Mouse sperm basic nuclear protein. Electrophoretic characterization and fate after fertilization.
Mouse sperm were labeled in vivo with [3H]arginine. The sperm were then followed autoradiographically from the time of label incorporation until after fertilization. The label was completely lost from the sperm head after fertilization, during the oocyte's second meiotic division. That the [3H]arginine was incorporated into a sperm-specific basic protein was demonstrated by fractionating acid extracts of epididymal and ejaculated sperm with polyacrylamide gel electrophoresis. All the histone fractions were resolved in the epididymal extracts, but in addition a band was present that migrated faster than histone F2al and slower than the salmon protamine used as a marker. This new fraction (proposed name: musculine) was also present in ejaculated sperm; it was shown to be the only fraction that was labeled. Musculine therefore represents the end product of a histone transition in mice. It is, however, according to our electrophoretic characterization, not identical to the classical fish protamines. Rather, musculine resembles bovine sperm nuclear protein. Since the loss of this fraction from the sperm head was coincident with the rearrangement of the male genome, before its resumption of transcription, it is suggested that musculine is involved in the control of chromatin that accompanies spermiogenesis and fertilization.


Pharmacological and genetic accumulation of hypoxia-inducible factor-1alpha enhances excitatory synaptic transmission in hippocampal neurons through the production of vascular endothelial growth factor.
Hypoxia-inducible factor-1 (HIF-1) is an important transcriptional factor in mammalian cells for coordination of adaptive responses to hypoxia. It consists of a regulatory subunit HIF-1alpha, which accumulates under hypoxic conditions, and a constitutively expressed subunit HIF-1beta. In addition to the well characterized oxygen-dependent mode of action of HIF-1, recent work has shown that various growth factors and cytokines stimulate HIF-1alpha expression, thereby triggering transcription of numerous hypoxia-inducible genes by oxygen-independent mechanisms. In this study, we examined whether accumulation of HIF-1alpha induced by insulin-like growth factor-1 (IGF-1) has a regulatory role in excitatory synaptic transmission in hippocampal neuron cultures. Our results show that IGF-1 induced a time- and dose-dependent increase in HIF-1alpha expression that was blocked by pretreatment with selective IGF-1 receptor antagonist, transcriptional inhibitor, and translational inhibitors. In addition, pharmacological blockade of the phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin signaling pathway, but not extracellular signal-regulated kinase, inhibited IGF-1-induced HIF-1alpha expression. More importantly, the increase in HIF-1alpha expression induced by IGF-1 was accompanied by increasing levels of vascular endothelial growth factor (VEGF) mRNA and protein, which enhanced excitatory synaptic transmission. In parallel, blockade of HIF-1alpha activity by echinomycin or lentiviral infection with dominant-negative mutant HIF-1alpha or short hairpin RNA targeting HIF-1alpha inhibited the increase in expression of VEGF and the enhancement of synaptic transmission induced by IGF-1. Conversely, transfection of constitutively active HIF-1alpha into neurons mimicked the effects of IGF-1 treatment. Together, these results suggest that HIF-1alpha accumulation can enhance excitatory synaptic transmission in hippocampal neurons by regulating production of VEGF.


Meningeal cell-derived semaphorin 3A inhibits neurite outgrowth.
The neural scar that forms after injury to the mammalian central nervous system is a barrier to sprouting and regenerating axons. In addition to reactive astrocytes that are present throughout the lesion site, leptomeningeal fibroblasts invade the lesion core. When isolated in vitro, these cells form a very poor substrate for growing neurites, even more so than reactive astrocytes. Nevertheless the molecular mechanisms involved in this growth inhibition are not well understood. Semaphorins have been reported to be upregulated in meningeal cells (MCs) on mechanical injury to the brain and spinal cord. In the present study, we show that Sema3A mRNA and active protein are produced by cultured meningeal cells. A protein extract from these cells induces the collapse of embryonic dorsal root ganglion (DRG) growth cones. This collapsing activity is partially blocked by neuropilin-1 antibodies and is absent in meningeal cells derived from Sema3A-knockout mice. In addition to growth cone collapse, recombinant Sema3A but not Sema3C inhibits neurite outgrowth of embryonic DRGs. Consistent with this result we find that the inhibitory effect of meningeal cells on neurite outgrowth is partially overcome on Sema3A-deficient MCs. Furthermore we show that the inhibitory effect of MC-derived Sema3A on neurite outgrowth is modulated by nerve growth factor. Our results show that Sema3A, a chemorepellent during nervous system development, is a major neurite growth-inhibitory molecule in meningeal fibroblasts and is therefore likely to contribute to the inhibitory properties of the neural scar.


Beer? Over here! Examining attentional bias towards alcoholic and appetitive stimuli in a visual search eye-tracking task.
Experimental tasks that demonstrate alcohol-related attentional bias typically expose participants to single-stimulus targets (e.g. addiction Stroop, visual probe, anti-saccade task), which may not correspond fully with real-world contexts where alcoholic and non-alcoholic cues simultaneously compete for attention. Moreover, alcoholic stimuli are rarely matched to other appetitive non-alcoholic stimuli. To address these limitations by utilising a conjunction search eye-tracking task and matched stimuli to examine alcohol-related attentional bias. Thirty social drinkers (Mage = 19.87, SD = 1.74) were asked to detect whether alcoholic (beer), non-alcoholic (water) or non-appetitive (detergent) targets were present or absent amongst a visual array of matching and non-matching distractors. Both behavioural response times and eye-movement dwell time were measured. Social drinkers were significantly quicker to detect alcoholic and non-alcoholic appetitive targets relative to non-appetitive targets in an array of matching and mismatching distractors. Similarly, proportional dwell time was lower for both alcoholic and non-alcoholic appetitive distractors relative to non-appetitive distractors, suggesting that appetitive targets were relatively easier to detect. Social drinkers may exhibit generalised attentional bias towards alcoholic and non-alcoholic appetitive cues. This adds to emergent research suggesting that the mechanisms driving these individual's attention towards alcoholic cues might 'spill over' to other appetitive cues, possibly due to associative learning.


Gender differences in cognitive deficits in schizophrenia with and without diabetes.
This study investigated gender differences in cognition in schizophrenia with and without diabetes. Cognition was assessed in 263 individuals with schizophrenia with age range (40-68): 67 males and 34 females with schizophrenia with diabetes; and 125 males and 37 females with schizophrenia without diabetes according to the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Fasting glucose, hemoglobin A1c (HbA1c) and lipid levels were measured. Results showed that male individuals performed worse on most cognitive tasks, especially attention, in schizophrenia with than without diabetes. This result was not observed in female individuals. Also, individuals of both genders showed higher fasting glucose and HbA1c in schizophrenia with than without diabetes. In schizophrenia with diabetes, males had significantly worse cognition than females in all cognitive domains. Higher HbA1c, lower high-density lipoprotein, and an earlier age of onset of schizophrenia were found in males compared with female individuals. HbA1c was negatively associated with attention and the RBANS total score for males but not for females. In schizophrenia without diabetes, males showed worse performance in immediate and delayed memory than females. This study support cognition was worse for males with schizophrenia irrespective of whether they have diabetes. However, diabetes exemplified the gender differences, especially in attention.


Current perception thresholds in ageing.
We studied 40 healthy elderly and 31 healthy young volunteers and 25 elderly diabetic and 37 young diabetic patients. All subjects received detailed neurological examinations focusing particularly on sensory symptom and physical evaluations. Standardized assessment of symptoms and physical testing of light touch, pain, vibratory and thermal sensation were performed at the hand, wrist, elbow, foot, ankle and knee. The total symptom score (SS) and the total physical score (PS) were defined by summing test scores at each site. Current perception threshold (CPT) testing using constant current sine wave alternating current was completed at the same anatomical sites. CPT findings did not differ significantly between young and old healthy subjects. Older diabetic patients had higher CPTs than younger diabetic patients, but the severity of clinical diabetic neuropathy was greater in the older group. CPTs correlated with the degree of clinical diabetic neuropathy (r = 0.47 with SS and r = 0.60 with PS) rather than with age (r = 0.12). We conclude that current perception does not decline with age. Nor does ageing by itself worsen CPT values in patients with neuropathy. CPT testing is easily performed, clinically applicable and the first objective sensory measure not affected by the process of ageing.


On-chip automation of cell-free protein synthesis: new opportunities due to a novel reaction mode.
Many pharmaceuticals are proteins or their development is based on proteins. Cell-free protein synthesis (CFPS) is an innovative alternative to conventional cell based systems which enables the production of proteins with complex and even new characteristics. However, the short lifetime, low protein production and expensive reagent costs are still limitations of CFPS. Novel automated microfluidic systems might allow continuous, controllable and resource conserving CFPS. The presented microfluidic TRITT platform (TRITT for Transcription - RNA Immobilization & Transfer - Translation) addresses the individual biochemical requirements of the transcription and the translation step of CFPS in separate compartments, and combines the reaction steps by quasi-continuous transfer of RNA templates to enable automated CFPS. In detail, specific RNA templates with 5' and 3' hairpin structures for stabilization against nucleases were immobilized during in vitro transcription by newly designed and optimized hybridization oligonucleotides coupled to magnetizable particles. Transcription compatibility and reusability for immobilization of these functionalized particles was successfully proven. mRNA transfer was realized on-chip by magnetic actuated particle transfer, RNA elution and fluid flow to the in vitro translation compartment. The applicability of the microfluidic TRITT platform for the production of the cytotoxic protein Pierisin with simultaneous incorporation of a non-canonical amino acid for fluorescence labeling was demonstrated. The new reaction mode (TRITT mode) is a modified linked mode that fulfills the precondition for an automated modular reactor system. By continual transfer of new mRNA, the novel procedure overcomes problems caused by nuclease digestion and hydrolysis of mRNA during TL in standard CFPS reactions.


