[Pre-randomisation in study designs: getting past the taboo].
In October 2006 the Dutch Ministry of Health, Welfare and Sport announced that the use of pre-randomisation in study designs is admissible and not in conflict with the Dutch Medical Research in Human Subjects Act. With pre-randomisation, the conventional sequence of obtaining informed consent followed by randomisation is reversed. According to the original pre-randomisation design (Zelen design), participants are randomised before they are asked to consent; after randomisation, only participants in the experimental group are asked to consent to treatment and effect measurement. In the past, pre-randomisation has seldom been used, and when it was, it was often under the wrong circumstances. Awareness regarding the ethical, legal and methodological objections to pre-randomisation is increasing. About a decade ago, we illustrated the applicability and acceptability of pre-randomisation by means of a fictitious heroin provision trial. In general, pre-randomisation is justified if valid evaluation of the effects of an intervention is impossible using a conventional randomised design, e.g., if knowledge of the intervention may lead to non-compliance or drop-out in the control group, or when the intervention is an educational programme. Other requirements for pre-randomisation include the following: the study has a clinically relevant objective, it is likely that the study will lead to important new insights, the informed consent procedure bears no potential harm to participants, at least standard care is offered to participants in the control group, and the approval of an independent research ethics committee is obtained.


Structural and physicochemical characteristics of a novel water-soluble gum from Lallemantia royleana seed.
In this study, the structural information (monosaccharide compositions, molecular weight parameters & FTIR analysis), chemical composition (moisture, protein, ash, carbohydrate & uronic acids), rheological properties, and surface activity of Lallemantia royleana seeds mucilage (BSG) were determined. The results showed BSG contains 8.51% (w.b.) moisture, 8.24% (d.b.) ash, 2.71% (d.b.) protein, 75.87% (d.b.) carbohydrate and 20.33% (d.b.) uronic acids. Monosaccharide analysis revealed the presence of arabinose (37.88%), galactose (33.54%), rhamnose (18.44%), xylose (6.02%) and glucose (4.11%) in the BSG polysaccharide. Although BSG had similar molecular weight (1.294×10(6) Da) compared to most seed gums, the intrinsic viscosity (23.06 dL/g) and gyration radius (104.84 nm) were higher. The BSG exhibited a strong shear-thinning behavior (n<0.29) over the shear rate range of 0.01 to 1000 s(-1). Flow behavior data was correlated with different time-independent models, which provided a good description of BSG rheological properties. Dynamic mechanical spectra demonstrated BSG is a typical of weak gel, which its rheological parameters were superior to those of many commercial gums. The FTIR spectra of the BSG polymer showed the presence of carboxyl groups, which may serve as binding sites for ions. BSG exhibited the ability to reduce the surface tension of water at concentrations lower than 0.75%.


Side effects of phytoestrogens: a meta-analysis of randomized trials.
Phytoestrogens are widely used by postmenopausal women for the treatment of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown. Using a fixed-effects model, we performed a meta-analysis of side effects comparing phytoestrogen treatment with placebo or no treatment in randomized controlled trials. We identified 174 randomized controlled trials. Side effects were reported in 92/174 randomized controlled trials with 9629 participants. The overall incidence of side effects in the phytoestrogen and control groups was 2019/5502 (36.7%) and 1824/4806 (38.0%), respectively (P=.2; incidence rate ratio [IRR] 1.01; 95% confidence interval [CI], 0.95-1.08). Comparing various side effect categories, we found significantly higher rates of gastrointestinal side effects among phytoestrogen users (P=.003; IRR 1.28; 95% CI, 1.08-1.50). Gynecological (IRR 0.94; 95% CI, 0.74-1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94-1.53), neurological (IRR 0.91; 95% CI, 0.70-1.19), and unspecific side effects (IRR 0.95; 95% CI, 0.88-1.03) were not significantly different between groups. Within side effect categories, we found no significantly higher rates of side effects in women using phytoestrogens. Specifically, the rates of hormone-related side effects such as endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly different between groups. Based on the available evidence, phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies.


Histological comparison of 1064 nm Nd:YAG and 1320 nm Nd:YAG laser lipolysis using an ex vivo model.
Body contouring with liposuction including laser liposuction is one of the most commonly performed cosmetic procedures. Laser lipolysis is generally well tolerated with high patient satisfaction rates. Laser lipoplasty has been postulated to offer the unique advantage of skin tightening following removal of subcutaneous fat. The search continues for an optimal wavelength that would allow for: (1) efficient targeting of adipocytes while targeting dermal collagen and collagen bound water to allow for dermal remodeling and (2) targeting hemoglobin and vessel wall collagen to decrease intra-operative bleeding and consequent post-operative bruising. The main objective of this study was to determine the effects of 1064 nm and 1320 nm Nd:YAG lipolysis on fresh ex vivo human abdominal fat pads. Ipsilateral 1064 nm Nd:YAG lipolysis and contralateral 1320 nm Nd:YAG lipolysis were performed on ex vivo human abdominal fat pads from comparable topographic areas of the body of the same patient. Biopsy specimens were assessed for alterations of the epidermis, papillary and reticular dermis and subcutaneous fat. Our histological analysis demonstrated a wavelength dependent differential dermal response. Increasing fluence led to progressively more extensive dermal coagulation with associated epidermal thermal injury with 1320 nm Nd:YAG leading to more extensive collagen coagulation as compared to 1064 nm Nd:YAG.


