Good performance in the management of acute heart failure in cardiogeriatric departments: the ICREX-94 experience.
A growing number of elderly patients hospitalized for Acute Heart Failure (AHF) are being managed in cardiogeriatrics departments, but their characteristics and prognosis are poorly known. This study aimed to investigate the profile and outcome (rehospitalization at 90 days) of patients hospitalized for AHF in cardiogeriatrics departments in the Val-de-Marne area in the suburbs of Paris, and to compare them to AHF patients hospitalized in cardiology departments in the same area. Observational study, ICREX-94, conducted in seven cardiology departments in France and three specific cardiogeriatrics departments in Val-de-Marne. A total of 308 patients were hospitalized for AHF between October 2017 and January 2019. During the 90 days following discharge, 29.6% patients were readmitted to the hospital. Compared with patients hospitalized in cardiology departments, patients in cardiogeriatrics departments were older (p < 0.001), less independent (living more often alone or in an institution) (p < 0.001), more often depressed (p < 0.001), had more often major neurocognitive disorder (p < 0.001), had a higher Human Development Index (HDI, p < 0.001), and were less often diagnosed with amyloidosis (p < 0.001). There was no difference in outcome whether patients were discharged from cardiology or cardiogeriatrics departments. The most frequent precipitating factors underlying AHF decompensation between the first and second hospitalization were arrhythmia and infection. AHF patients discharged from cardiogeriatrics departments, compared to cardiology departments, showed clinical differences but had the same prognosis regarding AHF rehospitalization at 90 days.


Complex antithrombotic therapy: determinants of patient preference and impact on medication adherence.
For years, older patients have been prescribed multiple blood-thinning medications (complex antithrombotic therapy [CAT]) to decrease their risk of cardiovascular events. These therapies, however, increase risk of adverse bleeding events. We assessed patient-reported trade-offs between cardioprotective benefit, gastrointestinal bleeding risk, and burden of self-management using adaptive conjoint analysis (ACA). As ACA could be a clinically useful tool to obtain patient preferences and guide future patient-centered care, we examined the clinical application of ACA to obtain patient preferences and the impact of ACA on medication adherence. An electronic ACA survey led 201 respondents through medication risk-benefit trade-offs, revealing patients' preferences for the CAT risk/benefit profile they valued most. The post-ACA prescription regimen was categorized as concordant or discordant with elicited preferences. Adherence was measured using VA pharmacy refill data to measure persistence of use prior to and 1 year following preference-elicitation. Additionally, we analyzed qualitative interviews of 56 respondents regarding their perception of the ACA and the preference elicitation experience. Participants prioritized 5-year cardiovascular benefit over preventing adverse events. Medication side effects, medication-associated activity restrictions, and regimen complexity were less important than bleeding risk and cardioprotective benefit. One year after the ACA survey, a 15% increase in adherence was observed in patients prescribed a preference-concordant CAT strategy. An increase of only 6% was noted in patients prescribed a preference-discordant strategy. Qualitative interviews showed that the ACA exercise contributed to increase inpatient activation, patient awareness of preferences, and patient engagement with clinicians about treatment decisions. By working through trade-offs, patients actively clarified their preferences, learning about CAT risks, benefits, and self-management. Patients with medication regimens concordant with their preferences had increased medication adherence at 1 year compared to those with discordant medication regimens. The ACA task improved adherence through enhanced patient engagement regarding treatment preferences.


An external focus of attention enhances manual tracking of occluded and visible targets.
The present study investigated the enhancement effects of an external focus of attention (FOA) in the context of a manual tracking task, in which participants tracked both visible and occluded targets. Three conditions were compared, which manipulated the distance of the FOA from the participant as well as the external/internal dimension. As expected, an external FOA resulted in lower tracking errors than an internal FOA. In addition, analyses of participants' movement patterns revealed a systematic shift toward higher-frequency movements in the external FOA condition, consistent with the idea that an external FOA exploits the natural movement dynamics available during skilled action. Finally, target visibility did not influence the effect of focused attention on tracking performance, which provides evidence for the proposal that the mechanisms that underlie FOA do not depend directly on vision.


Simplified bipartite concepts of functioning and disability recommended for interdisciplinary use of the ICF.
To argue for and propose bipartite concepts of functioning and disability, to tally with the structure of the ICF classification list, concepts of social models and clinical needs. The ICF concepts are discussed in relation to the history of ideas regarding disability concepts and the needs for such concepts in interdisciplinary rehabilitation. Bipartite concepts are presented; they refer to actual functioning, simply body functions/structures and participation, including functioning in standardized environments. Participation refers to actually performed "activities", with "activities" simply denoting things that people may do. Bipartite concepts are congruent with the ICF classification and the structure of social models of disability, suitable for clinical and interdisciplinary use and easy to understand. The issue of standardized environments represents a methodological issue rather than the conceptual issue of defining functioning and disability. An individual perspective on activity and activity limitations, i.e. the middle part of the tripartite ICF concept, is somewhat similar to concepts of traditional language that were regarded as too generalizing already in 1912, when the interactional concept of "disability in a social sense" was introduced in rehabilitation practices. Bipartite concepts of functioning and disability are recommended for interdisciplinary use of the ICF. The ICF classification is useful, but the ICF concept of activities in an individual perspective is confusing. We suggest a use of the term "activities" simply to denote things that people may do and "participation" to denote actually performed activities. Estimations of ability should be explicit about how they are related to environmental factors.


Spatiotemporal Expression of Wnt/β-catenin Signaling during Morphogenesis and Odontogenesis of Deciduous Molar in Miniature Pig.
The canonical Wnt/β-catenin signaling pathway has been shown to play essential roles in tooth initiation and early tooth development. However, the role of Wnt/β-catenin signaling in cusp patterning and crown calcification in large mammals are largely unknown. In our previous study, miniature pigs were used as the animal model due to the similarity of tooth anatomy and replacement pattern between miniature pig and human. Dynamic gene expression of third deciduous molar (DM3) in miniature pig at early stages was profiled using microarray method and expression of Wnt genes was significantly correlate with odontogenesis. In the present study, dynamic expression patterns of Wnt/β-catenin signaling genes of DM3 at cap, early bell and late bell (secretory) stage were identified. We found that Lef1 and Axin2 were expressed in the enamel knot and underlying mesenchyme regions. Meanwhile, Dkk1 was expressed in the peripheral and lower parts of dental papilla, thus forming the potential Wnt signaling gradient. We also found that β-Catenin, Axin2 and Lef1 were expressed strongly in undifferentiated cells of the inner enamel epithelium (IEE), but weakly in differentiated ameloblasts. Furthermore, we found that both Wnt signaling read-out gene Lef1 and the inhibitor Dkk1 were co-expressed in the pre-odontoblasts. In conclusion, the spatiotemporal distribution and potential gradient of Wnt signaling may contribute to cusp patterning and crown calcification. These data may yield insight into future study of precise control of crown morphogenesis and regeneration in large mammals.


A journey from calix[4]arene to calix[6] and calix[8]arene reveals more than a matter of size. Receptor concentration affects the stability and stoichiometric nature of the complexes.
The formation of inclusion complexes between lucigenin (N,N'-dimethyl-9,9'-biacridinium dinitrate) and p-sulfonatocalix[n]arenes (SCn; n = 6, 8) was investigated by fluorescence and NMR spectroscopy. Both SC6 and SC8 were found to form 1 : 1 and 1 : 2 host-guest complexes with lucigenin showing up to 109 M-1 binding affinities. Strong quenching of the lucigenin fluorescence upon complexation was observed. Fluorescence regeneration after competitive binding with other potential guests present in solution was used as an indicator displacement assay to characterize the binding mechanism and affinity of alkaline metal ions (Li+, Na+, K+ and Cs+) with SC6 and SC8. The results demonstrate the formation of 1 : 1 and 1 : 2 calixarene : metal complexes with association constants on the order of 103 M-1 and heteroternary calixarene : lucigenin : metal complexes that predominate at metal cation concentrations above the millimolar range. Owing to the ubiquitous presence of metal cations in SCn solutions as counterions (typically Na+), the detailed description of the complexation of these species is crucial to understand and quantify the host-guest binding properties of these receptors. This work demonstrates that both the thermodynamic stability and the stoichiometric nature of the complexes is dependent on the metal ion concentration and, consequently, on the calixarene concentration.


Pharmacological Threat to Lungs: A Case Series and Literature Review.
Drug-induced organ damage stands as a prevalent yet much-neglected issue globally. Keeping in view it's rising frequency, health care providers stand obliged to be well versed with the de-merits of the agents they prescribe. Drug therapies causing damage present with a non-specific clinical presentation, histological findings or radiology, which further elaborates on the necessity of a conscientious diagnosis. Pulmonary architecture ranging from the airways, lung parenchyma, mediastinum, pleura, pulmonary vasculature or the neuromuscular system, all can fall victim to the dreaded outcomes of this menace. In order to establish successful diagnosis, the definite temporal relation between initiation of drug therapy and the development of the respiratory symptoms needs to be drawn. The most common form of pharmacologically arising lung toxicity is drug-induced pneumonitis or interstitial lung disease. Unfortunately, there is no adequate data available to review the extensiveness of this medication-associated risk in Pakistan which further highlights the necessity of carefully monitoring this overlooked yet assessable malady. Furthermore, identification and surveillance of this drug attributed peril shall help diminish burden on healthcare resources of the country. We present three recent cases of different types of drug-induced lung damage under treatment at our University Hospital.