[Dreams and medicine in the pergamum asklepieion].
The article discusses the main aspects of the onirical theraphy in Greek theurgical medicine, practised, as well known, in Asklepius' temples all over Greek territories. Iamata, written sources and chronicles furnish reliable testimonies of activities performed in the sacred structures, most of which concerning the reading and interpretations of dreams. A privileged witness of these practices is Aelius Aristides, in the Ieroi Logoi describing the particular link connecting his psychological and metaphorical diseases to the divine power of Asklepius, revealing his healing terrific capacities mainly through therapeutic dreams.


Frequency-dependent taste-rejection by avian predation may select for defence chemical polymorphisms in aposematic prey.
Chemically defended insects advertise their unpalatability to avian predators using conspicuous aposematic coloration that predators learn to avoid. Insects utilize a wide variety of different compounds in their defences, and intraspecific variation in defence chemistry is common. We propose that polymorphisms in insect defence chemicals may be beneficial to insects by increasing survival from avian predators. Birds learn to avoid a colour signal faster when individual prey possesses one of two unpalatable chemicals rather than all prey having the same defence chemical. However, for chemical polymorphisms to evolve within a species, there must be benefits that allow rare chemical morphs to increase in frequency. Using domestic chicks as predators and coloured crumbs for prey, we provide evidence that birds taste and reject proportionally more of the individuals with rare defence chemicals than those with common defence chemicals. This indicates that the way in which birds attack and reject prey could enhance the survival of rare chemical morphs and select for chemical polymorphism in aposematic species. This is the first experiment to demonstrate that predators can directly influence the form taken by prey's chemical defences.


Life cycle assessment of sewage sludge management: a review.
In this article, 35 published studies on life cycle assessment (LCA) of sewage sludge were reviewed for their methodological and technological assumptions. Overall, LCA has been providing a flexible framework to quantify environmental impacts of wastewater and sewage sludge treatment and disposal processes for multiple scales, ranging from process selection to policy evaluation. The results of LCA are, in principle, unique to the goal and scope of each study, reflecting its local conditions and comparison between different LCAs is not intended. Furthermore, the assessments are limited by the methodological development of the life cycle impact assessment (LCIA) and the advancement of research in quantifying environmental emissions associated with wastewater and sewage sludge treatment processes. Thus, large discrepancies were found in the selection of the environmental emissions to be included and how they were estimated in the analysis. In order to reduce these choice uncertainties, consolidation of the modelling approach in the following area are recommended: quantification of fugitive gas emissions and modelling of disposal practices. Besides harmonization of the key technical assumptions, clear documentation of the modelling approach and the uncertainties associating with each assumption is encouraged so as to improve the integrity and robustness of assessment.


Idiosyncratic responses of Amazonian birds to primary forest disturbance.
As humans continue to alter tropical landscapes across the world, it is important to understand what environmental factors help determine the persistence of biodiversity in modified ecosystems. Studies on well-known taxonomic groups can offer critical insights as to the fate of biodiversity in these modified systems. Here we investigated species-specific responses of 44 forest-associated bird species with different behavioural traits to forest disturbance in 171 transects distributed across 31 landscapes in two regions of the eastern Brazilian Amazon. We investigated patterns of species occurrence in primary forests varyingly disturbed by selective-logging and fire and examined the relative importance of local, landscape and historical environmental variables in determining species occurrences. Within undisturbed and disturbed primary forest transects, we found that distance to forest edge and the biomass of large trees were the most important predictors driving the occurrence of individual species. However, we also found considerable variation in species responses to different environmental variables as well as inter-regional variation in the responses of the same species to the same environmental variables. We advocate the utility of using species-level analyses to complement community-wide responses in order to uncover highly variable and species-specific responses to environmental change that remain so poorly understood.


Classic and novel risk factor parameters in women with a history of preeclampsia.
Epidemiological studies demonstrate a relation between preeclampsia (PE) and an increased risk of maternal coronary heart disease (CHD) in later life. However, there are few data available to explain any underlying mechanism. We recruited 40 primigravid women with a history of proteinuric PE delivering between 1975 and 1985 and 40 controls, matched as a group for time of index pregnancy, smoking, and current body mass index to assess classic (lipids, blood pressure) and novel (adhesion molecules, insulin, leptin) risk factor pathways. Women with a history of PE had higher diastolic blood pressure compared with controls (83 vs 76 mm Hg, P<0.05), but there were no significant differences in fasting lipoprotein concentrations (P>0.20). However, concentrations of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 (ICAM-1) in particular were higher in the PE group by 14% (P=0.038) and 44% (P=0.002), respectively. The cases also demonstrated a tendency toward higher fasting insulin (P=0.08) concentrations and had higher glycosylated hemoglobin levels (P=0.004). Leptin concentrations were not significantly elevated. Interestingly, significantly more of the women with history of PE were classified as menopausal (37.55% vs 17.5%, P=0.045). The differences in ICAM-1 concentration persisted (P=0.010) after adjustment for potential confounders, including hormonal use/menopausal status, antihypertensive or lipid-lowering therapy, and social class. We conclude that classic risk factors alone cannot fully explain the elevated CHD risk in women with a history of PE. Rather markedly elevated ICAM-1 concentrations and specific but subtle features of the metabolic syndrome (glucose, blood pressure) are likely to be involved.


Carbon nanotubes: measuring dispersion and length.
Advanced technological uses of single-walled carbon nanotubes (SWCNTs) rely on the production of single length and chirality populations that are currently only available through liquid-phase post processing. The foundation of all of these processing steps is the attainment of individualized nanotube dispersions in solution. An understanding of the colloidal properties of the dispersed SWCNTs can then be used to design appropriate conditions for separations. In many instances nanotube size, particularly length, is especially active in determining the properties achievable in a given population, and, thus, there is a critical need for measurement technologies for both length distribution and effective separation techniques. In this Progress Report, the current state of the art for measuring dispersion and length populations, including separations, is documented, and examples are used to demonstrate the desirability of addressing these parameters.


A comprehensive rehabilitation programme tailored to the needs of adults with muscular dystrophy.
To assess if activities of daily living (ADL), coping and quality of life could be improved in adults with muscular dystrophy through a comprehensive rehabilitation programme. Quasi-experimental, controlled clinical study comparing patients with similar age and disease aspects. Two different counties in Sweden, being either study or control setting. The study group comprised 37 adults (21 women, 16 men; mean age 50 years), while the control group comprised 39 people (25 women, 14 men; mean age 46 years). Four rehabilitation sessions tailored to different medical, physical and psychosocial needs of the patients, comprising a total of 10 days over a period of 18 months. ADL, the Mental Adjustment to Cancer Scale measuring coping strategies, the Sickness Impact Profile measuring health-related quality of life, the Hospital Anxiety and Depression Scale, and the Psychosocial Well-being Questionnaire. No significant differences were found between groups with regard to the outcome measures. There was increased dependence on others in ADL after 18 months in both groups, but it was more pronounced in the control group. Furthermore, a clear trend was observed in the data with regard to coping patterns, the control group using more coping strategies such as 'Helplessness/hopelessness' (P= 0.057), 'Anxious preoccupation' (P = 0.085) and 'Fatalistic' (P= 0.073) when being compared to the study group. No apparent effects on ADL were found from the rehabilitation programme, although there was a tendency of reduction of maladaptive coping patterns in the study group. This initial study may provide the rationale and basis for a randomized controlled trial.


Brain-derived neurotrophic factor, impaired glucose metabolism, and bipolar disorder course.
The neurotrophin brain-derived neurotrophic factor (BDNF) has been proposed as a potential biomarker in bipolar disorder (BD). However, current evidence is limited and results have been highly heterogeneous. This study aimed to assess the moderating effect of impaired glucose metabolism (IGM) on plasma levels of BDNF in individuals with BD, and on the relationship between BDNF and variables of illness course. We measured and compared the plasma levels of BDNF in individuals with BD (n=57) and healthy controls (n=26). IGM was operationalized as pre-diabetes or type 2 diabetes mellitus. Information related to current and past psychiatric/medical history, as well as prescription of pharmacological treatments was also captured. Individuals with BD had lower levels of BDNF, relative to healthy controls, after adjustment for age, gender, current medications, smoking, alcohol use, and IGM (P=.046). There was no effect of IGM (P=.860) and no interaction between BD diagnosis and IGM (P=.893). Peripheral BDNF levels were positively correlated with lifetime depressive episodes (P<.001), psychiatric hospitalizations (P=.001) and suicide attempts (P=.021). IGM moderated the association between BDNF and the number of previous mood episodes (P<.001), wherein there was a positive correlation in euglycemic participants and a negative correlation in individuals with IGM. BD is independently associated with lower levels of BDNF; IGM may modify the relationship between BDNF and BD course, suggesting an interactive effect of BDNF with metabolic status on illness progression.


Urban particulate matter pollution: a tale of five cities.
Five case studies (Athens and Paris in Europe, Pittsburgh and Los Angeles in the United States, and Mexico City in Central America) are used to gain insights into the changing levels, sources, and role of atmospheric chemical processes in air quality in large urban areas as they develop technologically. Fine particulate matter is the focus of our analysis. In all cases reductions of emissions by industrial and transportation sources have resulted in significant improvements in air quality during the last few decades. However, these changes have resulted in the increasing importance of secondary particulate matter (PM) which dominates over primary in most cases. At the same time, long range transport of secondary PM from sources located hundreds of kilometres from the cities is becoming a bigger contributor to the urban PM levels in all seasons. "Non-traditional" sources including cooking, and residential and agricultural biomass burning contribute an increasing fraction of the now reduced fine PM levels. Atmospheric chemistry is found to change the chemical signatures of a number of these sources relatively fast both during the day and night, complicating the corresponding source apportionment.