Men on the Move-Nashville: Feasibility and Acceptability of a Technology-Enhanced Physical Activity Pilot Intervention for Overweight and Obese Middle and Older Age African American Men.
Men on the Move-Nashville was a quasi-experimental, 10-week pilot physical activity intervention. A total of 40 overweight or obese African American men ages 30 to 70 (mean age = 47) enrolled in the intervention. Participants attended 8 weekly, 90-minute small group sessions with a certified personal trainer. Each session consisted of discussions aimed to educate and motivate men to be more physically active, and an exercise component aimed to increase endurance, strength, and flexibility. Throughout each week, men used wearable activity trackers to promote self-monitoring and received informational and motivational SMS text messages. Of the 40 enrolled men, 85% completed the intervention, and 80% attended four or more small group sessions. Additionally, 70% of participants successfully used the activity tracker, but only 30% of men utilized their gym memberships. Participants benefited from both the small group discussions and activities through increasing social connection and guidance from their trainer and group members. These African American men reported being motivated to engage in physical activity through each of these technologies. Men reported that the activity trackers provided an important extension to their social network of physically active people. The intervention resulted in significant increases in men's self-reported levels of light, moderate, vigorous, and sports-related physical activities, and high-density lipoprotein cholesterol levels, and significant decreases in weight and body fat percentage with small, moderate and large effects shown. Including technology and didactic components in small group-based interventions holds promise in motivating African American men to increase their physical activity.


Alanine-261 in intracellular loop III of the human gonadotropin-releasing hormone receptor is crucial for G-protein coupling and receptor internalization.
Gonadotropin-releasing hormone (GnRH) is a decapeptide that regulates reproductive function via binding to the GnRH receptor, which is a G-protein-coupled receptor (GPCR). For several members of this family, the C-terminal domain of intracellular loop III is important in ligand-mediated coupling to G-proteins; mutations in that region can lead to constitutive activity. A specific alanine residue is involved in certain GPCRs, the equivalent of which is Ala-261 in the GnRH receptor. Mutation of this residue to Leu, Ile, Lys, Glu or Phe in the human GnRH receptor did not result in constitutive activity and instead led to complete uncoupling of the receptor (failure to support GnRH-stimulated inositol phosphate production). When this residue was mutated to Gly, Pro, Ser or Val, inositol phosphate production was still supported. All the mutants retained the ability to bind ligand, and the affinity for ligand, where measured, was unchanged. These results show that Ala-261 cannot be involved in ligand binding but is critical for coupling of the receptor to its cognate G-protein. Coupling is also dependent on the size of the residue in position 261. When the amino acid side chain has a molecular mass of less than 40 Da efficient coupling is still possible, but when its molecular mass exceeds 50 Da the receptor is uncoupled. Internalization studies on the Ala261-->Lys mutant showed a marked decrease in receptor internalization compared with the wild type, indicating that coupling is necessary for effective receptor internalization in the GnRH receptor system. Activation of protein kinase C (with PMA), but not protein kinase A (with forskolin) markedly increased the internalization of the mutant receptor while having a small effect on the wild-type receptor.


ARKS: chromosome-scale scaffolding of human genome drafts with linked read kmers.
The long-range sequencing information captured by linked reads, such as those available from 10× Genomics (10xG), helps resolve genome sequence repeats, and yields accurate and contiguous draft genome assemblies. We introduce ARKS, an alignment-free linked read genome scaffolding methodology that uses linked reads to organize genome assemblies further into contiguous drafts. Our approach departs from other read alignment-dependent linked read scaffolders, including our own (ARCS), and uses a kmer-based mapping approach. The kmer mapping strategy has several advantages over read alignment methods, including better usability and faster processing, as it precludes the need for input sequence formatting and draft sequence assembly indexing. The reliance on kmers instead of read alignments for pairing sequences relaxes the workflow requirements, and drastically reduces the run time. Here, we show how linked reads, when used in conjunction with Hi-C data for scaffolding, improve a draft human genome assembly of PacBio long-read data five-fold (baseline vs. ARKS NG50 = 4.6 vs. 23.1 Mbp, respectively). We also demonstrate how the method provides further improvements of a megabase-scale Supernova human genome assembly (NG50 = 14.74 Mbp vs. 25.94 Mbp before and after ARKS), which itself exclusively uses linked read data for assembly, with an execution speed six to nine times faster than competitive linked read scaffolders (~ 10.5 h compared to 75.7 h, on average). Following ARKS scaffolding of a human genome 10xG Supernova assembly (of cell line NA12878), fewer than 9 scaffolds cover each chromosome, except the largest (chromosome 1, n = 13). ARKS uses a kmer mapping strategy instead of linked read alignments to record and associate the barcode information needed to order and orient draft assembly sequences. The simplified workflow, when compared to that of our initial implementation, ARCS, markedly improves run time performances on experimental human genome datasets. Furthermore, the novel distance estimator in ARKS utilizes barcoding information from linked reads to estimate gap sizes. It accomplishes this by modeling the relationship between known distances of a region within contigs and calculating associated Jaccard indices. ARKS has the potential to provide correct, chromosome-scale genome assemblies, promptly. We expect ARKS to have broad utility in helping refine draft genomes.