Chronic AT(1) blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats.
It has been suggested that left ventricular fibrosis in spontaneously hypertensive rats (SHR) is the result of both exaggerated collagen synthesis and insufficient collagen degradation. We have shown previously that chronic treatment with the angiotensin II type 1 receptor antagonist losartan results in diminished synthesis of collagen type I molecules and reversal of myocardial fibrosis in SHR. This study was designed to investigate whether losartan also affects the extracellular degradation of collagen type I fibers in the left ventricle of SHR. The study was performed in 30-week-old normotensive Wistar-Kyoto rats (WKY), untreated SHR, and SHR treated with orally administered losartan (20 mg/kg per day) for 14 weeks before they were killed. Ventricular collagenase activity was determined by degradation of [(14)C]collagen with tissue extracts. Ventricular expression of tissue inhibitor of metalloproteinases 1 (TIMP-1) mRNA was analyzed by Northern blot. A histomorphometric study of the left ventricle was performed in all rats. Compared with WKY, SHR exhibited left ventricular hypertrophy, increased (P<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and diminished (P<0.05) collagenase activity. After the treatment period, blood pressure was higher (P<0.05) in losartan-treated SHR than in WKY, and no significant differences were noted in the remaining parameters between the 2 strains of rats. Compared with untreated SHR, treated SHR showed no left ventricular hypertrophy, diminished (P<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and increased (P<0.05) collagenase activity. These results suggest that the transcription of the TIMP-1 gene is upregulated in the hypertrophied and fibrotic left ventricle of adult SHR. Upregulation of TIMP-1 may account for diminished collagenase activity in the myocardium of those rats. Chronic angiotensin II type 1 receptor blockade with losartan resulted in inhibition of TIMP-1 expression and stimulation of collagenase activity in the left ventricle of SHR. It is proposed that angiotensin II may facilitate myocardial fibrosis in SHR by depressing the collagenase-mediated extracellular degradation of collagen fibers.


Nigerian propolis improves blood glucose, glycated hemoglobin A1c, very low-density lipoprotein, and high-density lipoprotein levels in rat models of diabetes.
According to our previous studies, propolis of Nigerian origin showed some evidence of hypoglycemic and hypolipidemic activities in addition to its ability to ameliorate oxidative-stress-induced organ dysfunction. This study was carried out to determine whether an ethanolic extract of Nigerian propolis (EENP) improves glycated hemoglobin A1c (HbA1c), fasting plasma glucose, very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) concentrations in rats that have alloxan diabetes. Diabetes was induced with alloxan (110 mg/kg). Animals were divided into 5 groups (n = 5); Group 1 was non-diabetic receiving normal saline and Group 2 was diabetic but also received only normal saline. Groups 3, 4, and 5 were diabetic receiving 200 mg/kg propolis, 300 mg/kg propolis, and 150 mg/kg metformin, respectively, for 42 days. Hyperglycemia, elevated serum level of VLDL, elevated plasma level of HbA1c, and decreased levels of HDL were observed in the diabetic untreated animals. Nigerian propolis decreased blood glucose level and serum level of VLDL but elevated HDL level. These changes were significant (P < 0.05). The levels of plasma HbA1c were also reduced in the propolis-treated groups, and the reduction was significant (P < 0.05). Nigerian propolis contains compounds exhibiting hypoglycemic, antihyperlipidemic, and HbA1c reducing activities.


Scientific Advising and Reviewing: On strengthening the bond between the Alzheimer's Association and the scientific community.
From its inception in 1980, advancement of research was one of the primary missions of the Alzheimer's Association (also known as Alzheimer's Disease and Related Disorders Association) in addition to leading in family caregiver support, better care, public education, and awareness. Over the past 30 years, the Association has grown and expanded its engagement with the scientific community. In the past 10 years, its research budget has more than doubled, greatly increasing the number of research grants funded and the number of strategic projects supported. The leadership and members of the Medical and Scientific Advisory Council recognized that the growth of the Alzheimer's Association and the expanded mission of Medical & Scientific Relations Division necessitated a change in the mission and charge of the external scientific advisory function to the Association.


Space mediates coexistence of females and hermaphrodites.
In gynodioecious populations of flowering plants females and hermaphrodites coexist. Gynodioecy is widespread and occurs in both asexual and sexual species but does not admit a satisfactory explanation from classical sex ratio theory. In sexual populations male fertility restoring genes have evolved to counter non-nuclear male sterility mutations. In pseudogamous asexual populations pollen retention and increased self-fertilization can make male sterility costly. Both of these mechanisms can promote coexistence. However, it remains unclear how either of these mechanisms could evolve if coexistence was not initially possible. In the absence of these adaptations non-spatial models predict that females either fail to invade hermaphrodite populations or else displace them until pollen shortage drives the population to extinction. We develop a pair approximation to a probabilistic cellular automata model in which females and hermaphrodites interact on a regular lattice. The model features independent pollination and colonization processes which take place on different timescales. The timescale separation is exploited to obtain, with perturbation methods, a more manageable aggregated pair approximation. We present both the mean field model which recreates the classical non-spatial predictions and the pair approximation, which strikingly predicts different invasion criteria and coexistence under a wide range of parameters. The pair approximation is shown to correspond well qualitatively with simulation behaviour.


Use of ethidium monoazide and PCR in combination for quantification of viable and dead cells in complex samples.
The distinction between viable and dead cells is a major issue in many aspects of biological research. The current technologies for determining viable versus dead cells cannot readily be used for quantitative differentiation of specific cells in mixed populations. This is a serious limitation. We have solved this problem by developing a new concept with the viable/dead stain ethidium monoazide (EMA) in combination with real-time PCR (EMA-PCR). A dynamic range of approximately 4 log(10) was obtained for the EMA-PCR viable/dead assay. Viable/dead differentiation is obtained by covalent binding of EMA to DNA in dead cells by photoactivation. EMA penetrates only dead cells with compromised membrane/cell wall systems. DNA covalently bound to EMA cannot be PCR amplified. Thus, only DNA from viable cells can be detected. We evaluated EMA-PCR with the major food-borne bacterium Campylobacter jejuni as an example. Traditional diagnosis of this bacterium is very difficult due to its specific growth requirements and because it may enter a state where it is viable but not cultivable. The conditions analyzed included detection in mixed and natural samples, survival in food, and survival after disinfection or antibiotic treatment. We obtained reliable viable/dead quantifications for all conditions tested. Comparison with standard fluorescence-based viable/dead techniques showed that the EMA-PCR has a broader dynamic range and enables quantification in mixed and complex samples. In conclusion, EMA-PCR offers a novel real-time PCR method for quantitative distinction between viable and dead cells with potentially very wide application.


Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 years follow-up in the randomized SweDCIS Trial.
Four randomized studies show that adjuvant radiotherapy (RT) lowers the risk of subsequent ipsilateral breast events (IBEs) after breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) by approximately 50% after 10 to 15 years. We present 20 years of follow-up data for the SweDCIS trial. Between 1987 and 1999 1,046 women were randomly assigned to RT or not after BCS for primary DCIS. Results up to 2005 have been published, and we now add another 7 years of follow-up. All breast cancer events and causes of death were registered. There were 129 in situ and 129 invasive IBEs. Absolute risk reduction in the RT arm was 12.0% at 20 years (95% CI, 6.5 to 17.7), with a relative risk reduction of 37.5%. Absolute reduction was 10.0% (95% CI, 6.0 to 14.0) for in situ and 2.0% (95% CI, -3.0 to 7.0) for invasive IBEs. There was a nonstatistically significantly increased number of contralateral events in the RT arm (67 v 48 events; hazard ratio, 1.38; 95% CI, 0.95 to 2.00). Breast cancer-specific death and overall survival were not influenced. Younger women experienced a relatively higher risk of invasive IBE and lower effect of RT. The hazard over time looked different for in situ and invasive IBEs. Use of adjuvant RT is supported by 20-year follow-up. Modest protection against invasive recurrences and a possible increase in contralateral cancers still call for a need to find groups of patients for whom RT could be avoided or mastectomy with breast reconstruction is indicated.


Aerodigestive cancers in HIV infection.
Aerodigestive (lung, head and neck) cancers are among the most prevalent and deadly neoplasms worldwide, and the incidence rates are rising. Given the improvements in life expectancy of persons with HIV/AIDS when treated with highly active antiretroviral agents, persons with HIV infection are therefore increasingly likely to develop these malignancies. This chapter focuses on the epidemiology of these malignancies and reviews the most recent literature and current understanding of the causes and treatment of these malignancies in HIV-positive populations. Aerodigestive neoplasms in patients with HIV infection are associated with younger age at diagnosis, cigarette smoking, advanced stage at presentation, and a more aggressive clinical course. The causes of these cancers, aside from the traditional risk factors of tobacco and alcohol exposure, are not clear. Although these neoplasms are non-AIDS defining, factors that might contribute to risk include HIV-related immunosuppression and co-infection with high-risk human papillomavirus subtypes. With continued improvements in therapies for HIV, the expected increase in incidence and mortality of persons with HIV infection from aerodigestive malignancies will likely become a major public health concern. Given the younger age of HIV-infected patients with these malignancies and the apparently higher rates of smoking among HIV-positive individuals, aggressive smoking cessation efforts should be directed to this high-risk population.


Characterization of Bacterial Communities in Selected Smokeless Tobacco Products Using 16S rDNA Analysis.
The bacterial communities present in smokeless tobacco (ST) products have not previously reported. In this study, we used Next Generation Sequencing to study the bacteria present in U.S.-made dry snuff, moist snuff and Sudanese toombak. Sample diversity and taxonomic abundances were investigated in these products. A total of 33 bacterial families from four phyla, Actinobacteria, Firmicutes, Proteobacteria and Bacteroidetes, were identified. U.S.-produced dry snuff products contained a diverse distribution of all four phyla. Moist snuff products were dominated by Firmicutes. Toombak samples contained mainly Actinobacteria and Firmicutes (Aerococcaceae, Enterococcaceae, and Staphylococcaceae). The program PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) was used to impute the prevalence of genes encoding selected bacterial toxins, antibiotic resistance genes and other pro-inflammatory molecules. PICRUSt also predicted the presence of specific nitrate reductase genes, whose products can contribute to the formation of carcinogenic nitrosamines. Characterization of microbial community abundances and their associated genomes gives us an indication of the presence or absence of pathways of interest and can be used as a foundation for further investigation into the unique microbiological and chemical environments of smokeless tobacco products.