Immature monocytes contribute to cardiopulmonary bypass-induced acute lung injury by generating inflammatory descendants.
As immune regulatory and effector cells, monocytes play an important role in the blood-extracorporeal circuit contact-related acute lung injury in patients undergoing cardiopulmonary bypass (CPB). However, circulating monocytes are phenotypically and functionally heterogeneous, so we characterised how immature monocytes affect acute lung injury induced by CPB. The identification and dynamic changes in monocyte subsets were monitored by flow cytometry in patients undergoing CPB and in a rat model of CPB. The differentiation and migration of monocyte subsets were explored by in vitro cultures and adoptive transfer in the CPB rat model. We observed a dramatic increase of two monocyte subsets in the peripheral blood of patients undergoing CPB, involving tumour necrosis factor (TNF)-α-producing, mature intermediate CD14highCD16+ monocytes and a novel immature CD14lowCD16- subset. The immature CD14lowCD16- monocytes possessed limited ability for TNF-α production, and failed to suppress T-cell proliferation mediated by T-cell receptor signalling. However, these immature cells were highly proliferative and could differentiate into TNF-α producing, mature CD14highCD16+ monocytes. In the rat model of CPB, we further demonstrated that CPB induced migration of immature monocytes into the lungs, either from the bone marrow or from the spleen. Moreover, we confirmed the hypothesis that immature subsets could contribute to CPB-induced acute lung injury by giving rise to TNF-α producing descendants. The immature CD14lowCD16- monocytes might contribute to blood-circuit contact-induced acute lung injury by generating TNF-α-producing, mature monocytes. New strategies based on monocyte manipulation could be a promising therapeutic approach for minimising CPB-related lung injury.


[Metronomic chemotherapy in pediatric oncology: hype or hope?].
Angiogenesis is crucial for the growth of cancer. As such, it has become an established target in fighting cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration at close regular intervals, with no prolonged drug-free breaks-is a potential novel approach to controlling advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property of killing resistant cancer cells while significantly reducing undesirable toxic side effects. We review the data regarding the use of metronomic chemotherapy in children with cancer and discuss its potential uses and limits.


Uncertainty evaluation for the spectroradiometric measurement of the averaged light-emitting diode intensity.
An uncertainty evaluation is presented for the spectroradiometric measurement of the averaged LED intensity (ALI), which is a standardized photometric quantity of LEDs introduced by the Commission Internationale de l'Eclairage. Using a spectral irradiance standard lamp as a calibration source for the spectroradiometer, 12 uncertainty components are sorted out and their propagation formulated with correlations between the components taken into account. The procedure of uncertainty evaluation is demonstrated for four LED samples of different colors; red, green, blue, and white. The relative uncertainties of the ALI of the test samples are determined to be in a range from 4.1% to 5.5% (k=2), but most of their dominant uncertainty components turn out to be systematic and correlated. In conclusion, correlations between the uncertainty components critically affect the overall uncertainty of the LED measurement using a spectroradiometer.


Competition between relatives and the evolution of dispersal in a parasitoid wasp.
Evolutionary theory predicts that levels of dispersal vary in response to the extent of local competition for resources and the relatedness between potential competitors. Here, we test these predictions by making use of a female dispersal dimorphism in the parasitoid wasp Melittobia australica. We show that there are two distinct female morphs, which differ in morphology, pattern of egg production, and dispersal behaviour. As predicted by theory, we found that greater competition for resources resulted in increased production of dispersing females. In contrast, we did not find support for the prediction that high relatedness between competitors increases the production of dispersing females in Melittobia. Finally, we exploit the close links between the evolutionary processes leading to selection for dispersal and for biased sex ratios to examine whether the pattern of dispersal can help distinguish between competing hypotheses for the lack of sex ratio adjustment in Melittobia.


A unified method for detecting secondary trait associations with rare variants: application to sequence data.
Next-generation sequencing has made possible the detection of rare variant (RV) associations with quantitative traits (QT). Due to high sequencing cost, many studies can only sequence a modest number of selected samples with extreme QT. Therefore association testing in individual studies can be underpowered. Besides the primary trait, many clinically important secondary traits are often measured. It is highly beneficial if multiple studies can be jointly analyzed for detecting associations with commonly measured traits. However, analyzing secondary traits in selected samples can be biased if sample ascertainment is not properly modeled. Some methods exist for analyzing secondary traits in selected samples, where some burden tests can be implemented. However p-values can only be evaluated analytically via asymptotic approximations, which may not be accurate. Additionally, potentially more powerful sequence kernel association tests, variable selection-based methods, and burden tests that require permutations cannot be incorporated. To overcome these limitations, we developed a unified method for analyzing secondary trait associations with RVs (STAR) in selected samples, incorporating all RV tests. Statistical significance can be evaluated either through permutations or analytically. STAR makes it possible to apply more powerful RV tests to analyze secondary trait associations. It also enables jointly analyzing multiple cohorts ascertained under different study designs, which greatly boosts power. The performance of STAR and commonly used RV association tests were comprehensively evaluated using simulation studies. STAR was also implemented to analyze a dataset from the SardiNIA project where samples with extreme low-density lipoprotein levels were sequenced. A significant association between LDLR and systolic blood pressure was identified, which is supported by pharmacogenetic studies. In summary, for sequencing studies, STAR is an important tool for detecting secondary-trait RV associations.


Coffee consumption and mortality in three Eastern European countries: results from the HAPIEE (Health, Alcohol and Psychosocial factors In Eastern Europe) study.
To test the association between coffee consumption and risk of all-cause, CVD and cancer death in a European cohort. Prospective cohort study. Cox proportional hazards models with adjustment for potential confounders to estimate multivariable hazard ratios (HR) and 95 % CI were used. Czech Republic, Russia and Poland. A total of 28561 individuals followed for 6·1 years. A total of 2121 deaths (43·1 % CVD and 35·7 % cancer mortality) occurred during the follow-up. Consumption of 3-4 cups coffee/d was associated with lower mortality risk in men (HR=0·83; 95 % CI 0·71, 0·99) and women (HR=0·63; 95 % CI 0·47, 0·84), while further intake showed non-significant reduced risk estimates (HR=0·71; 95 % CI 0·49, 1·04 and HR=0·51; 95 % CI 0·24, 1·10 in men and women, respectively). Decreased risk of CVD mortality was also found in men (HR=0·71; 95 % CI 0·54, 0·93) for consumption of 3-4 cups coffee/d. Stratified analysis revealed that consumption of a similar amount of coffee was associated with decreased risk of all-cause (HR=0·61; 95 % CI 0·43, 0·87) and cancer mortality (HR=0·59; 95 % CI 0·35, 0·99) in non-smoking women and decreased risk of all-cause mortality for >4 cups coffee/d in men with no/moderate alcohol intake. Coffee consumption was associated with decreased risk of mortality. The protective effect was even stronger when stratification by smoking status and alcohol intake was performed.


Medicinal benefits of Nigella sativa in bronchial asthma: A literature review.
Nigella sativa L. (NS) seeds, known as black seed, is a spice and a traditional herbal medicine used in various diseases including bronchial asthma. This review aimed to assess the studies supporting the medicinal use of NS in asthma and to highlight future research priorities. Various medical databases were searched for the effects of NS and its active secondary metabolites in asthma inflammation and outcomes. There were fourteen preclinical studies describing multiple effects of NS in animal or cellular models of asthma including bronchodilation, anti-histaminic, anti-inflammatory, anti-leukotrienes and immunomodulatory effects. Furthermore, seven clinical studies showed improvements in different asthma outcomes including symptoms, pulmonary function and laboratory parameters. However, often these studies are small and used ill-defined preparations. In conclusion, NS could be therapeutically beneficial in alleviating airway inflammation and the control of asthma symptoms, but the evidence remains scanty and is often based on poorly characterised preparations. Accordingly, well-designed large clinical studies using chemically well characterised NS preparation are required.


Phenotypic characterization and description of two major O-serotypes in Tenacibaculum maritimum strains from marine fishes.
Tenacibaculum maritimum is the etiological agent of marine flexibacteriosis disease, with the potential to cause severe mortalities in various cultured marine fishes. The development of effective preventive measures (i.e. vaccination) requires biochemical, serological and genetic knowledge of the pathogen. With this aim, the biochemical and antigenic characteristics of T. maritimum strains isolated from sole, turbot and gilthead sea bream were analysed. Rabbit antisera were prepared against sole and turbot strains to examine the antigenic relationships between the 29 isolates and 3 reference strains. The results of the slide agglutination test, dot-blot assay and immunoblotting of lipopolysaccharides (LPS) and membrane proteins were evaluated. All bacteria studied were biochemically identical to the T. maritimum reference strains. The slide agglutination assays using O-antigens revealed cross-reaction for all strains regardless of the host species and serum employed. However, when the dot-blot assays were performed, the existence of antigenic heterogeneity was demonstrated. This heterogeneity was supported by immunoblot analysis of the LPS, which clearly revealed 2 major serological groups that were distinguishable without the use of absorbed antiserum: Serotypes O1 and O2. These 2 serotypes seem to be host-specfic. In addition, 2 sole isolates and the Japanese reference strains displayed cross-reaction with both sera in all serological assays, and are considered to constitute a minor serotype, O1/O2. Analysis of total and outer membrane proteins revealed that all strains share a considerable number of common bands that are antigenically related.


Adjusting for Variation in Patient-Reported Outcome Measures Is Needed to Improve Care After Total Knee Arthroplasty.
Limited quantitative information exists about the patient and surgeon factors driving variation in patient-reported outcome measure (PROM) scores, limiting the use of these data in understanding and improving quality. The overall goal of this study was to learn how to adjust PROM scores to enable both individual and group quality improvement. Observational study in which preoperative Oxford Knee Score (OKS) and Patient Reported Outcomes Measurement System (PROMIS)-10 measures were prospectively obtained through patient survey from 1,173 of 1,435 possible patients before total knee arthroplasty and from 810 of the 1,173 patients at 12 months postoperatively (response rates = 81.7% and 69.0%). Regression analyses identified the relative contribution of patient and surgeon risk factors to OKS change from baseline to 12 months. Variation in patient scores and surgeon performance was described and quantified. Adjusted outcomes were used to calculate an observed and expected score for each surgeon. (1) Moderate variation was observed in pre-/post-OKS change among the surgeons (n = 16, mean change = 15.5 ± 2.2, range = 12.1-21.1). Forty-five percent of the variance in OKS change was explained by the factors included in our model. (2) Patient preoperative OKS and PROMIS physical score, race, and BMI were markedly associated with change in OKS, but other patient factors, surgeon volume, and years of experience were not. (3) Eight surgeons had observed scores greater than expected after adjustment, providing an opportunity to learn what strategies were associated with better outcomes. Traditional age/sex adjustment of patient mix would have had no effect on mean PROM scores by surgeon. An adjustment model that includes the factors found to be markedly associated with outcomes will allow care systems to identify individual surgeon care management strategies potentially important for improving patient outcomes.