Approaches in the risk assessment of genetically modified foods by the Hellenic Food Safety Authority.
Risk analysis has become important to assess conditions and take decisions on control procedures. In this context it is considered a prerequisite in the evaluation of GM food. Many consumers worldwide worry that food derived from genetically modified organisms (GMOs) may be unhealthy and hence regulations on GMO authorisations and labelling have become more stringent. Nowadays there is a higher demand for non-GM products and these products could be differentiated from GM products using the identity preservation system (IP) that could apply throughout the grain processing system. IP is the creation of a transparent communication system that encompasses HACCP, traceability and related systems in the supply chain. This process guarantees that certain characteristics of the lots of food (non-GM origin) are maintained "from farm to fork". This article examines the steps taken by the Hellenic Food Safety Authority to examine the presence of GMOs in foods. The whole integrated European legislation framework currently in place still needs to be implemented in Greece. Penalties should be enforced to those who import, process GMOs without special licence and do not label those products. Similar penalties should be enforced to those companies that issue false certificates beyond the liabilities taken by the food enterprises for farmers' compensation. We argue that Greece has no serious reasons to choose the use of GMOs due to the fact that the structural and pedologic characteristics of the Greek agriculture favour the biological and integrated cultivation more. Greece is not in favour of the politics behind coexistence of conventional and GM plants and objects to the use of GMOs in the food and the environment because the processor has a big burden in terms of money, time and will suffer a great deal in order to prove that their products are GMO free or that any contamination is adventitious or technically unavoidable. Moreover, Greece owns a large variety of genetic material that should try to protect from patenting and commercialisation. Finally, we should be aware of the requirements of movement of GMOs within borders, i.e. GMOs grown or used in other countries but which are not intended to cross into Greece, since Greece is very close to countries that are non-EU. This is where the development of a new, integrated, trustworthy and transparent food quality control system will help to satisfy the societal demands for safe and quality products. On the other hand, Greece should not be isolated from any recent scientific technological development and should assess the possible advantages for some cultivation using a case by case approach. Finally, the safety assessment of GM foods and feed has been discussed according to the risk assessment methodology applied by EFSA.


Effect of fragarin on the cytoplasmic membrane of the phytopathogen Clavibacter michiganensis.
Fragarin, an antibiotic that was isolated and purified from a soluble fraction of strawberry leaves, may be a new type of preformed antimicrobial compound (phytoanticipin). Here, we report that the growth and oxygen consumption of the phytopathogenic bacterium Clavibacter michiganensis were rapidly inhibited after the addition of fragarin to cultures. Also, dissipation of the membrane potential and an increase of cell membrane permeability were observed in the presence of fragarin. The ability of fragarin to dissipate the membrane potential was confirmed with the use of small unilamellar liposomes made with lipids extracted from C. michiganensis. Our results suggest that fragarin is able to act at the membrane level, and that this action is correlated with a decrease in cell viability.


Paternalism, autonomy and reciprocity: ethical perspectives in encounters with patients in psychiatric in-patient care.
Psychiatric staff members have the power to decide the options that frame encounters with patients. Intentional as well as unintentional framing can have a crucial impact on patients' opportunities to be heard and participate in the process. We identified three dominant ethical perspectives in the normative medical ethics literature concerning how doctors and other staff members should frame interactions in relation to patients; paternalism, autonomy and reciprocity. The aim of this study was to describe and analyse statements describing real work situations and ethical reflections made by staff members in relation to three central perspectives in medical ethics; paternalism, autonomy and reciprocity. All staff members involved with patients in seven adult psychiatric and six child and adolescent psychiatric clinics were given the opportunity to freely describe ethical considerations in their work by keeping an ethical diary over the course of one week and 173 persons handed in their diaries. Qualitative theory-guided content analysis was used to provide a description of staff encounters with patients and in what way these encounters were consistent with, or contrary to, the three perspectives. The majority of the statements could be attributed to the perspective of paternalism and several to autonomy. Only a few statements could be attributed to reciprocity, most of which concerned staff members acting contrary to the perspective. The result is presented as three perspectives containing eight values.•Paternalism; 1) promoting and restoring the health of the patient, 2) providing good care and 3) assuming responsibility.•Autonomy; 1) respecting the patient's right to self-determination and information, 2) respecting the patient's integrity and 3) protecting human rights.•Reciprocity; 1) involving patients in the planning and implementation of their care and 2) building trust between staff and patients. Paternalism clearly appeared to be the dominant perspective among the participants, but there was also awareness of patients' right to autonomy. Despite a normative trend towards reciprocity in psychiatry throughout the Western world, identifying it proved difficult in this study. This should be borne in mind by clinics when considering the need for ethical education, training and supervision.


Religious/Spiritual Well-being, personality and mental health: a review of results and conceptual issues.
The current paper provides background to the development of the Multidimensional Inventory for Religious/Spiritual Well-being and then summarises findings derived from its use with other measures of health and personality. There is substantial evidence for religiosity/spirituality being positively related to a variety of indicators of mental health, including subjective well-being and personality dimensions. Furthermore, religiosity/spirituality can play an important role in the process of recovering from mental illness as well as providing a protective function against addictive or suicidal behaviours. However, further research is needed to examine the mechanisms through which religiosity/spirituality have an impact on health-related conditions.