Working with complex problem behaviors in juvenile institutional care: staff's competence, organizational conditions and public value.
Institutional staff encounter juveniles with complex problems (externalizing and internalizing) which calls for adequate formal education/training and professional experience to deliver quality treatment, contributing to an effective organization and increasing public value. The purpose of this paper is to investigate staff's formal education, professional experience and the institutions' organizational strategies providing knowledge and clinical training to staff. The study includes staff questionnaires from eight wards (n=102). In addition, 39 in-depth interviews were conducted with management and staff members. Results show that institutions lack clearly defined target groups, 70 percent of staff members lack college education, 30 percent has never been offered education within the organization, and the vast majority of staff does not feel competent in performing their daily work. Practical implications - The results from this study shed light on an overlooked area in institutions, detention centers and prison settings, and are important to policy makers and governmental organizations responsible for coercive care of juveniles. Unlike previous studies, treatment and detention organizations are emphasized as similar to manufacturing industry and profit organizations, and the results are discussed with departure in organizational theory.


A mediating role of the auditory dorsal pathway in selective adaptation to speech: a state-dependent transcranial magnetic stimulation study.
In addition to sensory processing, recent neurobiological models of speech perception postulate the existence of a left auditory dorsal processing stream, linking auditory speech representations in the auditory cortex with articulatory representations in the motor system, through sensorimotor interaction interfaced in the supramarginal gyrus and/or the posterior part of the superior temporal gyrus. The present state-dependent transcranial magnetic stimulation study is aimed at determining whether speech recognition is indeed mediated by the auditory dorsal pathway, by examining the causal contribution of the left ventral premotor cortex, supramarginal gyrus and posterior part of the superior temporal gyrus during an auditory syllable identification/categorization task. To this aim, participants listened to a sequence of /ba/ syllables before undergoing a two forced-choice auditory syllable decision task on ambiguous syllables (ranging in the categorical boundary between /ba/ and /da/). Consistent with previous studies on selective adaptation to speech, following adaptation to /ba/, participants responses were biased towards /da/. In contrast, in a control condition without prior auditory adaptation no such bias was observed. Crucially, compared to the results observed without stimulation, single-pulse transcranial magnetic stimulation delivered at the onset of each target stimulus interacted with the initial state of each of the stimulated brain area by enhancing the adaptation effect. These results demonstrate that the auditory dorsal pathway contribute to auditory speech adaptation.


Performance analysis of a time-division-multiplexed fiber-optic gas-sensor array by wavelength modulation of a distributed-feedback laser.
The results of an investigation of the performance of a time-division-addressed fiber-optic gas-sensor array by means of wavelength modulation of a distributed-feedback (DFB) laser are reported. The system performance is found to be severely limited by the extinction ratio of the optical switch used for pulse amplitude modulation. Formulas that relate the cross-talk level to the extinction ratio of the switch, the modulation parameters of the DFB laser, and the optical path differences among sensing channels are derived. Computer simulation shows that an array of 20 methane gas sensors with a detection sensitivity of 2000 parts in 10(6) (ppm) (10-cm gas cell) for each sensor may be realized with a commercially available single Mach-Zehnder amplitude modulator (-35-dB extinction ratio). An array of 100 sensors with a 100-ppm detection sensitivity for each sensor may be realized if a double Mach-Zehnder amplitude modulator is used.


Sexual behaviour does not reflect HIV-1 prevalence differences: a comparison study of Zimbabwe and Tanzania.
Substantial heterogeneity in HIV prevalence has been observed within sub-Saharan Africa. It is not clear which factors can explain these differences. Our aim was to identify risk factors that could explain the large differences in HIV-1 prevalence among pregnant women in Harare, Zimbabwe, and Moshi, Tanzania. Cross-sectional data from a two-centre study that enrolled pregnant women in Harare (N = 691) and Moshi (N = 2654) was used. Consenting women were interviewed about their socio-demographic background and sexual behaviour, and tested for presence of sexually transmitted infections and reproductive tract infections. Prevalence distribution of risk factors for HIV acquisition and spread were compared between the two areas. The prevalence of HIV-1 among pregnant women was 26% in Zimbabwe and 7% in Tanzania. The HIV prevalence in both countries rises constantly with age up to the 25-30 year age group. After that, it continues to rise among Zimbabwean women, while it drops for Tanzanian women. Risky sexual behaviour was more prominent among Tanzanians than Zimbabweans. Mobility and such infections as HSV-2, trichomoniasis and bacterial vaginosis were more prevalent among Zimbabweans than Tanzanians. Reported male partner circumcision rates between the two countries were widely different, but the effect of male circumcision on HIV prevalence was not apparent within the populations. The higher HIV-1 prevalence among pregnant women in Zimbabwe compared with Tanzania cannot be explained by differences in risky sexual behaviour: all risk factors tested for in our study were higher for Tanzania than Zimbabwe. Non-sexual transmission of HIV might have played an important role in variation of HIV prevalence. Male circumcision rates and mobility could contribute to the rate and extent of spread of HIV in the two countries.


Atorvastatin therapy is associated with greater and faster cerebral hemodynamic response.
Hypercholesterolemia in midlife increases the risk of subsequent cognitive decline, neurovascular disease, and Alzheimer's disease (AD), and statin use is associated with reduced prevalence of these outcomes. While statins improve vasoreactivity in peripheral arteries and large cerebral arteries, little is known about the effects of statins on cerebral hemodynamic responses and cognition in healthy asymptomatic adults. At the final visit of a 4-month randomized, controlled, double-blind study comparing atorvastatin 40 mg daily to placebo, 16 asymptomatic middle-aged adults (15 had useable data) underwent blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI), arterial spin labeling (ASL) quantitative cerebral blood flow (qCBF), dynamic susceptibility contrast (DSC) and structural imagings of the brain. Using a memory recognition task requiring discrimination of previously viewed (PV) and novel (NV) human faces, fMRI was used to elicit activation from brain regions known to be vulnerable to changes associated with AD. The BOLD signal amplitude (PV > NV) and latency to each stimulus were tested on a voxel basis between the atorvastatin (n=8) and placebo (n=7) groups. Persons randomized to atorvastatin not only showed significantly greater BOLD amplitude in the right angular gyrus, left superior parietal lobule, right middle temporal and superior sulcus than the placebo group, but also decreased hemodynamic response latencies in the right middle frontal gyrus, left precentral gyrus, left cuneus and right posterior middle frontal gyrus. However, neither the resting cerebral blood flow (CBF) measured with ASL nor the mean transit time (MTT) of cerebral perfusion calculated from DSC showed differences in these regions in either group. The drug related BOLD differences during memory recognition suggest that atorvastatin may have improved cerebral small vessel vasoreactivity, possibly through an effect on endothelial function. Furthermore, these results suggest that the effect of atorvastatin on the task-induced BOLD signal may not be a simple consequence of baseline flow change.


Alcohol consumption among adults in Germany: heavy episodic drinking.
Consuming harmful amounts of alcohol is considered a contributing factor in over 200 diseases. Heavy episodic drinking is a particularly risky drinking pattern, with possible consequences such as acute alcohol intoxication, injuries and violence. GEDA 2014/2015-EHIS defines heavy episodic drinking as the consumption of six or more alcoholic beverages on one occasion at least once per month. 24.9% of women and 42.6% of men show this drinking pattern at least once per month. Regular heavy episodic drinking is most common among 18- to 29-year-olds. The prevalence of heavy episodic drinking among highly educated women (all age groups) and men (aged over 45) is lower than it is among those with lower levels of education. The prevention of harmful levels of alcohol consumption requires measures including social and environmental interventions as well as targeting the individual behaviour which are focused on young adults as well as the diverse drinking patterns seen among groups with different levels of education.


Short DNA sequences inserted for gene targeting can accidentally interfere with off-target gene expression.
Targeting of genes in mice, a key approach to study development and disease, often leaves a neo cassette, loxP, or FRT sites inserted in the mouse genome. Insertion of neo can influence the expression of neighboring genes, but similar effects have not been reported for loxP sites. We therefore performed microarray analyses of mice in which the Ncam or the Tnr gene were targeted either by insertion of neo or loxP/FRT sites. In the case of Ncam, neo, but not loxP/FRT insertion, led to a 2-fold reduction in mRNA levels of 3 genes located at distances between 0.2 and 3.1 Mb from the target. In contrast, after introduction of loxP/FRT sites into introns of Tnr, we observed a 2.5- to 4-fold reduction in the transcript level of the Gas5 gene, 1.1 Mb away from Tnr, most probably due to disruption of a conserved regulatory element in Tnr. Insertion of short DNA sequences such as loxP/FRT can thus influence off-target mRNA levels if these sites are accidentally placed into regulatory elements. Our results imply that conditional knockout mice should be analyzed for genomic positional side effects that may influence the animals' phenotypes.


Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism.
The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists. This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method. Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline. Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX. The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.