Maternal high-fat diet during lactation reprograms the dopaminergic circuitry in mice.
The maternal perinatal environment modulates brain formation, and altered maternal nutrition has been linked to the development of metabolic and psychiatric disorders in the offspring. Here, we showed that maternal high-fat diet (HFD) feeding during lactation in mice elicits long-lasting changes in gene expression in the offspring's dopaminergic circuitry. This translated into silencing of dopaminergic midbrain neurons, reduced connectivity to their downstream targets, and reduced stimulus-evoked dopamine (DA) release in the striatum. Despite the attenuated activity of DA midbrain neurons, offspring from mothers exposed to HFD feeding exhibited a sexually dimorphic expression of DA-related phenotypes, i.e., hyperlocomotion in males and increased intake of palatable food and sucrose in females. These phenotypes arose from concomitantly increased spontaneous activity of D1 medium spiny neurons (MSNs) and profoundly decreased D2 MSN projections. Overall, we have unraveled a fundamental restructuring of dopaminergic circuitries upon time-restricted altered maternal nutrition to induce persistent behavioral changes in the offspring.


Development of a genome-wide anchored microsatellite map for common bean (Phaseolus vulgaris L.).
A total of 150 microsatellite markers developed for common bean ( Phaseolus vulgaris L.) were tested for parental polymorphism and used to determine the positions of 100 genetic loci on an integrated genetic map of the species. The value of these single-copy markers was evident in their ability to link two existing RFLP-based genetic maps with a base map developed for the Mesoamerican x Andean population, DOR364 x G19833. Two types of microsatellites were mapped, based respectively on gene-coding and anonymous genomic-sequences. Gene-based microsatellites proved to be less polymorphic (46.3%) than anonymous genomic microsatellites (64.3%) between the parents of two inter-genepool crosses. The majority of the microsatellites produced single bands and detected single loci, however four of the gene-based and three of the genomic microsatellites produced consistent double or multiple banding patterns and detected more than one locus. Microsatellite loci were found on each of the 11 chromosomes of common bean, the number per chromosome ranging from 5 to 17 with an average of ten microsatellites each. Total map length for the base map was 1,720 cM and the average chromosome length was 156.4 cM, with an average distance between microsatellite loci of 19.5 cM. The development of new microsatellites from sequences in the Genbank database and the implication of these results for genetic mapping, quantitative trait locus analysis and marker-assisted selection in common bean are described.


Interaction between two auxin-resistant mutants and their effects on lateral root formation in rice (Oryza sativa L.).
Since root elongation is very sensitive to auxin, screening for reduced inhibition in root elongation has been an important method for the detection of auxin-resistant mutants. Two recessive auxin-resistant lines of rice (Oryza sativa L. ssp. indica cv. IR8), arm1 and arm2, have been isolated by screening for resistance to 2,4-dichlorophenoxyacetic acid (2,4-D). arm1 displays a variety of morphological defects including reduced lateral root formation, increased seminal root elongation, reduced root diameter, and impaired xylem development in roots, while the arm2 phenotype is almost similar to wild-type IR8 except for a slightly reduced lateral root formation, impaired xylem development in roots and an enhanced plant height. Although the growth of arm2 roots exhibited a resistance to 2,4-D, it was sensitive to 1-naphthaleneacetic acid (NAA) as the wild type. At the same time, the arm2 roots showed a reduced [14C]2,4-D uptake while uptake of [3H]NAA was normal, suggesting that the resistance to 2,4-D of arm2 roots is due to a defect in 2,4-D uptake. To investigate the possible interaction between arm1 and arm2 genes, a double mutant has been constructed. The roots of arm1 arm2 double mutant were more resistant to 2,4-D and formed fewer lateral roots than those of either single mutant, suggesting that the two genes show synergistic effects with respect to both auxin response and lateral root formation. By contrast, all these mutants displayed the normal gravitropic response in roots, as did the wild-type plants. Taken together, Arm1 and Arm2 genes seem to function in different processes in the auxin-response pathways leading to lateral root formation.


Unfolding individual nucleosomes by stretching single chromatin fibers with optical tweezers.
Single chromatin fibers were assembled directly in the flow cell of an optical tweezers setup. A single lambda phage DNA molecule, suspended between two polystyrene beads, was exposed to a Xenopus laevis egg extract, leading to chromatin assembly with concomitant apparent shortening of the DNA molecule. Assembly was force-dependent and could not take place at forces exceeding 10 pN. The assembled single chromatin fiber was subjected to stretching by controlled movement of one of the beads with the force generated in the molecule continuously monitored with the second bead trapped in the optical trap. The force displayed discrete, sudden drops upon fiber stretching, reflecting discrete opening events in fiber structure. These opening events were quantized at increments in fiber length of approximately 65 nm and are attributed to unwrapping of the DNA from around individual histone octamers. Repeated stretching and relaxing of the fiber in the absence of egg extract showed that the loss of histone octamers was irreversible. The forces measured for individual nucleosome disruptions are in the range of 20-40 pN, comparable to forces reported for RNA- and DNA-polymerases.


Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia.
Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser(473) and Thr(308); abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34(+) cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC(50) < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.


Unravelling the influence of carbon dioxide on the adsorptive recovery of butanol from fermentation broth using ITQ-29 and ZIF-8.
The vapor phase adsorption of butanol from ABE fermentation at the head space of the fermenter is an interesting route for the efficient recovery of biobutanol. The presence of gases such as carbon dioxide that are produced during the fermentation process causes a stripping of valuable compounds from the aqueous into the vapor phase. This work studies the effect of the presence of carbon dioxide on the adsorption of butanol at a molecular level. With this aim in mind Monte Carlo simulations were employed to study the adsorption of mixtures containing carbon dioxide, butanol and ethanol. Molecular models for butanol and ethanol that reproduce experimental properties of the molecules such as polarity, vapor-liquid coexistence or liquid density have been developed. Pure component isotherms and heats of adsorption have been computed and compared to experimental data to check the accuracy of the interacting parameters. Adsorption of butanol/ethanol mixtures has been studied in absence and presence of CO2 on two representative materials, a pure silica LTA zeolite and a hydrophobic metal-organic framework ZIF-8. To get a better understanding of the molecular mechanism that governs the adsorption of the targeted mixture in the selected materials, the distribution of the molecules inside the structures was analyzed. The combination of these features allows obtaining a deeper understanding of the process and to identify the role of carbon dioxide in the butanol purification process.


Genetic and environmental influences on adult attention deficit hyperactivity disorder symptoms: a large Swedish population-based study of twins.
Attention deficit hyperactivity disorder (ADHD) frequently persists into adulthood. Family and twin studies delineate a disorder with strong genetic influences among children and adolescents based on parent- and teacher-reported data but little is known about the genetic and environmental contribution to DSM-IV ADHD symptoms in adulthood. We therefore aimed to investigate the impact of genetic and environmental influences on the inattentive and hyperactive-impulsive symptoms of ADHD in adults. Twin methods were applied to self-reported assessments of ADHD symptoms from a large population-based Swedish twin study that included data from 15 198 Swedish male and female twins aged 20 to 46 years. The broad heritability [i.e., A + D, where A is an additive genetic factor and D (dominance) a non-additive genetic factor] was 37% (A = 11%, D = 26%) for inattention and 38% (A = 18%, D = 20%) for hyperactivity-impulsivity. The results also indicate that 52% of the phenotypic correlation between inattention and hyperactivity-impulsivity (r = 0.43) was explained by genetic influences whereas the remaining part of the covariance was explained by non-shared environmental influences. These results were replicated across age strata. Our findings of moderate broad heritability estimates are consistent with previous literature on self-rated ADHD symptoms in older children, adolescents and adults and retrospective reports of self-rated childhood ADHD by adults but differ from studies of younger children with informant ratings. Future research needs to clarify whether our data indicate a true decrease in the heritability of ADHD in adults compared to children, or whether this relates to the use of self-ratings in contrast to informant data.


Multi-kingdom characterization of the core equine fecal microbiota based on multiple equine (sub)species.
Equine gut microbiology studies to date have primarily focused on horses and ponies, which represent only one of the eight extant equine species. This is despite asses and mules comprising almost half of the world's domesticated equines, and donkeys being superior to horses/ponies in their ability to degrade dietary fiber. Limited attention has also been given to commensal anaerobic fungi and archaea even though anaerobic fungi are potent fiber degrading organisms, the activity of which is enhanced by methanogenic archaea. Therefore, the objective of this study was to broaden the current knowledge of bacterial, anaerobic fungal and archaeal diversity of the equine fecal microbiota to multiple species of equines. Core taxa shared by all the equine fecal samples (n = 70) were determined and an overview given of the microbiota across different equine types (horse, donkey, horse × donkey and zebra). Equine type was associated with differences in both fecal microbial concentrations and community composition. Donkey was generally most distinct from the other equine types, with horse and zebra not differing. Despite this, a common bacterial core of eight OTUs (out of 2070) and 16 genus level groupings (out of 231) was found in all the fecal samples. This bacterial core represented a much larger proportion of the equine fecal microbiota than previously reported, primarily due to the detection of predominant core taxa belonging to the phyla Kiritimatiellaeota (formerly Verrucomicrobia subdivision 5) and Spirochaetes. The majority of the core bacterial taxa lack cultured representation. Archaea and anaerobic fungi were present in all animals, however, no core taxon was detected for either despite several taxa being prevalent and predominant. Whilst differences were observed between equine types, a core fecal microbiota existed across all the equines. This core was composed primarily of a few predominant bacterial taxa, the majority of which are novel and lack cultured representation. The lack of microbial cultures representing the predominant taxa needs to be addressed, as their availability is essential to gain fundamental knowledge of the microbial functions that underpin the equine hindgut ecosystem.


