the existence of differences in some phenotypes, can provide important clues to the understanding of the pathogenesis of these disorders and are also very valuable for testing strategies for therapeutic approaches.


Acute effect of meal glycemic index and glycemic load on blood glucose and insulin responses in humans.
Foods with contrasting glycemic index when incorporated into a meal, are able to differentially modify glycemia and insulinemia. However, little is known about whether this is dependent on the size of the meal. The purposes of this study were: i) to determine if the differential impact on blood glucose and insulin responses induced by contrasting GI foods is similar when provided in meals of different sizes, and; ii) to determine the relationship between the total meal glycemic load and the observed serum glucose and insulin responses. Twelve obese women (BMI 33.7 +/- 2.4 kg/m2) were recruited. Subjects received 4 different meals in random order. Two meals had a low glycemic index (40-43%) and two had a high-glycemic index (86-91%). Both meal types were given as two meal sizes with energy supply corresponding to 23% and 49% of predicted basal metabolic rate. Thus, meals with three different glycemic loads (95, 45-48 and 22 g) were administered. Blood samples were taken before and after each meal to determine glucose, free-fatty acids, insulin and glucagon concentrations over a 5-h period. An almost 2-fold higher serum glucose and insulin incremental area under the curve (AUC) over 2 h for the high- versus low-glycemic index same sized meals was observed (p < 0.05), however, for the serum glucose response in small meals this was not significant (p = 0.38). Calculated meal glycemic load was associated with 2 and 5 h serum glucose (r = 0.58, p < 0.01) and insulin (r = 0.54, p < 0.01) incremental and total AUC. In fact, when comparing the two meals with similar glycemic load but differing carbohydrate amount and type, very similar serum glucose and insulin responses were found. No differences were observed for serum free-fatty acids and glucagon profile in response to meal glycemic index. This study showed that foods of contrasting glycemic index induced a proportionally comparable difference in serum insulin response when provided in both small and large meals. The same was true for the serum glucose response but only in large meals. Glycemic load was useful in predicting the acute impact on blood glucose and insulin responses within the context of mixed meals.


Mode-coupling polarization rotator based on plasmonic waveguide.
A novel polarization rotator (PR) based on mode coupling in plasmonic waveguides is demonstrated by simulation. A silicon waveguide with asymmetric claddings of silicon oxide and metal is applied to induce a hybridization of the polarization modes. Operating at the telecommunication wavelength of 1.55 μm, polarization conversion efficiency of 99.7% can be achieved in a device at a length of 9.7 μm with an insertion loss of 2.2 dB. This PR can be easily fabricated by oblique deposition of the claddings after etching the silicon waveguide without precise alignment for two-step lithography as required in a previous design.


The safety and efficacy of red cell transfusions in neonates: a systematic review of randomized controlled trials.
Premature neonates commonly receive red blood cell (RBC) transfusions. This study systematically identified and appraised randomized controlled trials (RCTs) where the intervention was 'transfusion of red blood cells' from searches of multiple databases. Primary review outcomes were mortality, neurodevelopmental and respiratory endpoints. Two reviewers extracted data and assigned overall quality. Twenty-seven RCTs were identified and grouped into four predefined categories: trials comparing RBC transfusion versus no transfusion/placebo (n = 3); different thresholds for transfusion (n = 6); differing doses or administration schedule (n = 4), or different types or products of RBC (n = 14). In the threshold group of trials, enrolling 679 neonates, no significant differences in mortality (relative risk 1·22, 95% confidence interval 0·84-1·75) or chronic lung disease were found. Only two trials assessed neurodevelopment outcomes, both within the threshold group, but with differing results. The largest subgroup of RCTs by number evaluated different media for storage of red cells (n = 7), enrolling 221 neonates. The methodological quality of many RCTs was poor. The design of future RCTs can be informed by the lessons from this review. Many trials failed to report on outcomes that would be considered of primary importance to clinicians. Consistent reporting of adverse events is required, and endpoints need to include neurodevelopmental outcomes.