Association of intercellular adhesion molecule-1 (ICAM-1) with actin-containing cytoskeleton and alpha-actinin.
We have studied the cytoskeletal association of intercellular adhesion molecule-1 (ICAM-1, CD54), an integral membrane protein that functions as a counterreceptor for leukocyte integrins (CD11/CD18). A linkage between ICAM-1 and cytoskeletal elements was suggested by studies showing a different ICAM-1 staining pattern for COS cells transfected with wild-type ICAM-1 or with an ICAM-1 construct that replaces the cytoplasmic and transmembrane domains of ICAM-1 with a glycophosphatidylinositol (GPI) anchor. Wild-type ICAM-1 appeared to localize most prominently in microvilli whereas GPI-ICAM-1 demonstrated a uniform cell surface distribution. Disruption of microfilaments with cytochalasin B (CCB) changed the localization of wild-type ICAM-1 but had no effect on GPI-ICAM-1. Some B-cell lines demonstrated a prominent accumulation of ICAM-1 into the uropod region whereas other cell surface proteins examined were not preferentially localized. CCB also induced redistribution of ICAM-1 in these cells. For characterization of cytoskeletal proteins interacting with ICAM-1, a 28-residue peptide that encompasses the entire predicted cytoplasmic domain (ICAM-1,478-505) was synthesized, coupled to Sepharose-4B, and used as an affinity matrix. One of the most predominant proteins eluted either with soluble ICAM-1,478-505-peptide or EDTA, was 100 kD, had a pI of 5.5, and in Western blots reacted with alpha-actinin antibodies. A direct association between alpha-actinin and ICAM-1 was demonstrated by binding of purified alpha-actinin to ICAM-1,478-505-peptide and to immunoaffinity purified ICAM-1 and by a strict colocalization of ICAM-1 with alpha-actinin, but not with the cytoskeletal proteins talin, tensin, and vinculin. The region of ICAM-1,478-505 interacting with alpha-actinin was mapped to the area close to the membrane spanning region. This region contains several positively charged residues and appears to mediate a charged interaction with alpha-actinin which is not highly dependent on the order of the residues.


The changing epidemiology of invasive pneumococcal disease in aboriginal and non-aboriginal western Australians from 1997 through 2007 and emergence of nonvaccine serotypes.
BACKGROUND. In 2001, Australia introduced a unique 7-valent pneumococcal conjugate vaccine (7vPCV) 2-, 4-, and 6-month schedule with a 23-valent pneumococcal polysaccharide vaccine (23vPPV) booster for Aboriginal children, and in 2005, 7vPCV alone in a 2-, 4-, and 6-month schedule for non-Aboriginal children. Aboriginal adults are offered 23vPPV but coverage is poor. We investigated trends in invasive pneumococcal disease (IPD) in Western Australia (WA). METHODS. Enhanced IPD surveillance has been ongoing since 1996. We calculated IPD incidence rates for Aboriginal and non-Aboriginal Australians before and after introduction of 7vPCV. RESULTS. A total of 1792 cases occurred during the period 1997-2007; the IPD incidence rate was 47 cases per 100,000 population per year among Aboriginal people and 7 cases per 100,000 population per year in non-Aboriginal people. After introduction of 7vPCV, IPD rates among Aboriginal children decreased by 46% for those <2 years of age and by 40% for those 2-4 years of age; rates decreased by 64% and 51% in equivalent age groups for non-Aboriginal children. IPD rates decreased by >30% in non-Aboriginal people 50 years of age but increased among Aboriginal adults (eg, from 59.1 to 109.6 cases per 100,000 population per year among those 30-49 years of age). Although IPD due to 7vPCV serotypes decreased in all age groups, IPD incidence due to non-7vPCV serotypes increased, and it almost doubled among Aboriginal adults 30-49 years of age (from 48.3 to 97.0 cases per 100,000 population per year). Among non-Aboriginal children, 37% of IPD is now due to serotype 19A. CONCLUSIONS. IPD incidence rates have decreased markedly among children and non-Aboriginal adults with a 3-dose infant 7vPCV schedule. However, IPD due to non-7vPCV serotypes has increased and is of particular concern among young Aboriginal adults, for whom an intensive 23vPPV campaign is needed. An immunization register covering all age groups should be established.


Comparison of distribution and toxicity following repeated oral dosing of different vanadium oxide nanoparticles in mice.
Vanadium is an important ultra-trace element derived from fuel product combustion. With the development of nanotechnology, vanadium oxide nanoparticles (VO NPs) have been considered for application in various fields, thus the possibility of release into the environment and human exposure is also increasing. Considering that verification of bioaccumulation and relevant biological responses are essential for safe application of products, in this study, we aimed to identify the physicochemical properties that determine their health effects by comparing the biological effects and tissue distribution of different types of VO NPs in mice. For this, we prepared five types of VO NPs, commercial (C)-VO2 and -V2O5 NPs and synthetic (S)-VO2, -V2O3, and -V2O5 NPs. While the hydrodynamic diameter of the two types of C-VO NPs was irregular and impossible to measure, those of the three types of S-VO NPs was in the range of 125-170nm. The S- and C-V2O5 NPs showed higher dissolution rates compared to other VO NPs. We orally dosed the five types of VO NPs (70 and 210μg/mouse, approximately 2 and 6mg/kg) to mice for 28 days and compared their biodistribution and toxic effects. We found that S-V2O5 and S-V2O3 NPs more accumulated in tissues compared to other three types of VO NPs, and the accumulated level was in order of heart>liver>kidney>spleen. Additionally, tissue levels of redox reaction-related elements and electrolytes (Na(+), K(+), and Ca(2+)) were most clearly altered in the heart of treated mice. Notably, all S- and C-VO NPs decreased the number of WBCs at the higher dose, while total protein and albumin levels were reduced at the higher dose of S-V2O5 and S-V2O3 NPs. Taken together, we conclude that the biodistribution and toxic effects of VO NPs depend on their dissolution rates and size (surface area). Additionally, we suggest that further studies are needed to clarify effects of VO NPs on functions of the heart and the immune system.


Analysis of mice carrying targeted mutations of the glucocorticoid receptor gene argues against an essential role of glucocorticoid signalling for generating adrenal chromaffin cells.
Molecular mechanisms underlying the generation of distinct cell phenotypes is a key issue in developmental biology. A major paradigm of determination of neural cell fate concerns the development of sympathetic neurones and neuroendocrine chromaffin cells from a common sympathoadrenal (SA) progenitor cell. Two decades of in vitro experiments have suggested an essential role of glucocorticoid receptor (GR)-mediated signalling in generating chromaffin cells. Targeted mutation of the GR should consequently abolish chromaffin cells. The present analysis of mice lacking GR gene product demonstrates that animals have normal numbers of adrenal chromaffin cells. Moreover, there are no differences in terms of apoptosis and proliferation or in expression of several markers (e.g. GAP43, acetylcholinesterase, adhesion molecule L1) of chromaffin cells in GR-deficient and wild-type mice. However, GR mutant mice lack the adrenaline-synthesizing enzyme PNMT and secretogranin II. Chromaffin cells of GR-deficient mice exhibit the typical ultrastructural features of this cell phenotype, including the large chromaffin granules that distinguish them from sympathetic neurones. Peripherin, an intermediate filament of sympathetic neurones, is undetectable in chromaffin cells of GR mutants. Finally, when stimulated with nerve growth factor in vitro, identical proportions of chromaffin cells from GR-deficient and wild-type mice extend neuritic processes. We conclude that important phenotypic features of chromaffin cells that distinguish them from sympathetic neurones develop normally in the absence of GR-mediated signalling. Most importantly, chromaffin cells in GR-deficient mice do not convert to a neuronal phenotype. These data strongly suggest that the dogma of an essential role of glucocorticoid signalling for the development of chromaffin cells must be abandoned.


The effect of long-term circulatory occlusion on pH and energy metabolism of the quadriceps muscle in man.
The effect of up to 2.5 h circulatory occlusion on muscle pH and energy metabolism of the quadriceps muscle was studied in 13 patients operated on for an inveterate knee injury. Muscle samples were taken by the percutaneous needle biopsy technique at different times during the arterial occlusion and after restoration of circulation. Energy was provided by a complete utilization of phosphocreatine and by a low rate of glycolysis during 2 h of occlusion. The ATP level remained unchanged throughout the occlusion period. Muscle pH decreased from 7.0-7.1 to about 6.8 after 2 h occlusion. Muscle pH was essentially normalized within 20 min after restoration of the blood flow.


Changes of the phagosomal elemental concentrations by Mycobacterium tuberculosis Mramp.
Pathogenic mycobacteria survive within phagosomes which are thought to represent a nutrient-restricted environment. Divalent cation transporters of the Nramp family in phagosomes and mycobacteria (Mramp) may compete for metals that are crucial for bacterial survival. The elemental concentrations in phagosomes of macrophages infected with wild-type Mycobacterium tuberculosis (M. tuberculosis strain H37Rv) and a M. tuberculosis Mramp knockout mutant (Mramp-KO), derived from a clinical isolate isogenic to the strain MT103, were compared. Time points of 1 and 24 h after infection of mouse peritoneal macrophages (bcg(S)) were compared in both cases. Increased concentrations of P, Ni and Zn and reduced Cl concentration in Mramp-KO after 1 h of infection were observed, compared to M. tuberculosis vacuoles. After 24 h of infection, significant differences in the P, Cl and Zn concentrations were still present. The Mramp-KO phagosome showed a significant increase of P, Ca, Mn, Fe and Zn concentrations between 1 and 24 h after infection, while the concentrations of K and Ni decreased. In the M. tuberculosis vacuole, the Fe concentration showed a similar increase, while the Cl concentration decreased. The fact that the concentration of several divalent cations increased in the Mramp-KO strain suggests that Mramp may have no impact on the import of these divalent cations into the mycobacterium, but may function as a cation efflux pump. The concordant increase of Fe concentrations within M. tuberculosis, as well as within the Mramp-KO vacuoles, implies that Mramp, in contrast to siderophores, might not be important for the attraction of Fe and its retention in phagosomes of unstimulated macrophages.