Immortalized porcine liver sinusoidal endothelial cells: an in vitro model of xenotransplantation-induced thrombocytopenia.
Xenotransplantation has the potential to solve the critical shortage of human organs available for allotransplantation. The major barrier to porcine liver xenotransplantation is sequestration of human platelets causing thrombocytopenia. Porcine liver sinusoidal endothelial cells (LSEC) bind and phagocytose human platelets at least in part through binding of the asialoglycoprotein receptor 1 (ASGR1). Our purpose was to generate an immortalized porcine LSEC (iLSEC) line that mimics primary LSEC in ASGR1 expression and phagocytosis of human platelets. Porcine iLSEC would enable continued study of xenotransplantation-induced thrombocytopenia in vitro with fewer animals sacrificed. Primary domestic porcine LSEC were transduced with lentiviral vector expressing the large and small T antigen of SV40 (SV40 TAg). The phenotype and genotype of the immortalized LSEC were compared with primary LSEC. A total of eight clones expressing SV40 TAg were isolated, and one clone was subcultured and analyzed for growth, phenotype, and function during passages 15-40. Expression of the SV40 TAg was confirmed by confocal microscopy and western blot. MTS cell proliferation assay demonstrated that the clone rapidly grew in culture medium with 2-10% fetal bovine serum. iLSEC expressed the endothelial cell marker, CD31, as determined by confocal microscopy and flow cytometry. Activation of iLSEC by treatment with lipopolysaccharide (LPS) resulted in upregulation of the inflammatory cytokine interleukin 6 (IL 6) by qPCR and ELISA. iLSEC phagocytosed human serum albumin and latex beads as measured by flow cytometry. Human platelets were phagocytosed by immortalized porcine LSEC. Immortalized porcine LSEC retain a phagocytic phenotype, making them a good model for the study of xenotransplantation-induced thrombocytopenia and may provide further insight into the phagocytic role of LSEC.


A field trial of competitive displacement of Aedes polynesiensis by Aedes albopictus on a Pacific atoll.
Prior laboratory studies and field observations suggested that it might be possible to reduce the size of the population of, or eliminate, Aedes polynesiensis by the introduction of Aedes albopictus. The former mosquito is the principal vector of nonperiodic filariasis caused by Wuchereria bancrofti and the latter is a closely related species refractory to the development of human filariae. The practicability of such competitive displacement was studied by a field trial on a remote coral atoll where there was an established population of A. polynesiensis. Three strains of Al albopictus were liberated at separate localities on the atoll and their fate was followed for 4 years. One strain disappeared within 12 months after release and the other two disappeared within 48 months. It was not clear whether A. albopicuts failed to become established because the strains were unsuitable, the general environment was inappropriate, or A. polynesiensis was present in such numbers that A. albopictus rarely succeded in mating with its own species.


[Stress, blood pressure reactivity and arterial hypertension: not an unambiguous relation].
In order to determine the different ways the hypertensives' blood pressure would react during mental stress, 49 patients, 27 women and 22 men, were submitted at the Stroop Word Colour Conflict Test. Their haemodynamic parameters were recorded by finger photoplethysmography (Finapres device), with equidistant sampling (2 Hz). Temporal and spectral analysis showed evidence of: a quick and short elevation of BP and HR and a greater variability of SBP, as shown by the increase of the MF (66-128 mHZ) module. Patients can be divided into 3 clusters according to the reactivity of SBP. Group I (N, mean +/- sigma) 13, + 32.7 +/- 8 mmHg; group II 24, + 10.3 +/- 6; group III 12, -10.2 +/- 7. They were comparable on anxiety level and on any demographic and clinical feature. In group III, the higher NA at rest, the bigger the fall of SBP when stressed. The cognitive efficiency of these patients is increased by stress. Spectral analysis: Mid frequency (66-128 mHz) components are markedly higher in group III, before, during and after SWCCT showing a higher sympathetic tonus. The reactivity of BP is not homogeneous. One fourth of our patients showed a decrease of SBP during the cognitive treatment stage of the test without showing a decrease of sympathetic tone. Anxiety level is not predictive of BP's response.


Mitochondria-Endoplasmic Reticulum Contacts in Reactive Astrocytes Promote Vascular Remodeling.
Astrocytes have emerged for playing important roles in brain tissue repair; however, the underlying mechanisms remain poorly understood. We show that acute injury and blood-brain barrier disruption trigger the formation of a prominent mitochondrial-enriched compartment in astrocytic endfeet, which enables vascular remodeling. Integrated imaging approaches revealed that this mitochondrial clustering is part of an adaptive response regulated by fusion dynamics. Astrocyte-specific conditional deletion of Mitofusin 2 (Mfn2) suppressed perivascular mitochondrial clustering and disrupted mitochondria-endoplasmic reticulum (ER) contact sites. Functionally, two-photon imaging experiments showed that these structural changes were mirrored by impaired mitochondrial Ca2+ uptake leading to abnormal cytosolic transients within endfeet in vivo. At the tissue level, a compromised vascular complexity in the lesioned area was restored by boosting mitochondrial-ER perivascular tethering in MFN2-deficient astrocytes. These data unmask a crucial role for mitochondrial dynamics in coordinating astrocytic local domains and have important implications for repairing the injured brain.


Baseline CD4 Count and Adherence to Antiretroviral Therapy: A Systematic Review and Meta-Analysis.
In light of recent changes to antiretroviral treatment (ART) guidelines of the World Health Organization and ongoing concerns about adherence with earlier initiation of ART, we conducted a systematic review of published literature to review the association between baseline (pre-ART initiation) CD4 count and ART adherence among adults enrolled in ART programs worldwide. We performed a systematic search of English language original studies published between January 1, 2004 and September 30, 2015 using Medline, Web of Science, LILACS, AIM, IMEMR, and WPIMR databases. We calculated the odds of being adherent at higher CD4 count compared with lower CD4 count according to study definitions and pooled data using random effects models. Twenty-eight articles were included in the review and 18 in the meta-analysis. The odds of being adherent was marginally lower for patients in the higher CD4 count group (pooled odds ratio, 0.90; 95% confidence interval, 0.84 to 0.96); however, the majority of studies found no difference in the odds of adherence when comparing CD4 count strata. In analyses restricted to comparisons above and below a CD4 count of 500 cells per microliter, there was no difference in adherence (pooled odds ratio, 1.01; 95% confidence interval: 0.97 to 1.05). This review was unable to find consistent evidence of differences in adherence according to baseline CD4 count. Although this is encouraging for the new recommendations to treat all HIV-positive individuals irrespective of CD4 count, there is a need for additional high-quality studies, particularly among adults initiating ART at higher CD4 cell counts.