Survival of anti-Clostridium difficile bovine immunoglobulin concentrate in the human gastrointestinal tract.
To be therapeutically active, oral hyperimmune bovine immunoglobulin concentrate (BIC) must survive its passage through the intestinal tract. This led us to study the gastrointestinal stability of orally administered BIC directed against Clostridium difficile toxins (BIC-C. difficile). BIC-C. difficile was stable at neutral pH in vitro but was degraded at low pH, particularly in the presence of pepsin. Healthy volunteers (n = 6) took BIC-C. difficile (45 or 8 g) as a single oral dose. Total bovine immunoglobulin G (IgG) and specific anti-C. difficile IgG were measured in the stool. BIC was given under the following conditions: in the fasting state, in the fed state, with antacid, during omeprazole therapy, or in enteric capsules (released at pH > 6). The mean fecal bovine IgG content of 3-day stool collections was similar in the fasting (536 mg; 3.8% of the ingested dose of BIC), fed (221 mg; 1.6%), and antacid (381 mg; 2.7%) groups. Omeprazole therapy was associated with increased fecal bovine IgG levels (1253 mg; 8.8%), but this difference did not reach statistical significance (P = 0.07). Administration of 8 g of BIC-C. difficile in enteric capsules resulted in substantially higher fecal bovine IgG levels (1,124 mg; 32.7% of the oral dose) than those obtained after administration of nonencapsulated BIC (22 MG; 0.6%; P = 0.004). An inverse relationship was noted between intestinal transit time and fecal bovine IgG content (R = 0.83; P = 0.04 [data from omeprazole group]). Filtrates of stool samples collected after oral administration of BIC-C. difficile neutralized the cytotoxicity of C. difficile toxins A and B, whereas control stool filtrates did not. Bovine colostral IgG undergoes partial degradation in the intestinal tract. Exposure to acidic gastric secretions and prolonged colonic transit may both contribute to IgG degradation. Nonetheless, humans taking BIC-C. difficile orally have neutralizing antitoxin activity in their stool.


Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure.
Long-term functional capacities of marrow cell lines were defined by competitive repopulation, a technique capable of detecting a small decline in repopulating abilities. There was little or no difference between cells from old and young donors, but a single serial transplantation caused a large decline in repopulating ability. Varying the numbers of marrow cells transplanted into the initial carrier from 10(5) to 10(7) did not alter the ability of the carrier's marrow cells to repopulate in competition with previously untransplanted cells. This ability was improved only in carriers that had received 10(8) marrow cells, although deleterious effects of transplantation were still present. These effects were not solely caused by cell damage from the transplantation procedure, because transplantation by parabiosis, or recovery from sublethal irradiation without transplantation, reduced repopulating abilities as much as transplanting 10(5) to 10(7) marrow cells. The transplantation effect also was not caused solely by irradiation, because the same effect appeared in unirradiated W/Wv carriers. The transplantation effect was more pronounced when donors were identified by hemoglobin type than by chromosome markers, implying that nonerythroid cell lines may be less affected by transplantation than erythroid precursor cells. When the effects of a lifetime of normal function and a single transplantation were compared, the latter caused 3-7 times more decline in repopulating abilities of phytohemagglutinin-responsive cell precursors, and at least 10-20 times more decline in erythroid cell precursors. Stem cell lines can be serially transplanted at least five times before losing their ability to repopulate and save lethally irradiated recipients or to cure genetically anemic mice. Therefore, if transplantation causes an acceleration of the normal aging process, these figures suggest that stem cells should be able to function normally through at least 15-50 life spans.


The neural basis of financial risk taking.
Investors systematically deviate from rationality when making financial decisions, yet the mechanisms responsible for these deviations have not been identified. Using event-related fMRI, we examined whether anticipatory neural activity would predict optimal and suboptimal choices in a financial decision-making task. We characterized two types of deviations from the optimal investment strategy of a rational risk-neutral agent as risk-seeking mistakes and risk-aversion mistakes. Nucleus accumbens activation preceded risky choices as well as risk-seeking mistakes, while anterior insula activation preceded riskless choices as well as risk-aversion mistakes. These findings suggest that distinct neural circuits linked to anticipatory affect promote different types of financial choices and indicate that excessive activation of these circuits may lead to investing mistakes. Thus, consideration of anticipatory neural mechanisms may add predictive power to the rational actor model of economic decision making.


Self-management for medication reduction in chronic low back pain.
It has been demonstrated that pain relief is seldom produced by medication or surgical methods where there is evidence of emotional disturbance, as indicated by the MMPI. A program that attempts to engender a high level of patient responsibility in a population of chronic low back pain patients is described. Self-managed reduction of drug dependence is a major component of this program. The data indicate that the program produces a significant reduction in dependence on opiates, derivatives, synthetic opiates, hypnotics, sedatives, tranquilizers, and analgesics. Follow-up data (with attrition controlled) at six months and 12 months postdischarge do not provide any evidence for deterioration (ie, return to pretreatment levels of drug dependence). Thus, it appears that the programmatic impact is stable over at least a 12-month period postdischarge. Implications of these findings for the low back pain population, as well as other chronic pain populations, are discussed.