Effects of inducers of differentiation on protein kinase C and CMP-N-acetylneuraminic acid:lactosylceramide sialyltransferase activities of HL-60 leukemia cells.
Exposure of HL-60 leukemia cells to either 12-O-tetradecanoylphorbol-13-acetate (TPA), dimethylsulfoxide (DMSO), exogenous gangliosides GM3, GM1, or bovine brain ganglioside mixture (BBG) resulted in a marked inhibition of the growth of cells. The order of the inhibitory potency was TPA greater than GM3 greater than DMSO greater than BBG greater than GM1. In contrast, sulfatides were without effect on cellular replication. Treatment of HL-60 cells with TPA or GM3 induced differentiation along the monocyte/macrophage lineage, while treatment with DMSO induced maturation along the granulocytic pathway. These effects were accompanied by more than a twofold increase in protein kinase C (PKC) activity. In contrast, treatment with GM1, BBG, or sulfatides caused only a relatively small increase in PKC activity. The activity of CMP-N-acetylneuraminic acid:lactosylceramide sialyltransferase (ST1), a key enzyme for membrane gangliosides synthesis, in HL-60 cells was also influenced by the exposure to TPA, GM3, DMSO, GM1, or sulfatides. The inducers of differentiation, TPA and DMSO, caused an increase in ST1 activity, whereas GM3, which also induced cellular differentiation, inhibited ST1 activity, perhaps through the action of end-product inhibition. The non-inducers of differentiation, GM1 and sulfatides, also increased the activity of ST1, but to a much lesser extent. The findings suggest that the direct or indirect modulation of PKC activity by some of these agents may be involved, at least in part, in the regulation of cellular growth and differentiation. Furthermore, it is conceivable that differences in PKC activity may be responsible for the changes in ST1 activity associated with cell differentiation and proliferation.


Comparison between tinzaparin and standard heparin for chronic hemodialysis in a Canadian center.
Low-molecular-weight heparins offer several advantages over standard heparins, but their use for maintenance hemodialysis has been limited in North America because of their higher cost. Our objective was to compare tinzaparin to standard heparin during maintenance hemodialysis over an 8-week period, in regard to the visual aspect of the extracorporeal circuit, filter reuse, bleeding and time for compression of vascular access at the end of hemodialysis session, nursing time devoted to anticoagulation administration, level of satisfaction of patients and nurses, and relative cost. Thirty-two chronic hemodialysis adult patients with peripheral accesses were randomly divided into two groups in a cross-over design: tinzaparin for 4 weeks followed by standard heparin for 4 weeks, or vice versa. Hemodialysis was performed thrice weekly over 3.5-4 h using large surface reused filters. Standard heparin was administered as an initial bolus of 50-75 units per kilogram followed by an infusion to maintain an activated clotting time (ACTESTER) between 150 and 200 s and discontinued 30-45 min before the end of the session. The initial dose of tinzaparin was 3,500 IU anti-Xa for patients usually receiving 7,500 units or less of standard heparin, or 4,500 IU anti-Xa for patients receiving more than 7,500 units of standard heparin, and it was injected as a bolus in the arterial line at the beginning of hemodialysis. Dosage adjustments were made by increments or decrements of 500 IU. A total of 6 patients did not require any adjustment in their dose of tinzaparin and remained at the initial dose, while the remaining 26 necessitated adjustments of the initial dose of tinzaparin: 20 patients required increments from the initial dose whereas 6 required reductions. For most patients, 27 of them, the standard heparin dose was kept at the same level throughout the study period (since it was their usual regimen and they were in stable medical conditions). According to the monitoring scale, the visual aspects of the tubing of the extracorporeal circuit and of the dialyzers at the end of the session were similar for both tinzaparin and standard heparin. The time of compression of the vascular access at the end of the hemodialysis sessions was not significantly different with tinzaparin than with standard heparin. However, as indicated below, most patients noted less bleeding (or oozing) from their access (during compression and thereafter, in the few hours after hemodialysis) with tinzaparin than with standard heparin. Clotting was observed more frequently in the arterial and venous bubble traps with tinzaparin than with standard heparin. The presence of clot(s) was observed in the arterial and venous bubble traps in, respectively, 18 +/- 12 and 10 +/- 6% of the sessions with tinzaparin, while in, respectively, 3 +/- 4 and 2 +/- 4% of the sessions with standard heparin (p < 0.005). Despite a tendency for a reduced reuse number of the dialyzers, the difference did not reach statistical significance. Among the 30 patients who completed the study, 2 reported excessive bleeding from their vascular access with tinzaparin whereas 8 reported such an excessive bleeding with standard heparin. The level of satisfaction of patients and nurses for tinzaparin was extremely good. The main reasons stated by the patients was reduced bleeding from their access after dialysis. The nurses preferred tinzaparin because of the simplicity and the rapidity of its administration, the lack of monitoring required, and the decreased bleeding/oozing tendency from the vascular access sites. The time spent for anticoagulation during a hemodialysis session was reported as 5 min with standard heparin (if no ACTESTER monitoring), 25-30 min with standard heparin (if ACTESTER monitoring required), and 1 min with tinzaparin. The cost analysis revealed that although tinzaparin is more than six times more expensive than standard heparin, the use of tinzaparin becomes similar to the use of standard heparin (USD 7.33 vs. USD 7.62 Canadian dollars for one hemodialysis session) if ACTESTER monitoring is performed (assuming that 22% of the sessions are routinely monitored and that one ACTESTER device is necessary for 8-10 dialysis stations, as applied in our unit). Our experience with tinzaparin was positive: it represents a simple and easy way to offer anticoagulation during maintenance hemodialysis, it seems associated with less postdialysis bleeding, it saves precious nursing time and is widely appreciated by patients and staff.


Genotyping of two populations of Southern Baltic Sea trout Salmo trutta m. trutta using an Atlantic salmon derived SNP-array.
The sea trout (Salmo trutta m. trutta) is an anadromous, teleost fish species characterized by homing behaviour. The sea trout has considerable ecological and economic significance. It reproduces naturally in rivers flowing into, and is common in, the Baltic Sea. In Poland spawning aggregations occur in the Vistula River and the rivers of Pomerania. Two populations from the Vistula River (TW) and a Pomeranian river, the Słupia (TP) were mixed in the past by stocking. The main purpose of this study was an assessment of the applicability of the Atlantic salmon custom design Illumina iSelect SNP (Single Nucleotide Polymorphisms) array containing 15,225 markers for identification of genetic diversity between sea trout populations. A diagnostic panel of 39 SNPs with a mean FST=0.1298 was selected from a pool of 15,225. At each locus, minor allele frequency was higher than 0.01 and mean expected heterozygosity for TW and TP populations were 0.343 and 0.271 respectively. Individuals tested were clustered in one of two groups which corresponded to their origins where the TW population was genetically more homogenous (membership coefficients ranked from 88.8% to 98.6%) while the TP population was more diverse (membership coefficients ranked from 53.8% to 98.5%). The results demonstrated the applicability of the Salmon 15K SNP-chip for determining the differences between Southern Baltic populations of the sea trout, a closely related salmonid species.


Postural control in a simulated saturation dive to 240 msw.
There is evidence that increased ambient pressure causes an increase in postural sway. This article documents postural sway at pressures not previously studied and discusses possible mechanisms. Eight subjects participated in a dry chamber dive to 240 msw (2.5 MPa) saturation pressure. Two subjects were excluded due to unilateral caloric weakness before the dive. Postural sway was measured on a force platform. The path length described by the center of pressure while standing quietly for 60 seconds was used as test variable. Tests were repeated 38 times in four conditions: with eyes open or closed, while standing on bare platform or on a foam rubber mat. Upon reaching 240 msw, one subject reported vertigo, disequilibrium and nausea, and in all subjects, mean postural sway increased 26% on bare platform with eyes open (p < 0.05) compared to predive values. There was no significant improvement in postural sway during the bottom phase, but a trend was seen toward improvement when the subjects were standing with eyes closed on foam rubber (p = 0.1). Postural sway returned to predive values during the decompression phase. Postural imbalance during deep diving has been explained previously as HPNS possibly including a specific effect on the vestibulo-ocular reflex. Although vertigo and imbalance are known to be related to compression rate, this study shows that there remains a measurable increase in postural sway throughout the bottom phase at 240 msw, which seems to be related to absolute pressure.


Dynamic guardianship of potato landraces by Andean communities and the genebank of the International Potato Center.
Potato landraces (Solanum spp.) are not only crucial for food security and sustenance in Andean communities but are also deeply rooted in the local culture. The crop originated in the Andes, and while a great diversity of potato persists, some landraces have been lost. Local communities and the genebank of the International Potato Center (CIP) partnered to re-establish some of these landraces in situ by supplying clean seed potatoes to farmers. Over time, the genebank formalized a repatriation program of potato landraces. Repatriation is the process of returning native germplasm back to its place of origin, allowing a dynamic exchange between ex situ and in situ conditions. So far, no comprehensive description of CIP's repatriation program, the changes it induced, nor its benefits, has been carried out. We addressed this research gap by analyzing CIP genebank distribution data for repatriated accessions, conducting structured interviews with experts of the repatriation program, and applying duration and benefit analyses to a survey dataset of 301 households. Between 1997 and 2020, 14,950 samples, representing 1519 accessions, were distributed to 135 communities in Peru. While most households (56%) abandoned the repatriated material by the fourth year after receiving it, the in situ survival probability of the remaining material stabilized between 36% in year 5 and 18% in year 15. Households where the plot manager was over 60 years old were more likely to grow the repatriated landraces for longer periods of times. While male plot management decreased survival times compared to female plot management, higher levels of education, labor force, wealth, food insecurity, and geographic location in the southern part of Peru were associated with greater survival times. Most farmers reported nutritional and cultural benefits as reasons for maintaining landrace material. Repatriated potatoes enabled farmers to conserve potato diversity, and hence, re-establish and broaden culinary diversity and traditions. Our study is the first to apply an economic model to analyze the duration of in situ landrace cultivation by custodian farmers. We provide an evidence base that describes the vast scope of the program and its benefits.