Paratransgenic control of vector borne diseases.
Conventional methodologies to control vector borne diseases with chemical pesticides are often associated with environmental toxicity, adverse effects on human health and the emergence of insect resistance. In the paratransgenic strategy, symbiotic or commensal microbes of host insects are transformed to express gene products that interfere with pathogen transmission. These genetically altered microbes are re-introduced back to the insect where expression of the engineered molecules decreases the host's ability to transmit the pathogen. We have successfully utilized this strategy to reduce carriage rates of Trypanosoma cruzi, the causative agent of Chagas disease, in the triatomine bug, Rhodnius prolixus, and are currently developing this methodology to control the transmission of Leishmania donovani by the sand fly Phlebotomus argentipes. Several effector molecules, including antimicrobial peptides and highly specific single chain antibodies, are currently being explored for their anti-parasite activities in these two systems. In preparation for eventual field use, we are actively engaged in risk assessment studies addressing the issue of horizontal gene transfer from the modified bacteria to environmental microbes.


An experimental study of microneedle-assisted microparticle delivery.
A set of well-defined experiments has been carried out to explore whether microneedles (MNs) can enhance the penetration depths of microparticles moving at high velocity such as those expected in gene guns for delivery of gene-loaded microparticles into target tissues. These experiments are based on applying solid MNs that are used to reduce the effect of mechanical barrier function of the target so as to allow delivery of microparticles at less imposed pressure as compared with most typical gene guns. Further, a low-cost material, namely, biomedical-grade stainless steel microparticle with size ranging between 1 and 20 μm, has been used in this study. The microparticles are compressed and bound in the form of a cylindrical pellet and mounted on a ground slide, which are then accelerated together by compressed air through a barrel. When the ground slide reaches the end of the barrel, the pellet is separated from the ground slide and is broken down into particle form by a mesh that is placed at the end of the barrel. Subsequently, these particles penetrate into the target. This paper investigates the implications of velocity of the pellet along with various other important factors that affect the particle delivery into the target. Our results suggest that the particle passage increases with an increase in pressure, mesh pore size, and decreases with increase in polyvinylpyrrolidone concentration. Most importantly, it is shown that MNs increase the penetration depths of the particles.


Wave-train-induced termination of weakly anchored vortices in excitable media.
A free vortex in excitable media can be displaced and removed by a wave train. However, simple physical arguments suggest that vortices anchored to large inexcitable obstacles cannot be removed similarly. We show that unpinning of vortices attached to obstacles smaller than the core radius of the free vortex is possible through pacing. The wave-train frequency necessary for unpinning increases with the obstacle size and we present a geometric explanation of this dependence. Our model-independent results suggest that decreasing excitability of the medium can facilitate pacing-induced removal of vortices in cardiac tissue.


The timing of high sea levels over the past 200,000 years.
The (230)Th ages and (234)U/(238)U ratios were determined for Barbados corals that grew during periods of high sea level within the last 200,000 years. The similarity of the initial (234)U/(238)U ratios of some of the corals to the modern marine value suggests that these samples are pristine and that the marine (234)U/(238)U ratio 83,000 and 200,000 years ago was within 2 per mil of the modern value. The accuracies of the (230)Th ages are evaluated on the basis of the (234)U/(238)U values and a model of the behavior of uranium and thorium isotopes during diagenesis. For the last three interglacial and two intervening interstadial periods, sea level peaked at or after peaks in summer insolation in the Northern Hemisphere. This overall pattern supports the idea that glacial-interglacial cycles are caused by changes in Earth's orbital geometry. The sea-level drop at the end of the penultimate interglacial, the last interglacial, and a subsequent interstadial period lagged behind the decrease in insolation by 5,000 to 10,000 years.


Kinetic analysis of the mechanism of action of beta-glucosidase from Botryodiplodia theobromae Pat.
1. The kinetic mechanism of beta-glucosidase (beta-D-glucoside glucohydrolase, EC 22.214.171.124) of Botryodiplodia theobromae Pat. has been studied in the presence of competing glucosyl acceptors. 2. Glycerol, fructose, sucrose, cellobiose and to a much lesser extent, maltose can act as glucosyl acceptors, apart from water. 3. Evidence confirming and supporting the kinetic mechanism previously postulated (Umezurike, G.M. (1971) Biochim. Biophys. Acta. 250, 182-191) is presented. 4. A theoretical kinetic analysis of the behaviour of the enzyme in the presence of two alternative glucosyl acceptors in addition to water is found to be consistent with experimental observation, suggesting a system in which both donor and acceptors bind to the enzyme in a random fashion to form ternary complexes. 5. The results are discussed in terms of the mechanism of group-transfer reactions.