Snapshots during the catalytic cycle of a histidine acid phytase reveal an induced-fit structural mechanism.
Highly engineered phytases, which sequentially hydrolyze the hexakisphosphate ester of inositol known as phytic acid, are routinely added to the feeds of monogastric animals to improve phosphate bioavailability. New phytases are sought as starting points to further optimize the rate and extent of dephosphorylation of phytate in the animal digestive tract. Multiple inositol polyphosphate phosphatases (MINPPs) are clade 2 histidine phosphatases (HP2P) able to carry out the stepwise hydrolysis of phytate. MINPPs are not restricted by a strong positional specificity making them attractive targets for development as feed enzymes. Here, we describe the characterization of a MINPP from the Gram-positive bacterium Bifidobacterium longum (BlMINPP). BlMINPP has a typical HP2P-fold but, unusually, possesses a large α-domain polypeptide insertion relative to other MINPPs. This insertion, termed the U-loop, spans the active site and contributes to substrate specificity pockets underpopulated in other HP2Ps. Mutagenesis of U-loop residues reveals its contribution to enzyme kinetics and thermostability. Moreover, four crystal structures of the protein along the catalytic cycle capture, for the first time in an HP2P, a large ligand-driven α-domain motion essential to allow substrate access to the active site. This motion recruits residues both downstream of a molecular hinge and on the U-loop to participate in specificity subsites, and mutagenesis identified a mobile lysine residue as a key determinant of positional specificity of the enzyme. Taken together, these data provide important new insights to the factors determining stability, substrate recognition, and the structural mechanism of hydrolysis in this industrially important group of enzymes.


Two-wave mixing in an erbium-doped fiber amplifier for modulation depth enhancement of optically carried microwave signals.
We experimentally and theoretically analyze an original method based on two-wave mixing in an erbium-doped fiber amplifier for optical carrier reduction of microwave signals. 75% optical carrier attenuation has been observed, and a 10 dB modulation depth increase of the microwave signal is experimentally demonstrated. Moreover, calculated results are in good agreement with measurements and predict that up to 80% carrier attenuation is easily possible.


A novel animal model for pseudoxanthoma elasticum: the KK/HlJ mouse.
Pseudoxanthoma elasticum is a multisystem ectopic mineralization disorder caused by mutations in the ABCC6 gene. A mouse model with targeted ablation of the corresponding gene (Abcc6(tm1JfK)) develops ectopic mineralization on the dermal sheath of vibrissae as biomarker of the progressive mineralization disorder. Survey of 31 mouse strains in a longitudinal aging study has identified three mouse strains with similar ectopic mineralization of the vibrissae, particularly the KK/HlJ strain. We report here that this mouse strain depicts, in addition to ectopic mineralization of the dermal sheath of vibrissae, mineral deposits in a number of internal organs. Energy dispersive X-ray analysis and topographic mapping found the presence of calcium and phosphate as the principal ions in the mineral deposits, similar to that in Abcc6(tm1JfK) mice, suggesting the presence of calcium hydroxyapatite. The mineralization was associated with a splice junction mutation at the 3' end of exon 14 of the Abcc6 gene, resulting in a 5-bp deletion from the coding region and causing frame-shift of translation. As a consequence, essentially no Abcc6 protein was detected in the liver of the KK/HlJ mice, similar to that in Abcc6(tm1JfK) mice. Collectively, our studies found that the KK/HlJ mouse strain is characterized by ectopic mineralization due to a mutation in the Abcc6 gene and therefore provides a novel model system to study pseudoxanthoma elasticum.


Effects of age, weight, and fat slaughter end points on estimates of breed and retained heterosis effects for carcass traits.
The influence of different levels of adjusted fat thickness (AFT) and HCW slaughter end points (covariates) on estimates of breed and retained heterosis effects was studied for 14 carcass traits from serially slaughtered purebred and composite steers from the US Meat Animal Research Center (MARC). Contrasts among breed solutions were estimated at 0.7, 1.1, and 1.5 cm of AFT, and at 295.1, 340.5, and 385.9 kg of HCW. For constant slaughter age, contrasts were adjusted to the overall mean (432.5 d). Breed effects for Red Poll, Hereford, Limousin, Braunvieh, Pinzgauer, Gelbvieh, Simmental, Charolais, MARC I, MARC II, and MARC III were estimated as deviations from Angus. In addition, purebreds were pooled into 3 groups based on lean-to-fat ratio, and then differences were estimated among groups. Retention of combined individual and maternal heterosis was estimated for each composite. Mean retained heterosis for the 3 composites also was estimated. Breed rankings and expression of heterosis varied within and among end points. For example, Charolais had greater (P < 0.05) dressing percentages than Angus at the 2 largest levels of AFT and smaller (P < 0.01) percentages at the 2 largest levels of HCW, whereas the 2 breeds did not differ (P > or = 0.05) at a constant age. The MARC III composite produced 9.7 kg more (P < 0.01) fat than Angus at AFT of 0.7 cm, but 7.9 kg less (P < 0.05) at AFT of 1.5 cm. For MARC III, the estimate of retained heterosis for HCW was significant (P < 0.05) at the lowest level of AFT, but at the intermediate and greatest levels estimates were nil. The pattern was the same for MARC I and MARC III for LM area. Adjustment for age resulted in near zero estimates of retained heterosis for AFT, and similarly, adjustment for HCW resulted in nil estimates of retained heterosis for LM area. For actual retail product as a percentage of HCW, the estimate of retained heterosis for MARC III was negative (-1.27%; P < 0.05) at 0.7 cm but was significantly positive (2.55%; P < 0.05) at 1.5 cm of AFT. Furthermore, for MARC III, estimates of heterosis for some traits (fat as a percentage of HCW as another example) also doubled in magnitude depending on different levels of AFT end point. Rational exploitation of breeds requires special attention to use of different end points and levels of those end points, mainly for fat thickness.


How effective are biodiversity conservation payments in Mexico?
We assess the additional forest cover protected by 13 rural communities located in the southern state of Chiapas, Mexico, as a result of the economic incentives received through the country's national program of payments for biodiversity conservation. We use spatially explicit data at the intra-community level to define a credible counterfactual of conservation outcomes. We use covariate-matching specifications associated with spatially explicit variables and difference-in-difference estimators to determine the treatment effect. We estimate that the additional conservation represents between 12 and 14.7 percent of forest area enrolled in the program in comparison to control areas. Despite this high degree of additionality, we also observe lack of compliance in some plots participating in the PES program. This lack of compliance casts doubt on the ability of payments alone to guarantee long-term additionality in context of high deforestation rates, even with an augmented program budget or extension of participation to communities not yet enrolled.


Antidepressant augmentation using the N-methyl-D-aspartate antagonist memantine: a randomized, double-blind, placebo-controlled trial.
Intravenous N-methyl-d-aspartate (NMDA) antagonists have shown promising results in rapidly ameliorating depression symptoms, but placebo-controlled trials of oral NMDA antagonists as monotherapy have not observed efficacy. We conducted a randomized, double-blind, placebo-controlled trial of the NMDA antagonist memantine as an augmentation treatment for patients with DSM-IV major depressive disorder. Adult outpatients with major depressive disorder and partial response or nonresponse to their current antidepressant (as indicated by a 17-item Hamilton Depression Rating Scale score of ≥ 16 at baseline) were randomized (from July 2006-December 2011) to add memantine (flexible dose 5-20 mg/d, with all memantine group participants reaching the dose of 20 mg/d) (n = 15) or placebo (n = 16) to their existing treatment for 8 weeks. The primary outcome, change in Montgomery-Asberg Depression Rating Score (MADRS), was evaluated with repeated-measures mixed effects models using last-observation-carried-forward methods. Secondary outcomes included other depression and anxiety rating scales, suicidal and delusional ideation, and other adverse effects. 84% of participants completed the trial, including 93% of participants receiving memantine. Participants receiving memantine did not show a statistically or clinically significant change in MADRS scores compared to placebo, either over the entire study (β = 0.133, favoring placebo, P = .74) or at study completion (week 8 mean [SD] MADRS score change = -7.13 [6.61] [memantine]; -7.25 [11.14] [placebo]; P = .97). A minimal to small effect size (comparing change to baseline variability) favoring placebo was observed (Cohen d = 0.19). Similarly, no substantial effect sizes favoring memantine nor statistically significant between-group differences were observed on secondary efficacy outcomes. This trial did not detect significant statistical or effect size differences between memantine and placebo augmentation among nonresponders or poor responders to conventional antidepressants. While the small number of participants is a limitation, this study suggests memantine lacks substantial efficacy as an augmentation treatment for major depressive disorder. ClinicalTrials.gov identifier: NCT00344682.


Comparing laparoscopic appendectomy to open appendectomy in managing generalised purulent peritonitis from complicated appendicitis: the uncharted path.
The objective of the study was to compare the outcomes of patients with generalised purulent peritonitis from complicated appendicitis diagnosed intraoperatively who were managed laparoscopically to those managed via the open approach in a single institution. Data were collected from all cases admitted at Sebokeng Hospital, Johannesburg, over the past two years (2008 and 2009) with an intraoperative diagnosis of generalised purulent peritonitis from complicated appendicitis. Cases managed laparoscopically or by the open approach were analysed. The demographic findings, theatre duration, complications, days to the commencement of a full ward diet and the length of the hospital stay were the analysed parameters. One hundred and twenty appendectomies with generalised purulent peritonitis were performed during the study period. Of these, 58 patients underwent open appendectomy, and 62 patients had laparoscopic appendectomy. Both groups were comparable with regard to the demographics and preoperative findings. Theatre duration was significantly higher in the laparoscopic appendectomy group -116 minutes for a laparoscopic appendectomy compared to 87 minutes for an open appendectomy. The rate of intra-abdominal sepsis was also higher in the laparoscopic appendectomy group - 13% for a laparoscopic appendectomy, and 9% for an open appendectomy. A statistically significant decrease in the wound sepsis rate was shown in the laparoscopic appendectomy group. No statistical significant difference was demonstrated with regard to other postoperative complications, days to the commencement of a full ward diet and the length of hospital stay in both groups. More time (an average of 3.7 days) was spent in the intensive care unit and high care unit by those in the open appendectomy group, than those in the laparoscopic appendectomy group (an average of 2.0 days). However, age, duration of symptoms, clinical presentation and white blood cell count were influencing factors on the outcome measures in the open appendectomy group. Generalised purulent peritonitis from complicated appendicitis can be managed successfully laparoscopically. Both approaches are feasible, safe and have comparable outcomes. The laparoscopic approach resulted in fewer postoperative wound sepsis complications.