Fabrication and THz loss measurements of porous subwavelength fibers using a directional coupler method.
We report several strategies for the fabrication of porous subwavelength fibers using low density Polyethylene plastic for low-loss terahertz light transmission applications. We also characterize transmission losses of the fabricated fibers in terahertz using a novel non-destructive directional coupler method. Within this method a second fiber is translated along the length of the test fiber to probe the power attenuation of a guided mode. The method is especially suitable for measuring transmission losses through short fiber segments, a situation in which standard cutback method is especially difficult to perform. We demonstrate experimentally that introduction of porosity into a subwavelength rod fiber, further reduces its transmission loss by as much as a factor of 10. The lowest fiber loss measured in this work is 0.01 cm(-1) and it is exhibited by the 40% porous subwavelength fiber of diameter 380 microm. For comparison, the loss of a rod-in-the-air subwavelength fiber of a similar diameter was measured to be approximately 0.1 cm(-1), while the bulk loss of a PE plastic used in the fabrication of such fibers is >or= 1 cm(-1). Finally, we present theoretical studies of the optical properties of individual subwavelength fibers and a directional coupler. From these studies we conclude that coupler setup studied in this paper also acts as a low pass filter with a cutoff frequency around 0.3 THz. Considering that the spectrum of a terahertz source used in this work falls off rapidly below 0.25 THz, the reported loss measurements are, thus, the bolometer averages over the approximately 0.25 THz-0.3 THz region.


Mechanical Thrombectomy in Distal Residual Occlusions of the Middle Cerebral Artery after Large Vessel Recanalization in Acute Stroke: 2b or not 2b? A Pragmatic Approach in Real-Life Scenarios.
Recent studies have suggested that a recanalization grade of modified Thrombolysis in Cerebral Infarction (mTICI) score ≥2c is strongly related with good clinical outcome rather than the current therapeutic angiography target ≥2b. To achieve better recanalization, additional further maneuvers on distal residual vessel occlusion (RVO) may be required. The aim of this study was to evaluate the safety and efficacy of rescue treatment in RVOs after recanalization of large vessel occlusions in the anterior circulation. A single-center retrospective review of a prospectively maintained stroke databank was performed. Patients presenting with RVOs after mechanical thrombectomy on the M1/internal carotid artery terminus were included and further divided into treated and untreated groups: the former underwent additional maneuvers on RVOs, whereas the latter did not. Baseline and posttreatment clinical, radiologic, and angiographic data were compared between the 2 groups. End points included good functional outcome (modified Rankin Scale [mRS] score ≤2) rates of hemorrhagic transformations, neurologic deterioration and mortality. RVOs were observed in 183/488 patients (37.5%). 74/183 (40.4%) underwent rescue treatment, showing a better outcome in terms of median 24 hours National Institutes of Health Stroke Scale score (13 vs. 18; P < 0001), 24 hours Alberta Stroke Programme Early CT Score (6 vs. 5; P < 0.001) and 3 months mRS score 0-2 (47.3% vs. 33.1%; P = 0.06). Recanalization of the superior (frontal) branch of the middle cerebral artery was particularly critical in terms of outcome. Hemorrhagic transformation was higher in the untreated group (53.6% vs. 66.6%; P = 0.1) as well as symptomatic intracranial hemorrhage (13.1% vs. 29.4%; P = 0.01). Neurologic deterioration occurred more often among untreated patients (16.2% vs. 25.7%; P = 0.1). Three complications (1.3%) occurred during rescue treatment. When feasible, improving mTICI score 2a-2b recanalization to mTICI 2c/3 is safe and associated with a better clinical outcome, particularly for residual occlusions involving the superior branch of bifurcation.


The antimicrobial activity of lactoferrin: current status and perspectives.
Lactoferrin (Lf) is a multifunctional iron glycoprotein which is known to exert a broad-spectrum primary defense activity against bacteria, fungi, protozoa and viruses. Its iron sequestering property is at the basis of the bacteriostatic effect, which can be counteracted by bacterial pathogens by two mechanisms: the production of siderophores which bind ferric ion with high affinity and transport it into cells, or the expression of specific receptors capable of removing the iron directly from lactoferrin at the bacterial surface. A particular aspect of the problem of iron supply occurs in bacteria (e.g. Legionella) which behave as intracellular pathogens, multiplying in professional and non professional macrophages of the host. Besides this bacteriostatic action, Lf can show a direct bactericidal activity due to its binding to the lipid A part of bacterial LPS, with an associated increase in membrane permeability. This action is due to lactoferricin (Lfc), a peptide obtained from Lf by enzymatic cleavage, which is active not only against bacteria, but even against fungi, protozoa and viruses. Additional antibacterial activities of Lf have also been described. They concern specific effects on the biofilm development, the bacterial adhesion and colonization, the intracellular invasion, the apoptosis of infected cells and the bactericidal activity of PMN. The antifungal activity of Lf and Lfc has been mainly studied towards Candida, with direct action on Candida cell membranes. Even the sensitivity of the genus tricophyton has been studied, indicating a potential usefulness of this molecule. Among protozoa, Toxoplasma gondii is sensitive to Lf, both in vitro and in vivo tests, while Trichomonads can use lactoferrin for iron requirements. As to the antiviral activity, it is exerted against several enveloped and naked viruses, with an inhibition which takes place in the early phases of viral invection, as a consequence of binding to the viral particle or to the cell receptors for virus. The antiviral activity of Lf has also been demonstrated in in vivo model invections and proposed for a selective delivery of antiviral drugs. The new perspectives in the studies on the antimicrobial activity of Lf appear to be linked to its potential prophylactic and therapeutical use in a considerable spectrum of medical conditions, taking advantage of the availability of the recombinant human Lf. But the historical evolution of our knowledge on Lf indicates that its antimicrobial activity must be considered in a general picture of all the biological properties of this multifunctional protein.


Size at birth and cognitive function among rural adolescents: a life course epidemiology study protocol of the Kisalaya cohort in Mysuru, South India.
It is proven that adverse intrauterine environment results in 'early life programming,' alterations in metabolism and physiological development of the fetus, often termed as 'Developmental Origins of Health and Disease' (DOHaD) resulting in a smaller size at birth, greater non-communicable diseases (NCD) risk factors during childhood and adolescence, and cardiometabolic disorders in adulthood. Nevertheless, very few studies have examined the relationship between DOHaD programming and cognition. This study aims to examine if impaired prenatal growth indicated by birth weight is associated with cognition among adolescents in the Kisalaya cohort, a rural birth cohort in South India, thus providing newer insights into DOHaD programming for adolescent mental health in a low-income and middle-income country setting. Kisalaya cohort was established in 2008, to provide integrated antenatal care and HIV testing using mobile clinics to improve maternal and child health outcomes. This cohort included pregnant women residing in 144 villages of Mysuru Taluk (rural) who received antenatal care through mobile clinics and delivered their children between 2008 and 2011. Data related to mother-infant dyads for all pregnant women who received care in the Kisalaya programme are available for this study. Presently, children born to women who received care through Kisalaya are adolescents between 10 and 12 years. At this point, information would be collected on sociodemographic data and assessments of mental health, stressful life events, cognition, vision, speech, language, hearing and anthropometric measures would be done and relevant maternal data and child data, available from the cohort would be retracted for analysis. We plan to retrace as many adolescents as possible out of 1544 adolescents who are currently available for study excluding twins, abortions, stillbirths and postdelivery deaths. Analyses will be extended to construct a life course pathway for cognition using structural equation modelling.


Nanostructured Li₂S-C composites as cathode material for high-energy lithium/sulfur batteries.
With a theoretical capacity of 1166 mA·h·g(-1), lithium sulfide (Li(2)S) has received much attention as a promising cathode material for high specific energy lithium/sulfur cells. However, the insulating nature of Li(2)S prevents the achievement of high utilization (or high capacity) and good rate capability. Various efforts have been made to ameliorate this problem by improving the contact between Li(2)S and electronic conductors. In the literature, however, a relatively high capacity was only obtained with the Li(2)S content below 50 wt %; therefore, the estimated cell specific energy values are often below 350 W·h·kg(-1), which is insufficient to meet the ever-increasing requirements of newly emerging technologies. Here, we report a cost-effective way of preparing nanostructured Li(2)S-carbon composite cathodes by high-energy dry ball milling of commercially available micrometer-sized Li(2)S powder together with carbon additives. A simple but effective electrochemical activation process was used to dramatically improve the utilization and reversibility of the Li(2)S-C electrodes, which was confirmed by cyclic voltammetry and electrochemical impedance spectroscopy. We further improved the cycling stability of the Li(2)S-C electrodes by adding multiwalled carbon nanotubes to the nanocomposites. With a very high specific capacity of 1144 mA·h·g(-1) (98% of the theoretical value) obtained at a high Li(2)S content (67.5 wt %), the estimated specific energy of our cell was ∼610 W·h·kg(-1), which is the highest demonstrated so far for the Li/Li(2)S cells. The cells also maintained good rate capability and improved cycle life. With further improvement in capacity retention, nanostructured Li(2)S-C composite cathodes may offer a significant opportunity for the development of rechargeable cells with a much higher specific energy.


Relationship between body mass index and depression in women: A 7-year prospective cohort study. The APNA study.
The association between body mass index (BMI) and depression is complex and controversial. The present study examined the relationship between BMI and new-onset depression during 7 years of follow-up in 20,212 adult women attending Primary Health Care Centres in Navarra, Spain. The Atención Primaria de Navarra (APNA) study is a dynamic prospective cohort study. A total of 20,212 women aged 18-99 years (mean age: 50.7 ± 18.5 years) without depression at baseline were selected from 2004 to 2011. We estimated the incidence of depression. We used the Kaplan-Meier analysis to predict the survival curve. The risk of depression onset according to different measures of BMI at baseline was assessed using Cox regression analyses. During the 7 years of follow-up, depression appeared in 8.9% (95% CI 8.5-9.3). The highest rates of depression incidence at follow-up occurred in underweight and obese women (9.8% [95% CI 7.3-12.9] and 10.3% [95% CI 9.5-11.1] respectively). The distribution of depression incidence by weight category was U-shaped. The risk of depression increased over time with an observed Kaplan-Meier estimation of 6.67. After adjusting for age, underweight and obese women at baseline have increased risk of depression onset during the follow-up period compared with normal weight women (HR=1.48, 95% CI=1.09-2.00 and HR=1.14, 95% CI=1.01-1.29 respectively). In this 7-year prospective study in the APNA women population, depression emerged in 8.9%. Being underweight or obese (not overweight) at baseline is significantly associated with future onset of depression.