Prospective randomized comparative evaluation of proximal valve polyurethane and distal valve silicone peripherally inserted central catheters.
The objective of this study was to evaluate and compare the relative durability and complications between the proximal valve polyurethane and distal valve silicone peripherally inserted central catheters (PICCs). Institutional review board approval was obtained. A total of 326 patients (mean age, 50.4 years) was assigned randomly to receive either a proximal valve polyurethane PICC (n = 198) or a distal valve silicone Groshong PICC (n = 194). All PICCs were inserted under radiologic guidance by interventional radiologists. Follow-up data were collected until catheter removal because of complications or treatment completion. The mean catheter dwell time was 25.6 days (range, 1-245 days). Complications were encountered in 26.8% and 47.9% of the proximal valve polyurethane PICCs and distal valve silicone PICCs, respectively (P < .001). Significantly higher incidences of phlebitis (23.2% versus 11.6%, P = .003) and catheter-related infection (6.2% versus 2%, P = 0.043) were noted in the distal valve silicone PICCs. No significant differences in the incidence of catheter occlusion, fracture, or dislodgement were found. Multivariate logistic regression analysis showed a higher complication rate in the distal valve silicone PICCs corrected for patients' age, sex, underlying morbidity, indication, peripheral vein accessed, arm used, catheter tip placement, and the number of venepunctures attempted. Proximal valve polyurethane PICCs were more durable than distal valve silicone PICCs, which were associated with a higher incidence of phlebitis and infection, probably related to the materials of the catheters and the designs and placements of the catheter valves.


The effectiveness of mindfulness-based stress reduction (MBSR) for survivors of breast cancer: study protocol for a randomized controlled trial.
After treatment completion, breast cancer (BC) survivors frequently experience residual symptoms of pain, fatigue, high levels of psychological stress, anxiety, depression, fear of recurrence, and metastasis. Post-treatment stress, in particular, can adversely affect health-related quality of life, which, in turn, induces onset or recurrence of chronic diseases. Effective interventions that target these psychological symptoms and their physiological consequences are needed, especially for economically disadvantaged patients. However, in China, few evidence-based intervention strategies have been established among BC survivors. This study will formally adapt, develop, and evaluate an intensive mindfulness-based stress reduction (MBSR) intervention protocol to improve mental health, quality of life, and compliance with medication among Chinese BC survivors. A randomized, waitlist-controlled clinical trial will be conducted. Based on our power calculation, 418 BC survivors will be recruited from 10 low-income communities in Shanghai. All subjects will be randomly assigned either to the MBSR program or to a waitlisted usual care regimen that will offer the MBSR program after the completion of the other trial arm (after 6 months follow-up). Our 8-week MBSR intervention program will provide systematic training to promote stress reduction by self-regulating arousal to stress. Assessments will be made at baseline, 4 weeks (in the middle of the first MBSR intervention), 8 weeks (at the end of the first MBSR intervention), 6 months, and 12 months, and will include measures of psychological symptoms (depression, anxiety, and perceived stress), quality of life, and medication adherence. The expected outcome will be the improvement in psychological symptoms, quality of life, and medication compliance in the MBSR intervention group. This study will help develop an affordable, self-care psychological intervention protocol to help Chinese BC survivors improve their quality of life, and could be helpful in further developing affordable disease management plans for patients of other chronic diseases. ChiCTR-IOR-14005390 (10/27/2014).


Phospholipase Dζ Enhances Diacylglycerol Flux into Triacylglycerol.
Plant seeds are the primary source of triacylglycerols (TAG) for food, feed, fuel, and industrial applications. As TAG is produced from diacylglycerol (DAG), successful engineering strategies to enhance TAG levels have focused on the conversion of DAG to TAG. However, the production of TAG can be limited by flux through the enzymatic reactions that supply DAG. In this study, two Arabidopsis phospholipase Dζ genes (AtPLDζ1 and AtPLDζ2 ) were coexpressed in Camelina sativa to test whether the conversion of phosphatidylcholine to DAG impacts TAG levels in seeds. The resulting transgenic plants produced 2% to 3% more TAG as a component of total seed biomass and had increased 18:3 and 20:1 fatty acid levels relative to wild type. Increased DAG and decreased PC levels were examined through the kinetics of lipid assembly by [14C]acetate and [14C]glycerol incorporation into glycerolipids. [14C]acetate was rapidly incorporated into TAG in both wild-type and overexpression lines, indicating a significant flux of nascent and elongated acyl-CoAs into the sn-3 position of TAG. Stereochemical analysis revealed that newly synthesized fatty acids were preferentially incorporated into the sn-2 position of PC, but the sn-1 position of de novo DAG and indicated similar rates of nascent acyl groups into the Kennedy pathway and acyl editing. [14C]glycerol studies demonstrated PC-derived DAG is the major source of DAG for TAG synthesis in both tissues. The results emphasize that the interconversions of DAG and PC pools can impact oil production and composition.