The evolution of the avian bill as a thermoregulatory organ.
The avian bill is a textbook example of how evolution shapes morphology in response to changing environments. Bills of seed-specialist finches in particular have been the focus of intense study demonstrating how climatic fluctuations acting on food availability drive bill size and shape. The avian bill also plays an important but under-appreciated role in body temperature regulation, and therefore in energetics. Birds are endothermic and rely on numerous mechanisms for balancing internal heat production with biophysical constraints of the environment. The bill is highly vascularised and heat exchange with the environment can vary substantially, ranging from around 2% to as high as 400% of basal heat production in certain species. This heat exchange may impact how birds respond to heat stress, substitute for evaporative water loss at elevated temperatures or environments of altered water availability, or be an energetic liability at low environmental temperatures. As a result, in numerous taxa, there is evidence for a positive association between bill size and environmental temperatures, both within and among species. Therefore, bill size is both developmentally flexible and evolutionarily adaptive in response to temperature. Understanding the evolution of variation in bill size however, requires explanations of all potential mechanisms. The purpose of this review, therefore, is to promote a greater understanding of the role of temperature on shaping bill size over spatial gradients as well as developmental, seasonal, and evolutionary timescales.


Evaluation of a drug-drug interaction: fax alert intervention program.
Clinicians often encounter information about drug-drug interactions (DDIs) during clinical practice. This information is found within product information (hardcopy and electronic) and various electronic systems. Prescribers may receive medication-related communications in practice that are distributed by facsimile (fax), mail, or telephone from pharmacies and pharmacy benefit managers (PBMs). The purpose of this study was to determine if near-real time fax alerts for potential drug-drug interactions (PDDIs) would influence prescribing. A prospective study, in cooperation with a pharmacy benefit manager (PBM), was conducted targeting 18 clinically important PDDIs. Fax alerts included an individualized letter to the prescriber with a list of the interacting drugs, PDDI evidence summaries with citations, and recommended clinical management strategies. Among the 18 PDDIs, 13 PDDIs could be assessed for prescription therapy changes using pharmacy claims data. A prospective cohort design was used to evaluate changes in prescription dispensing 90-days following a PDDI fax alert. A total of 8,075 fax alerts were sent to prescribers and there were 4,712 alerts for the 13 PDDIs that could be assessed for change using pharmacy claims data. There were 2,019 patients (interventions) for which fax alerts were sent to their prescribers who were matched with a control group consisting of patients with the same PDDIs but for whom no fax alert was sent. Overall, this study found 154 (7.6%) of patients in the fax alert group compared to 132 (6.5%) in the control group had changes in therapy (p = 0.177). This fax alert intervention program observed no statistically significant differences in prescribing with a fax alert compared to the control group. If PBMs chose to send individualized, evidence-based information to clinicians regarding drug-drug interactions, this study suggests it may not be an effective intervention to mitigate harm.


Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots.
Chronic hepatitis C (CHC) is associated with lipid-related changes and insulin resistance; the latter predicts response to antiviral therapy, liver disease progression and the risk of diabetes. We sought to determine whether insulin sensitivity improves following CHC viral eradication after antiviral therapy and whether this is accompanied by changes in fat depots or adipokine levels. We compared 8 normoglycaemic men with CHC (genotype 1 or 3) before and at least 6 months post viral eradication and 15 hepatitis C antibody negative controls using an intravenous glucose tolerance test and two-step hyperinsulinaemic-euglycaemic clamp with [6,6-(2) H2 ] glucose to assess peripheral and hepatic insulin sensitivity. Magnetic resonance imaging and spectroscopy quantified abdominal fat compartments, liver and intramyocellular lipid. Peripheral insulin sensitivity improved (glucose infusion rate during high-dose insulin increased from 10.1 ± 1.6 to 12 ± 2.1 mg/kg/min/, P = 0.025), with no change in hepatic insulin response following successful viral eradication, without any accompanying change in muscle, liver or abdominal fat depots. There was corresponding improvement in incremental glycaemic response to intravenous glucose (pretreatment: 62.1 ± 8.3 vs post-treatment: 56.1 ± 8.5 mm, P = 0.008). Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid-binding protein and lipocalin-2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance.


Aboriginal Drained-Field Cultivation in the Americas: Pre-Columbian reclamation of wet lands was widespread in the savannas and highlands of Latin America.
The three main types of land reclamation in aboriginal America were irrigation, terracing, and drainage. Of these, drainage techniques have received the least attention, probably because they are no longer important and because the remnants are not conspicuous. Nevertheless, drained-field cultivation was widespread and was practiced in varied environments, including high-land basins, tropical savannas, and temperate flood plains. Sites ranged from seasonally waterlogged or flooded areas to permanent lakes. Ridging, mounding, and ditching were emphasized, rather than diking. Tools were simple, crops varied, and fertilization was accomplished mainly by mulching.


Prognostic value of changes in N-terminal pro-brain natriuretic peptide in Val-HeFT (Valsartan Heart Failure Trial).
This study sought to evaluate the association between changes over time of N-terminal pro-brain natriuretic peptide (NT-proBNP) expressed in different ways and outcome in patients with stable and chronic heart failure (HF). Although previous studies examined the prognostic value of repeated determinations of BNP in HF, there are only limited data on the clinical utility of serial measurements of the inactive peptide NT-proBNP in a large population of ambulatory patients with chronic HF with sufficient follow-up time. The NT-proBNP was measured at randomization and after 4 months in 1,742 patients enrolled in the placebo arm of Val-HeFT (Valsartan Heart Failure Trial). Changes in NT-proBNP concentrations over 4 months were expressed as absolute change from baseline, percent relative changes, or categorical changes across a threshold value and related to subsequent mortality. A single determination of NT-proBNP (area under the curve at 4 months: 0.702, 95% confidence interval [CI]: 0.669 to 0.735) showed a higher prognostic discrimination than continuous changes of concentrations, expressed either as absolute (0.592, 95% CI: 0.549 to 0.634) or relative changes (0.602, 95% CI: 0.566 to 0.639). A Cox proportional hazards model showed that stratification of patients into 4 categories according to NT-proBNP levels at 2 time points 4 months apart with respect to a threshold concentration provided prognostic information in patients with chronic HF beyond that of a single determination. Serial determinations of NT-proBNP concentration and classification into few categories of changes according to threshold levels may be a superior strategy for risk stratification of patients with chronic and stable HF.


MicroRNA-based diagnostic tools for advanced fibrosis and cirrhosis in patients with chronic hepatitis B and C.
Staging fibrosis is crucial for the prognosis and to determine the rapid need of treatment in patients with chronic hepatitis B (CHB) and C (CHC). The expression of 13 fibrosis-related microRNAs (miRNAs) (miR-20a, miR-21, miR-27a, miR-27b, miR-29a, miR-29c, miR-92a, miR-122, miR-146a, miR-155, miR-221, miR-222, and miR-224) was analyzed in 194 serums and 177 liver biopsies of patients with either CHB or CHC to develop models to diagnose advanced fibrosis and cirrhosis (Metavir F3-F4). In CHB patients, the model (serum miR-122, serum miR-222, platelet count and alkaline phosphatase) was more accurate than APRI and FIB-4 to discriminate in between mild and moderate fibrosis (F1-F2) and F3-F4 (AUC of CHB model: 0.85 vs APRI: 0.70 and FIB-4: 0.81). In CHC patients, the model (hepatic miR-122, hepatic miR-224, platelet count, albumin and alanine aminotransferase) was more accurate than both APRI and FIB-4 to discriminate in between patients with F3-F4 and F1-F2 (AUC of the CHC model = 0.93 vs APRI: 0.86 and FIB-4: 0.79). Most of the miRNAs tested were differentially expressed in patients with CHB and CHC. In particular, serum miR-122 was 28-fold higher in patients with CHB than in those with CHC. Both CHB and CHC models may help for the diagnosis of advanced fibrosis and cirrhosis (F3-F4).