Switch from Asexual to Sexual Reproduction in the Planarian Dugesia ryukyuensis.
Many metazoans convert the reproductive modes presumably depending upon the environmental conditions and/or the phase of life cycle, but the mechanisms underlying the switching from asexual to sexual reproduction, and vice versa, remain unknown. We established an experimental system, using an integrative biology approach, to analyze the mechanism in the planarian, Dugesia ryukyuensis (Kobayashi et al., 1999). Worms of exclusively asexual clone (OH strain) of the species gradually develop ovaries, testes and other sexual organs, then copulate and eventually lay cocoons filled with fertilized eggs, if they are fed with sexually mature worms of Bdellocephala brunnea (an exclusively oviparous species). This suggests the existence of a sexualizing substance(s) in sexually mature worms. Random inbreeding of experimentally sexualized worms (acquired sexuals) produces an F1 population of spontaneous sexuals (innate sexuals) and asexuals in a ratio of approximately 2:1. All regenerants from various portions of innate sexuals become sexuals. In the case of acquired sexuals, head fragments without sexual organs regenerated into asexuals though regenerants from other portions became sexuals. Thus, we conclude that neoblasts, the totipotent stem cells in the planarians, of acquired sexuals remain "asexual" and the worms require external supply of a sexualizing substance for the differentiation of sexual organs and gametes. On the other hand, some, if not all, neoblasts in innate sexuals are somehow "sexual" and do not require external supply of a sexualizing substance for the eventual differentiation of themselves and/or other neoblasts into sexual organs and gametes. It is also shown that sexuality in acquired sexuals is maintained by the putative sexualizing substance(s) of their own. The sexualization is closely coupled with cessation of fission, and the worms seem to have an unknown way of controlling the karyotype. Our integrative approach integrates multiple fields of study, including classic breeding, regeneration, and genetics experiments, as well as karyotyping, and biochemical and molecular biological analyses; none of which would have revealed much about the intricate mechanisms that regulate sex and fission in these animals.


Tertiary structure of RBD2 and backbone dynamics of RBD1 and RBD2 of the human U1A protein determined by NMR spectroscopy.
The human U1A protein has two putative RNA binding domains, one at the N-terminal region of the protein (RBD1) and the other at the C-terminal end (RBD2). RBD1 binds tightly and specifically to one of the stem loops of the U1 snRNA, as well as to its own 3'-UTR. In contrast, RBD2 does not appear to associate with any RNA. The two domains share 25% amino acid identity, and both have the same betaalphabeta-betaalphabeta secondary structure fold. In this work, 13C/15N/1H multidimensional NMR methods were used to obtain side-chain assignments for RBD2, and then the tertiary structure was calculated using a distance geometry/simulated annealing algorithm that employs pairwise Gaussian metrization. RBD2 is shown to fold into an alpha/beta sandwich with a four-stranded antiparallel beta-sheet, which is the typical global topology of these domains. Specific structural features of RBD2 include a beta-bulge in beta2, N-capping boxes for both alpha-helices, and an extremely shallow twist of its beta-sheet. The 15N backbone dynamics of these two structurally homologous RBDs are significantly different, compared using order parameters and T2 exchange terms in the Lipari and Szabo model-free formalism. Conformational exchange observed in RBD1, which is absent in RBD2, may correlate to the mechanism of RNA binding.


The transverse magnetic reflectivity minimum of metals.
Metal surfaces, which are generally regarded as excellent reflectors of electromagnetic radiation, may, at high angles of incidence, become strong absorbers for transverse magnetic radiation. This effect, often referred to as the pseudo-Brewster angle, results in a reflectivity minimum, and is most strongly evident in the microwave domain, where metals are often treated as perfect conductors. A detailed analysis of this reflectivity minimum is presented here and it is shown why, in the limit of very long wavelengths, metals close to grazing incidence have a minimum in reflectance given by (square root 2-1)2.


Molecular Testing for Gastrointestinal Cancer.
With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2-4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus-positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.


Long, processive enzymatic DNA synthesis using 100% dye-labeled terminal phosphate-linked nucleotides.
We demonstrate the efficient synthesis of DNA with complete replacement of the four deoxyribonucleoside triphosphate (dNTP) substrates with nucleotides carrying fluorescent labels. A different, spectrally separable fluorescent dye suitable for single molecule fluorescence detection was conjugated to each of the four dNTPs via linkage to the terminal phosphate. Using these modified nucleotides, DNA synthesis by phi 29 DNA polymerase was observed to be processive for products thousands of bases in length, with labeled nucleotide affinities and DNA polymerization rates approaching unmodified dNTP levels. Results presented here show the compatibility of these nucleotides for single-molecule, real-time DNA sequencing applications.


Addressing intimate partner violence in substance-abuse treatment.
As the use of partner-involved therapies for alcoholism and drug abuse become more common in substance-abuse treatment programs, providers are more frequently encountering one of the most challenging and politically charged public health issues of our time: intimate partner violence (IPV). Recent investigations reveal 40-60% of married or cohabiting substance-abusing patients report episodes of partner aggression in the year preceding entry into treatment. In this article, the interrelationship between substance use and IPV is examined, with an emphasis on clinical implications and options for substance-abuse treatment providers who are often called upon to address IPV during the course of working with their patients. We also describe different intervention options for IPV, offer recommendations for substance-abuse treatment providers who work with partner-violent couples, and outline future research directions.


Phenotypic characterization of lung macrophages in asthmatic patients: overexpression of CCL17.
Studies with monocyte-derived macrophages (MDMs) and animal models have suggested a role for alternatively activated (M2) macrophages in asthmatic inflammation, but in vivo evidence for this phenotype in human asthma is lacking. To characterize the phenotype of lung macrophages from asthmatic patients in relation to disease severity and treatment. M2 biomarkers were first identified by using MDMs exposed to T(H)2 cytokines and then used to phenotype sputum and bronchoalveolar lavage (BAL) macrophages from 12 healthy control subjects, 12 patients with mild asthma, and 14 patients with moderate asthma and to assess the effects of corticosteroids and phosphatidylinositol 3-kinase (PI3K) inhibitors. Sputum macrophages from asthmatic patients expressed significantly more CCL17 mRNA but less CD163 than macrophages from healthy subjects. However, none of the other M2 biomarkers were differentially expressed in asthmatic patients, and ex vivo BAL cells spontaneously produced similar amounts of M2 cytokines/chemokines (IL-10, CCL17, and CCL22). CCL17 mRNA overexpression correlated weakly but significantly with sputum eosinophilia (P = .0252) and was also observed in macrophages from patients with moderate asthma treated with inhaled steroids, suggesting relative insensitivity to inhibition by corticosteroids. The PI3K inhibitor LY294002 inhibited basal CCL17 release from BAL cells and IL-4-stimulated release from MDMs. This study does not support the existence in human asthma of the full M2 phenotype described to date but points to upregulation of CCL17 in both patients with mild and those with moderate asthma, providing a further source for this ligand of CCR4(+) cells that contributes to airways inflammation. CCL17 expression is corticosteroid resistant but suppressed by PI3K enzyme inhibitors.


Effectiveness and safety of adalimumab in patients with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy.
Tumor necrosis factor (TNF) antagonists reduce the signs and symptoms of spondyloarthritides, including ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Our objective was to evaluate the effectiveness and safety of adalimumab, 40 mg every other week, for patients with AS or PsA and prior treatment with infliximab (IFX) and/or etanercept (ETN). Both trials were 12-week, open-label studies with an optional extension period up to week 20. Patients were stratified by history of anti-TNF treatment, prior anti-TNF therapy received (IFX, ETN, or both), and reason for discontinuation of prior TNF antagonist. ETN was discontinued>or=3 weeks, and IFX was discontinued>or=2 months before the first adalimumab administration. Effectiveness at week 12 was evaluated by using observed standard-outcome measurements for AS and PsA. At week 12 of adalimumab treatment, Bath Ankylosing Spondylitis Disease Activity Index 50 responses were achieved by 40.8% of 326 patients with AS who had received prior anti-TNF therapy and by 63.0% of 924 patients with AS who were naive to TNF antagonist. Observed response rates were generally greater for patients who discontinued the prior anti-TNF therapy because of loss of response or intolerance than for patients who discontinued because of lack of response. Median changes in swollen-joint count and in enthesitis score were similar in patients with and without prior TNF-antagonist treatment. Modified PsA response criteria were fulfilled by 71.2% of 66 patients with PsA, with prior exposure to TNF antagonists, and by 78.8% of 376 patients with no history of anti-TNF therapy. The percentages of patients with PsA attaining a Physician's Global Assessment of psoriasis of "Clear/Almost clear" increased from 33.3% to 61.0% for patients with prior IFX and/or ETN treatment and from 34.6% to 69.7% for patients without anti-TNF therapy. The median change in the Nail Psoriasis Severity Index was -6 for both groups. In both studies, patterns of adverse events were similar for patients with and without prior anti-TNF therapy and were consistent with the known safety profile of adalimumab. Patients with AS or PsA previously treated with IFX and/or ETN experienced clinically relevant improvements of their diseases after 12 weeks of adalimumab. ClinicalTrials.gov NCT00478660 and NCT00235885.