Enzymatic interesterification of butterfat with rapeseed oil in a continuous packed bed reactor.
Lipase-catalyzed interesterification of butterfat blended with rapeseed oil (70/30, w/w) was investigated both in batch and in continuous reactions. Six commercially available immobilized lipases were screened in batch experiments, and the lipases, Lipozyme TL IM and Lipozyme RM IM, were chosen for further studies in a continuous packed bed reactor. TL IM gave a fast reaction and had almost reached equilibrium with a residence time of 30 min, whereas RM IM required 60 min. The effect of reaction temperature was more pronounced for RM IM. TL IM showed little effect on the interesterification degree when the temperature was raised from 60 degrees C to 90 degrees C, whereas RM IM had a positive effect when the temperature was increased from 40 degrees C to 80 degrees C. Even though TL IM is an sn-1,3 specific lipase, small changes in the sn-2 position of the triacylglycerol could be seen. The tendency was toward a reduction of the saturated fatty acid C14:0 and C16:0 and an increase of the long-chain saturated and unsaturated fatty acids (C18:0 and C18:1), especially at longer residence times (90 min). In prolonged continuous operation the activity of TL IM was high for the first 5 days, whereafter it dramatically decreased over the next 10 days to an activity level of 40%. In general, the study shows no significant difference for butterfat interesterification in terms of enzyme behavior from normal vegetable oils and fats even though it contains short-chain fatty acids and cholesterol. However, the release of short-chain fatty acids from enzymatic reactions makes the sensory quality unacceptable for direct edible applications.


A mobile clinic approach to the delivery of community-based mental health services in rural Haiti.
This study evaluates the use of a mental health mobile clinic to overcome two major challenges to the provision of mental healthcare in resource-limited settings: the shortage of trained specialists; and the need to improve access to safe, effective, and culturally sound care in community settings. Employing task-shifting and supervision, mental healthcare was largely delivered by trained, non-specialist health workers instead of specialists. A retrospective chart review of 318 unduplicated patients assessed and treated during the mobile clinic's first two years (January 2012 to November 2013) was conducted to explore outcomes. These data were supplemented by a quality improvement questionnaire, illustrative case reports, and a qualitative interview with the mobile clinic's lead community health worker. The team evaluated an average of 42 patients per clinic session. The most common mental, neurological, or substance abuse (MNS) disorders were depression and epilepsy. Higher follow-up rates were seen among those with diagnoses of bipolar disorder and neurological conditions, while those with depression or anxiety had lower follow-up rates. Persons with mood disorders who were evaluated on at least two separate occasions using a locally developed depression screening tool experienced a significant reduction in depressive symptoms. The mental health mobile clinic successfully treated a wide range of MNS disorders in rural Haiti and provided care to individuals who previously had no consistent access to mental healthcare. Efforts to address these common barriers to the provision of mental healthcare in resource-limited settings should consider supplementing clinic-based with mobile services.


Prism adaptation and other tasks involving spatial abilities in patients with Parkinson's disease, patients with frontal lobe lesions and patients with unilateral temporal lobectomies.
Patients in the early stages of Parkinson's disease were compared with patients who had sustained damage specific to either the frontal or temporal lobes and normal controls on a delayed alternation task, a test of the left right orientation and a prism adaptation task. On the former two tasks age accounted for more of the variability in performance than did site of brain lesion. However, patients with frontal lobe, right temporal lobe or basal ganglia damage were significantly impaired on the adaptation task. The results are discussed with regard to "switching", "sequencing" and "internal guidance" of movement hypotheses.


Potential biomarker identification for Friedreich's ataxia using overlapping gene expression patterns in patient cells and mouse dorsal root ganglion.
Friedreich's ataxia (FA) is a neurodegenerative disease with no approved therapy that is the result of frataxin deficiency. The identification of human FA blood biomarkers related to disease severity and neuro-pathomechanism could support clinical trials of drug efficacy. To try to identify human biomarkers of neuro-pathomechanistic relevance, we compared the overlapping gene expression changes of primary blood and skin cells of FA patients with changes in the Dorsal Root Ganglion (DRG) of the KIKO FA mouse model. As DRG is the primary site of neurodegeneration in FA, our goal was to identify which changes in blood and skin of FA patients provide a 'window' into the FA neuropathomechanism inside the nervous system. In addition, gene expression in frataxin-deficient neuroglial cells and FA mouse hearts were compared for a total of 5 data sets. The overlap of these changes strongly supports mitochondrial changes, apoptosis and alterations of selenium metabolism. Consistent biomarkers were observed, including three genes of mitochondrial stress (MTIF2, ENO2), apoptosis (DDIT3/CHOP), oxidative stress (PREX1), and selenometabolism (SEPW1). These results prompted our investigation of the GPX1 activity as a marker of selenium and oxidative stress, in which we observed a significant change in FA patients. We believe these lead biomarkers that could be assayed in FA patient blood as indicators of disease severity and progression, and also support the involvement of mitochondria, apoptosis and selenium in the neurodegenerative process.


The mismeasure of Terry stops: Assessing the psychological and emotional harms of stop and frisk to individuals and communities.
In Terry v. Ohio, the US Supreme Court relied on a balancing test to uphold the reasonableness of the practice known as "stop and frisk," balancing the contribution of the practice to effective crime prevention and detection against the nature and quality of the intrusion to individual rights. In recent years, statistics have been powerfully deployed by legal scholars, jurists, and policymakers to challenge the assumption that stop and frisk leads to frequent discovery of contraband or other criminal behavior, and to address stark racial and ethnic disparities in the deployment of stop and frisk. However, the other side of the Terry equation-the nature and quality of the intrusion-has received far less attention from the legal community. With few exceptions, Terry jurisprudence portrays the Terry frisk simply as a brief pat-down of the outer clothing and treats each Terry stop as an isolated encounter for purposes of measuring the harm involved. Yet there is a robust social science literature on the effects of stop and frisk on individuals, including data on its effects on individuals from marginalized or vulnerable groups, on individuals over time, and on communities as a whole. Moreover, stop and frisk in the current era has evolved from a tool in the arsenal of individual officers to a systematic, widely deployed strategy. This article argues that the failure to grapple with the application of modern knowledge to modern policing practices leads to a mismeasurement on both sides of the Terry equation. Not only does stop and frisk cause a wide range of emotional and psychological harms; these harms may also interfere with the ability of law enforcement to prevent and investigate crime. Even apart from any legal doctrinal implications for stop and frisk jurisprudence, recognizing the flawed assumptions described in this article should encourage all the relevant stakeholders to re-evaluate the consequences of the Terry regime.