T cell and non-T cell compartments can independently determine resistance to Leishmania major.
In experimental murine cutaneous leishmaniasis caused by Leishmania major (Lm), the cellular determinants governing development of protective or exacerbative T cells are not well understood. We, therefore, attempted to determine the influence of T cell and non-T cell compartments on disease outcome. To this end, T cell chimeric mice were constructed using adult thymectomized lethally irradiated, bone marrow-reconstituted (ATXBM) animals of genetically resistant, C57BL/6, or susceptible, BALB/c, backgrounds. These hosts were engrafted with naive T cell populations from H-2-congenic susceptible, BALB.B6-H-2b, or resistant, C57BL/6.C-H-2d, animals, respectively. Chimeric mice were then infected with Lm, and disease outcome was monitored. BALB/c T cell chimeric mice, BALB/c ATXBM hosts given naive C57BL/6.C-H-2d T cells, resolved their infections as indicated by reductions in both lesion size and parasite numbers. Furthermore, the mice developed typical Th1 (interferon[IFN]-gamma hiinterleukin[IL]-4lo) cytokine patterns. In contrast, both sham chimeric, BALB/c ATXBM hosts given naive BALB/c T cells, and control irradiated euthymic mice succumbed to infection, producing Th2 profiles (IFN-gamma loIL-4hiIL-10hi). C57BL/6 T cell chimeras, C57BL/6 ATXBM hosts given naive BALB.B6-H-2b T cells, resolved their infections as did C57BL/6 sham chimeras and euthymic controls. Interestingly, whereas C57BL/6 control animals produced Th1 cytokines, chimeric animals progressed from Th0 (IFN-gamma hiIL-4hiIL-10hi) to Th2 (IFN-gamma loIL-4hiIL-10hi) cytokine profiles as cure ensued. Both reconstitution and chimeric status of all mice were confirmed by flow cytometry. In addition, T cell receptor V beta usage of Lm-specific blasts was determined. In all cases, V beta use was multiclonal, involving primarily V beta 2, 4, 6, 8.1, 8.2, 8.3, 10, and 14, with relative V beta frequencies differing between H-2b and H-2d animals. Most importantly, however, these differences did not segregate between cure and noncure outcomes. These findings indicate that: (a) genetic traits determining cure in Lm infection can direct disease outcome from both T cell and non-T cell compartments; (b) the presence of the curing genotype in only one compartment is sufficient to confer cure; (c) curing genotype T cells autonomously assume a Th1 cytokine profile-mediating cure; (d) noncuring genotype T cells can mediate cure in a curing environment, despite the onset of Th2 cytokine production; and lastly, (e) antigen specificity of responding T cells, as assessed by V beta T cell receptor diversity, is not a critical determinant of disease outcome.


Cardiac coherence, self-regulation, autonomic stability, and psychosocial well-being.
The ability to alter one's emotional responses is central to overall well-being and to effectively meeting the demands of life. One of the chief symptoms of events such as trauma, that overwhelm our capacities to successfully handle and adapt to them, is a shift in our internal baseline reference such that there ensues a repetitive activation of the traumatic event. This can result in high vigilance and over-sensitivity to environmental signals which are reflected in inappropriate emotional responses and autonomic nervous system dynamics. In this article we discuss the perspective that one's ability to self-regulate the quality of feeling and emotion of one's moment-to-moment experience is intimately tied to our physiology, and the reciprocal interactions among physiological, cognitive, and emotional systems. These interactions form the basis of information processing networks in which communication between systems occurs through the generation and transmission of rhythms and patterns of activity. Our discussion emphasizes the communication pathways between the heart and brain, as well as how these are related to cognitive and emotional function and self-regulatory capacity. We discuss the hypothesis that self-induced positive emotions increase the coherence in bodily processes, which is reflected in the pattern of the heart's rhythm. This shift in the heart rhythm in turn plays an important role in facilitating higher cognitive functions, creating emotional stability and facilitating states of calm. Over time, this establishes a new inner-baseline reference, a type of implicit memory that organizes perception, feelings, and behavior. Without establishing a new baseline reference, people are at risk of getting "stuck" in familiar, yet unhealthy emotional and behavioral patterns and living their lives through the automatic filters of past familiar or traumatic experience.


Unwinding the functions of the Pif1 family helicases.
Helicases are ubiquitous enzymes found in all organisms that are necessary for all (or virtually all) aspects of nucleic acid metabolism. The Pif1 helicase family is a group of 5'-->3' directed, ATP-dependent, super family IB helicases found in nearly all eukaryotes. Here, we review the discovery, evolution, and what is currently known about these enzymes in Saccharomyces cerevisiae (ScPif1 and ScRrm3), Schizosaccharomyces pombe (SpPfh1), Trypanosoma brucei (TbPIF1, 2, 5, and 8), mice (mPif1), and humans (hPif1). Pif1 helicases variously affect telomeric, ribosomal, and mitochondrial DNA replication, as well as Okazaki fragment maturation, and in at least some cases affect these processes by using their helicase activity to disrupt stable nucleoprotein complexes. While the functions of these enzymes vary within and between organisms, it is evident that Pif1 family helicases are crucial for both nuclear and mitochondrial genome maintenance.


Current status and challenges in sentinel node navigation surgery for early gastric cancer.
Although a number of feasibility studies for sentinel node (SN) concepts in gastric cancer have been conducted since 2000, there remains a debate regarding detailed detection techniques and oncological safety. Two important multicenter phase II clinical trials were performed in Japan that used different methods and reached different conclusions; one confirmed acceptable results with a false-negative rate of 7%, and the other showed an unacceptably high false-negative rate of 46.4%. The Sentinel Node Oriented Tailored Approach (SENORITA) trial is a multicenter randomized controlled phase III trial being performed in Korea. Patient enrollment is now complete and the long-term results are currently awaited. Recently, an image-guided SN mapping technique using infrared ray/fluorescence was introduced. This method might be a promising technology because it allows the clear visualization of SNs. With regard to the primary tumor, the non-exposed endoscopic wall-inversion surgery technique and non-exposure endolaparoscopic full-thickness resection with simple suturing technique have been reported. These methods prevent abdominal infection and tumor seeding and can be good alternatives to conventional laparoscopic gastric wedge resection. For indications, SN navigation surgery can be extended to patients who underwent non-curative endoscopic resection. Although a few studies have been performed on these patients, sentinel concepts may be beneficial to patients as they omit the need for additional gastrectomy. SN navigation surgery can lead to actual organ-preserving surgery and plays a key role in improving the quality of life of patients with early gastric cancer in the future.


Does exercise motivation predict engagement in objectively assessed bouts of moderate-intensity exercise? A self-determination theory perspective.
This study examined the utility of motivation as advanced by self-determination theory (Deci & Ryan, 2000) in predicting objectively assessed bouts of moderate intensity exercise behavior. Participants provided data pertaining to their exercise motivation. One week later, participants wore a combined accelerometer and heart rate monitor (Actiheart; Cambridge Neurotechnology Ltd) and 24-hr energy expenditure was estimated for 7 days. After controlling for gender and a combined marker of BMI and waist circumference, results showed autonomous motivation to positively predict moderate-intensity exercise bouts of >or=10 min, or=20 min, and an accumulation needed to meet public health recommendations for moderate intensity activity (i.e., ACSM/AHA guidelines). The present findings add bouts of objectively assessed exercise behavior to the growing body of literature that documents the adaptive consequences of engaging in exercise for autonomous reasons. Implications for practice and future work are discussed.


In Vitro Comparative Evaluation of Different Types of Impression Trays and Impression Materials on the Accuracy of Open Tray Implant Impressions: A Pilot Study.
Purpose. For a precise fit of multiple implant framework, having an accurate definitive cast is imperative. The present study evaluated dimensional accuracy of master casts obtained using different impression trays and materials with open tray impression technique. Materials and Methods. A machined aluminum reference model with four parallel implant analogues was fabricated. Forty implant level impressions were made. Eight groups (n = 5) were tested using impression materials (polyether and vinylsiloxanether) and four types of impression trays, two being custom (self-cure acrylic and light cure acrylic) and two being stock (plastic and metal). The interimplant distances were measured on master casts using a coordinate measuring machine. The collected data was compared with a standard reference model and was statistically analyzed using two-way ANOVA. Results. Statistically significant difference (p < 0.05) was found between the two impression materials. However, the difference seen was small (36 μm) irrespective of the tray type used. No significant difference (p > 0.05) was observed between varied stock and custom trays. Conclusions. The polyether impression material proved to be more accurate than vinylsiloxanether impression material. The rigid nonperforated stock trays, both plastic and metal, could be an alternative for custom trays for multi-implant impressions when used with medium viscosity impression materials.


Evidence for heightened hexokinase II immunoexpression in hepatocyte dysplasia and hepatocellular carcinoma.
Normal hepatocytes exhibit low-affinity hexokinase (glucokinase [HKIV]), but during oncogenesis, there is a switch from HKIV to HKII expression. The aims of this study were to compare the immunoexpression of HKII in non-dysplastic cirrhosis (NDC), liver cell change/dysplasia in cirrhosis (LCD), HCC, and normal liver control tissues, and to correlate HKII expression with clinical and histopathological parameters. Immunohistochemistry was performed on a liver cancer progression tissue array consisting of specimens from explants with cirrhosis, including 45 tissue samples with HCC, 108 without HCC, 143 with LCD, and 8 normal liver control tissues. HKII expression was quantified as positive pixel counts/square millimeter (ppc/mm(2)) by image analysis. There was a stepwise increase in HKII level from normal liver tissue to NDC, to LCD, and to HCC (p = 0.001). HKII levels were significantly higher in areas of LCD versus NDC (p ≤ 0.001), and in LCD and HCC versus NDC (p = 0.007). HKII levels were similar in LCD and HCC (p = 0.124). HKII levels were higher in grade 2-4 versus grade 1 HCCs (p = 0.044), and in pleomorphic versus non-pleomorphic HCC variants (p = 0.041). Higher levels of HKII expression in LCD and HCC versus NDC and in higher tumor grade remained significant in multivariate analysis. Higher levels of HKII immunoexpression in LDC and HCC compared with NDC suggest that upregulation of HKII occurs during the process of hepatocarcinogenesis in humans. In HCC, higher levels of HKII are associated with more aggressive histological features.


A matter of potential concern: natural organic matter alters the electrical properties of fish gills.
Natural organic matter (NOM) is an important constituent of aquatic environments; however, its influence on aquatic biota remains poorly studied. In the current study, NOM was isolated from nine different sites in southern Ontario, Canada, by the on-site treatment of water by reverse osmosis, followed by cation exchange. NOM from each site was reconstituted to 10 mg of C/L and pH 7.0 and exposed to either adult rainbow trout implanted with indwelling catheters or to in vitro primary cultures of the gill epithelium grown on semipermeable membranes. In both the in vivo and in vitro preparations, NOM was found to hyperpolarize transepithelial potential (TEP), with the magnitude of this change correlating extremely well to the absorptivity of the NOM at 340 nm, which is an index of its aromaticity. Gill hyperpolarization appeared to be independent of Ca2+ complexation by the NOM in all but two samples tested. We argue that NOM has direct actions on the ionic transport and/or permeability properties of fish gills. While NOM effects on the bioavailability of contaminants are well-known, NOM actions on such fundamental physiological properties of the gills have previously been overlooked. These may be of comparable or greater magnitude than commonly reported for other water-quality variables (e.g., hardness, pH, salinity) and therefore of critical importance in ecological understanding and risk assessment.