Assessment of changes in photosystem II structure and function as affected by water deficit in Amaranthus hypochondriacus L. and Amaranthus hybridus L.
The present study describes the behaviour of photosystem II (PSII) in Amaranthus hypochondriacus and Amaranthus hybridus under water stress conditions, assessed by the analyses of the polyphasic rise in chlorophyll a fluorescence (O-J-I-P). We determined the adaptive behaviour in relation to the regulation of the different functional and structural parameters of PSII, which was a direct and rapid response due to changes in soil water status indicated by a decrease in leaf water potential and relative water content. It allows for the identification of specific key or limiting chlorophyll fluorescence parameters which could be used to identify traits conveying tolerance. For the above partial processes of PSII function studied, it seems that A. hybridus remained the more stable upon water stress (after 17 days of withholding water), concerning the specific energy fluxes of absorption/reaction centre (ABS/RC) apparent (antenna size) and trapping/reaction centre (TR/RC) (maximum trapping flux), as well as the density of the reaction centres/cross section (RC/CS) and the phenomenological trapping flux/cross section (TR(o)/CS). It was clear that amaranth adjusts the non-photochemical (k(n)) deactivation constant of PSII and to a less extend also the photochemical (k(p)) deactivation constant by means of photoregulation, which forms the basis of the quenching of chlorophyll a fluorescence. Although drought stress caused the deactivation of RCs leading to a decrease in the density of active RCs, the plants compensated by increasing the efficiency of the conversion of trapped excitation energy to electron transport beyond Q(A) (efficiency of exciton trapping/reaction centre: ET(o)/TR(o)). Subsequent damage to PSII might be the reason for the slow, or lack of recovery, for most of the parameters measured.


Projection angle dependence in grating-based X-ray dark-field imaging of ordered structures.
Over the recent years X-ray differential phase-contrast imaging was developed for the hard X-ray regime as produced from laboratory X-ray sources. The technique uses a grating-based Talbot-Lau interferometer and was shown to yield image contrast gain, which makes it very interesting to the fields of medical imaging and non-destructive testing, respectively. In addition to X-ray attenuation contrast, the differential phase-contrast and dark-field images provide different structural information about a specimen. For the dark-field even at length scales much smaller than the spatial resolution of the imaging system. Physical interpretation of the dark-field information as present in radiographic and tomographic (CT) images requires a detailed look onto the geometric orientation between specimen and the setup. During phase-stepping the drop in intensity modulation, due to local scattering effects within the specimen is reproduced in the dark-field signal. This signal shows strong dependencies on micro-porosity and micro-fibers if these are numerous enough in the object. Since a grating-interferometer using a common unidirectional line grating is sensitive to X-ray scattering in one plane only, the dark-field image is influenced by the fiber orientations with respect to the grating bars, which can be exploited to obtain anisotropic structural information. With this contribution, we attempt to extend existing models for 2D projections to 3D data by analyzing dark-field contrast tomography of anisotropically structured materials such as carbon fiber reinforced carbon (CFRC).


A parallel coiled-coil tetramer with offset helices.
Specific helix-helix interactions are fundamental in assembling the native state of proteins and in protein-protein interfaces. Coiled coils afford a unique model system for elucidating principles of molecular recognition between alpha helices. The coiled-coil fold is specified by a characteristic seven amino acid repeat containing hydrophobic residues at the first (a) and fourth (d) positions. Nonpolar side chains spaced three and four residues apart are referred to as the 3-4 hydrophobic repeat. The presence of apolar amino acids at the e or g positions (corresponding to a 3-3-1 hydrophobic repeat) can provide new possibilities for close-packing of alpha-helices that includes examples such as the lac repressor tetramerization domain. Here we demonstrate that an unprecedented coiled-coil interface results from replacement of three charged residues at the e positions in the dimeric GCN4 leucine zipper by nonpolar valine side chains. Equilibrium circular dichroism and analytical ultracentrifugation studies indicate that the valine-containing mutant forms a discrete alpha-helical tetramer with a significantly higher stability than the parent leucine-zipper molecule. The 1.35 A resolution crystal structure of the tetramer reveals a parallel four-stranded coiled coil with a three-residue interhelical offset. The local packing geometry of the three hydrophobic positions in the tetramer conformation is completely different from that seen in classical tetrameric structures yet bears resemblance to that in three-stranded coiled coils. These studies demonstrate that distinct van der Waals interactions beyond the a and d side chains can generate a diverse set of helix-helix interfaces and three-dimensional supercoil structures.


Two-dimensional metal NaCu6.3Sb3 and solid-state transformations of sodium copper antimonides.
A novel layered compound, NaCu6.3Sb3, has been successfully synthesized from elements. This unique structure crystallizes in the hexagonal space group P63/mmc and has lattice constants of a = 4.2166(2) Å and c = 24.041(1) Å. The structure consists of complex Cu/Sb 2D blocks separated by Na ions. These blocks contain graphene-like hexagonal layers of either Cu or CuSb. The solid-state transformations in the Na-Cu-Sb system between Cu2Sb-NaCu6.3Sb3-NaCu4Sb2 were explored using annealing at different partial vapor pressures of Na, differential scanning calorimetry, and in situ synchrotron powder X-ray diffraction. Full reversibility of the transformation was observed, indicating that the bulk 3D Cu2Sb phase is capable of reversible intercalation of Na ions, forming layered intercalated phases similar to intercalated graphite. The characterization of the transport properties shows that the metallic nature of the electrical conductivity is preserved, even for the Na-rich phase of NaCu4Sb2. Electronic structure calculations support metallic properties in the Cu-Sb layers and predict that no bands cross the Fermi level across the layers, supporting NaCu6.3Sb3 as a two-dimensional metal.


Endothelial PFKFB3 plays a critical role in angiogenesis.
Vascular cells, particularly endothelial cells, adopt aerobic glycolysis to generate energy to support cellular functions. The effect of endothelial glycolysis on angiogenesis remains unclear. 6-Phosphofructo-2-kinase/fructose-2, 6-bisphosphatase, isoform 3 (PFKFB3) is a critical enzyme for endothelial glycolysis. By blocking or deleting PFKFB3 in endothelial cells, we investigated the influence of endothelial glycolysis on angiogenesis both in vitro and in vivo. Under hypoxic conditions or after treatment with angiogenic factors, endothelial PFKFB3 was upregulated both in vitro and in vivo. The knockdown or overexpression of PFKFB3 suppressed or accelerated endothelial proliferation and migration in vitro, respectively. Neonatal mice from a model of oxygen-induced retinopathy showed suppressed neovascular growth in the retina when endothelial PFKFB3 was genetically deleted or when the mice were treated with a PFKFB3 inhibitor. In addition, tumors implanted in mice deficient in endothelial PFKFB3 grew more slowly and were provided with less blood flow. A lower level of phosphorylated protein kinase B was observed in PFKFB3-knockdown endothelial cells, which was accompanied by a decrease in intracellular lactate. The addition of lactate to PFKFB3-knockdown cells rescued the suppression of endothelial proliferation and migration. The blockade or deletion of endothelial PFKFB3 decreases angiogenesis both in vitro and in vivo. Thus, PFKFB3 is a promising target for the reduction of endothelial glycolysis and its related pathological angiogenesis.


Effect of socioeconomic deprivation and health service utilisation on antepartum and intrapartum stillbirth: population cohort study from rural Ghana.
No studies have examined the effect of socioeconomic deprivation on antepartum and intrapartum stillbirths in the poorest women in low income countries. This study used data from a prospective population based surveillance system involving all women of childbearing age and their babies in rural Ghana. The primary objective was to evaluate associations between household wealth and risk of antepartum and intrapartum stillbirth. The secondary objective was to assess whether any differences in risk were mediated by utilisation of health services during pregnancy. Data were analysed using multivariable logistic regression. Random effect models adjusted for clustering of women who delivered more than one infant. There were 80267 babies delivered from 1 July 2003 to 30 September 2008: 77666 live births and 2601 stillbirths. Of the stillbirths 1367 (52.6%) were antepartum, 989 (38.0%) were intrapartum and 245 (9.4%) had no data on the timing of death. 94.8% of the babies born in the study (76129/80267) had complete data on all covariates and outcomes. 36 878 (48.4%) of babies were born to women in the two poorest quintiles and 3697 (4.9%) had no pregnancy care. There was no association between wealth and antepartum stillbirths. There was a marked 'dose response' of increasing risk of intrapartum stillbirth with increasing levels of socioeconomic deprivation (adjOR 1.09 [1.03-1.16] p value 0.002). Women in the poorest two quintiles had greater risk of intrapartum stillbirth (adjOR 1.19 [1.02-1.38] p value 0.023) compared to the richest women. Adjusting for heath service utilisation and other variables did not alter results. Poor women had a high risk of intrapartum stillbirth and this risk was not influenced by health service utilisation. Health system strengthening is required to meet the needs of poor women in our study population.


A simulation-based analysis of motor unit number index (MUNIX) technique using motoneuron pool and surface electromyogram models.
Motor unit number index (MUNIX) measurement has recently achieved increasing attention as a tool to evaluate the progression of motoneuron diseases. In our current study, the sensitivity of the MUNIX technique to changes in motoneuron and muscle properties was explored by a simulation approach utilizing variations on published motoneuron pool and surface electromyogram (EMG) models. Our simulation results indicate that, when keeping motoneuron pool and muscle parameters unchanged and varying the input motor unit numbers to the model, then MUNIX estimates can appropriately characterize changes in motor unit numbers. Such MUNIX estimates are not sensitive to different motor unit recruitment and rate coding strategies used in the model. Furthermore, alterations in motor unit control properties do not have a significant effect on the MUNIX estimates. Neither adjustment of the motor unit recruitment range nor reduction of the motor unit firing rates jeopardizes the MUNIX estimates. The MUNIX estimates closely correlate with the maximum M-wave amplitude. However, if we reduce the amplitude of each motor unit action potential rather than simply reduce motor unit number, then MUNIX estimates substantially underestimate the motor unit numbers in the muscle. These findings suggest that the current MUNIX definition is most suitable for motoneuron diseases that demonstrate secondary evidence of muscle fiber reinnervation. In this regard, when MUNIX is applied, it is of much importance to examine a parallel measurement of motor unit size index (MUSIX), defined as the ratio of the maximum M-wave amplitude to the MUNIX. However, there are potential limitations in the application of the MUNIX methods in atrophied muscle, where it is unclear whether the atrophy is accompanied by loss of motor units or loss of muscle fiber size.