Diabetes self-assessment score and the development of diabetes: A 10-year prospective study.
To verify that the Korean Diabetes Score (KDS), a self-assessment, predicts the risk of diabetes in various comprehensive risk models, and to investigate factors that enhance its predictive ability in a large cohort. We analyzed 8735 adults without diabetes in the Korean Genome and Epidemiology Study, an ongoing large community-based 10-year cohort study. Incident diabetes was defined as fasting blood glucose ≥126 mg/dL or postload 2-hour glucose ≥200 mg/dL by 75 g oral glucose tolerance test conducted biennually, or currently taking medication for diabetes. Hazard ratios (HRs) using Cox regression were calculated for relative risk of developing diabetes as associated with the KDS, and performance of risk models was assessed by area under the receiver-operating characteristic curve (AUC). Of 8735 participants, 1497 (17.1%) developed diabetes over 10 years. The prevalence of incident diabetes was 10.3% in people with a KDS <5 and was 21.8% in those with KDS ≥5 (P < .001). Increasing KDS was significantly associated with developing diabetes (adjusted HR: 1.13; 95% confidence interval:1.09,1.18). The comprehensive prediction model with KDS added to fasting glucose, glycated hemoglobin, postload 2-hour glucose, and triglyceride showed a markedly higher AUC (0.782) compared to KDS alone (0.641). A low insulinogenic index (IGI) level, but not insulin resistance, was a significant determinant of developing diabetes in subjects who had baseline KDS < 5. We confirmed that KDS as a 10-year risk model to predict diabetes becomes more potent when added to relevant laboratory parameters. Beta-cell function as assessed by IGI should be taken into account when predicting diabetes using the KDS.


Supramolecular gels based on boronate esters and imidazolyl donors.
Dative boron-nitrogen bonds can be used for the controlled assembly of boronate esters and N-donor ligands. So far, most investigations have focused on crystalline assemblies. In contrast, there are very few reports about soft materials based on dative B-N bonds. Here, we describe the formation of gels by aggregation of diboronate esters and ditopic bisimidazolyl donor ligands. Analyses of low molecular weight model compounds by NMR spectroscopy, isothermal titration calorimetry, and X-ray crystallography reveal that imidazolyl ligands form particularly strong dative bonds with boronate esters. The strong interaction allows gel formation in competitive polar solvents such as THF and acetone. In less polar solvents, very low critical gel concentrations of down to 0.02 wt% are observed. By using a diboronate ester linked by an azobenzene group, it is possible to form a photoresponsive gel.


Epirubicin With Cyclophosphamide Followed by Docetaxel With Trastuzumab and Bevacizumab as Neoadjuvant Therapy for HER2-Positive Locally Advanced Breast Cancer or as Adjuvant Therapy for HER2-Positive Pathologic Stage III Breast Cancer: A Phase II Trial of the NSABP Foundation Research Group, FB-5.
The purpose of this study was to determine the cardiac safety and clinical activity of trastuzumab and bevacizumab with docetaxel after epirubicin with cyclophosphamide (EC) in patients with HER2-positive locally advanced breast cancer (LABC) or pathologic stage 3 breast cancer (PS3BC). Patients received every 3 week treatment with 4 cycles of EC (90/600 mg/m2) followed by 4 cycles of docetaxel (100 mg/m2). Targeted therapy with standard-dose trastuzumab with bevacizumab 15 mg/kg was given for a total of 1 year. Coprimary end points were (1) rate of cardiac events (CEs) in all patients defined as clinical congestive heart failure with a significant decrease in left ventricular ejection fraction or cardiac deaths; and (2) pathologic complete response (pCR) in breast and nodes in the neoadjuvant cohort. An independent cardiac review panel determined whether criteria for a CE were met. A total of 105 patients were accrued, 76 with LABC treated with neoadjuvant therapy and 29 with PS3BC treated with adjuvant therapy. Median follow-up was 59.2 months. Among 99 evaluable patients for cardiac safety, 4 (4%; 95% confidence interval [CI], 1.1%-10.0%) met CE criteria. The pCR percentage in LABC patients was 46% (95% CI, 34%-59%). Five-year recurrence-free survival (RFS) and overall survival (OS) for all patients was 79.9% and 90.8%, respectively. The regimen met predefined criteria for activity of interest with an acceptable rate of CEs. Although the pCR percentage was comparable with chemotherapy regimens with trastuzumab alone the high RFS and OS are of interest in these high-risk populations.


Advanced drug delivery and targeting technologies for the ocular diseases.
Ocular targeted therapy has enormously been advanced by implementation of new methods of drug delivery and targeting using implantable drug delivery systems (DDSs) or devices (DDDs), stimuli-responsive advanced biomaterials, multimodal nanomedicines, cell therapy modalities and medical bioMEMs. These technologies tackle several ocular diseases such as inflammation-based diseases (e.g., scleritis, keratitis, uveitis, iritis, conjunctivitis, chorioretinitis, choroiditis, retinitis, retinochoroiditis), ocular hypertension and neuropathy, age-related macular degeneration and mucopolysaccharidosis (MPS) due to accumulation of glycosaminoglycans (GAGs). Such therapies appear to provide ultimate treatments, even though much more effective, yet biocompatible, noninvasive therapies are needed to control some disabling ocular diseases/disorders. In the current study, we have reviewed and discussed recent advancements on ocular targeted therapies. On the ground that the pharmacokinetic and pharmacodynamic analyses of ophthalmic drugs need special techniques, most of ocular DDSs/devices developments have been designed to localized therapy within the eye. Application of advanced DDSs such as Subconjunctival insert/implants (e.g., latanoprost implant, Gamunex-C), episcleral implant (e.g., LX201), cationic emulsions (e.g., Cationorm™, Vekacia™, Cyclokat™), intac/punctal plug DDSs (latanoprost punctal plug delivery system, L-PPDS), and intravitreal implants (I-vitaion™, NT-501, NT- 503, MicroPump, Thethadur, IB-20089 Verisome™, Cortiject, DE-102, Retisert™, Iluvein™ and Ozurdex™) have significantly improved the treatment of ocular diseases. However, most of these DDSs/devices are applied invasively and even need surgical procedures. Of these, use of de novo technologies such as advanced stimuli-responsive nanomaterials, multimodal nanosystems (NSs)/nanoconjugates (NCs), biomacromolecualr scaffolds, and bioengineered cell therapies need to be further advanced to get better compliance and higher clinical impacts. Despite mankind successful battle on ocular diseases, our challenge will continue to battle the ocular disease that happen with aging. Yet, we need to understand the molecular aspects of eye diseases in a holistic way and develop ultimate treatment protocols preferably as non-invasive systems.


Overview of preventable industrial causes of occupational cancer.
This paper summarizes what is known about preventable causes of occupational cancer, including single agents, complex mixtures, and broad occupational associations. Epidemiologic methods have been very successful in documenting cancer risks associated with single agents. Epidemiologic data are most conclusive when an exposure-response relationship can be demonstrated. Examples of agents for which epidemiologic studies provide evidence of an exposure-response relationship include benzene and (concurrent exposure to) ortho-toluidine and aniline. Vinyl chloride and bischloromethyl ether are examples of associations between single agents and rare histologic types of cancer. It is more difficult to conduct epidemiologic studies to identify cancer risks associated with complex mixtures. Studies of diesel exhaust and lung cancer and metal machining oils are cited as having employed advanced industrial hygiene and epidemiologic methods for studies of complex mixtures. Elevated cancer risks have also been identified in broad occupational groups, including painters and dry cleaners. Epidemiologic case-control studies are often used to detect such associations but are limited in their abilities to detect the causal agents. Major gaps exist in knowledge of occupational cancer risks among women workers and workers of color. Because epidemiologic research measures illness and mortality that have already occurred, a positive study can be interpreted to represent a failure in prevention. The challenge we face in the next decade is to identify interventions earlier in the causal pathway (toxicologic testing, biomarkers of exposure or precancerous changes, institution of engineering and good industrial hygiene practices to reduce occupational exposure levels) so that occupational cancer can be prevented.


Effects of functional ability and training on chair-rise biomechanics in older adults.
Difficulty in rising from a chair is common in older adults and may be assessed by examining the biomechanics of the rise. The purposes of this study were (i) to analyze the biomechanics of rise performance during chair-rise tasks with varying task demand in older adults with varying rise ability and (ii) to determine whether a strength-training program might improve chair-rise success and alter chair-rise biomechanics, particularly under situations of increased task demand. A training group (n = 16; mean age, 82 years) completed a 12-week strength-training regimen while a control group (n = 14; mean age, 84 years) participated in a seated flexibility program. Outcomes included the ability to complete seven chair-rise tasks, and, if the chair-rise tasks were successful, the biomechanics of these rises. Chair-rise task demand was increased by lowering the seat height, restricting the use of hands, increasing rise speed, and limiting foot support. At baseline, increased chair-rise task demand generally required increased task completion time, increased anterior center of pressure (COP) placement, increased momentum, increased hip flexion, and increased hip and knee torque output. Those unable to rise at 100% knee height without the use of their hands (task NH-100), compared with those able to rise during task NH-100, followed this pattern in requiring increased time, more anterior placement of the COP, and increased hip flexion to rise in the least demanding tasks allowing the use of hands. However, the unable subjects generated less momentum and knee torque in these tasks. At 12 weeks, and compared with baseline and controls, the training group demonstrated changes in chair-rise biomechanics but no significant changes in rise success. The training subjects, as compared with the controls, maintained a more posterior COP, increased their vertical and horizontal momentum, maintained their knees in greater extension, and maintained their knee-torque output. These data demonstrate that subtle yet significant changes can be demonstrated in chair-rise performance as a result of a controlled resistance-training program. These biomechanical changes may represent a shift away from impairment in chair-rise ability, and, although the changes are small, they represent how training may reduce rise difficulty.