Glioblastoma heterogeneity and the tumour microenvironment: implications for preclinical research and development of new treatments.
Glioblastoma is the deadliest form of brain cancer. Aside from inadequate treatment options, one of the main reasons glioblastoma is so lethal is the rapid growth of tumour cells coupled with continuous cell invasion into surrounding healthy brain tissue. Significant intra- and inter-tumour heterogeneity associated with differences in the corresponding tumour microenvironments contributes greatly to glioblastoma progression. Within this tumour microenvironment, the extracellular matrix profoundly influences the way cancer cells become invasive, and changes to extracellular (pH and oxygen levels) and metabolic (glucose and lactate) components support glioblastoma growth. Furthermore, studies on clinical samples have revealed that the tumour microenvironment is highly immunosuppressive which contributes to failure in immunotherapy treatments. Although technically possible, many components of the tumour microenvironment have not yet been the focus of glioblastoma therapies, despite growing evidence of its importance to glioblastoma malignancy. Here, we review recent progress in the characterisation of the glioblastoma tumour microenvironment and the sources of tumour heterogeneity in human clinical material. We also discuss the latest advances in technologies for personalised and in vitro preclinical studies using brain organoid models to better model glioblastoma and its interactions with the surrounding healthy brain tissue, which may play an essential role in developing new and more personalised treatments for this aggressive type of cancer.


Economic burden of transformed migraine: results from the American Migraine Prevalence and Prevention (AMPP) Study.
To evaluate the impact of incident transformed migraine on health care resource utilization, medication use, and productivity loss. In addition, the study estimates the total direct and indirect costs associated with transformed migraine. Emerging evidence indicates that migraine may be a chronic progressive disorder characterized by escalating frequency of headache attacks, often termed transformed migraine. Little is known about the economic impact of transformed migraine. AMPP is a 5-year, national, longitudinal survey study of headache in the US. The study utilized data from the 2006 follow-up survey based on an initial sample of 14,544 adults identified as having migraine in either the 2004 screening or 2005 baseline survey. A diagnosis of migraine was assigned based on criteria proposed by the International Classification of Headache Disorders, 2nd Edition. Participants completed self-administered, validated questionnaires on headache features, frequency, impairment, resource use, medication use, and productivity loss. Direct and indirect headache-related costs were estimated using unit cost assumptions from the PharMetrics Patient-Centric database, wholesale acquisition costs (Red Book), and wage data from the US Bureau of Labor Statistics. Those who developed transformed migraine were compared with those who did not develop transformed migraine in the 1-2 year interval between screening/baseline and follow-up. A total of 7796 (54%) identified migraine cases completed the 2006 follow-up survey. Of those cases, 359 (4.6%) developed transformed migraine. Participants who developed transformed migraine reported significantly more primary care visits, neurologist or headache specialist visits, pain clinic visits, and emergency room visits compared with participants whose migraine remained episodic. Hospital nights and urgent care visits did not reach statistical significance. Transformed migraine participants reported significantly more time missed at work or school because of headaches and more time where work or school productivity was reduced by >50% in the previous 3 months because of headaches. Average per-person annual total costs, including direct and indirect costs, were 4.4-fold greater for those who developed transformed migraine ($7750) compared with those who remained episodic ($1757). Transformed migraine exacts a significantly higher economic toll on patients and health care systems compared with other forms of migraine. Our findings support the need to prevent migraine progression and to provide appropriate management and treatment of transformed migraine.


Antagonistic effects of TrkB and p75(NTR) on NMDA receptor currents in post-synaptic densities transplanted into Xenopus oocytes.
Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are essential regulators of synaptic function in the adult CNS. A TrkB-mediated effect at excitatory synapses is enhancement of NMDA receptor (NMDA-R)-mediated currents. Recently, opposing effects of TrkB and the pan-neurotrophin receptor p75(NTR) on long-term synaptic depression and long-term potentiation have been reported in the hippocampus. To further study the regulation of NMDA-Rs by neurotrophin receptors in their native protein environment, we micro-transplanted rat forebrain post-synaptic densities (PSDs) into Xenopus oocytes. One-minute incubations of oocytes with BDNF led to dual effects on NMDA-R currents: either TrkB-dependent potentiation or TrkB-independent inhibition were observed. Pro-nerve growth factor, a ligand for p75(NTR) but not for TrkB, produced a reversible, dose-dependent, TrkB-independent and p75(NTR)-dependent inhibition of NMDA-Rs. Fractionation experiments showed that p75(NTR) is highly enriched in the PSD protein fraction. Immunoprecipitation and pull-down experiments further revealed that p75(NTR) is a core component of the PSD, where it interacts with the PDZ3 domain of the scaffolding protein SAP90/PSD-95. Our data provide striking evidence for a rapid inhibitory effect of p75(NTR) on NMDA-R currents that antagonizes TrkB-mediated NMDA-R potentiation. These opposing mechanisms might be present in a large proportion of forebrain synapses and may contribute importantly to synaptic plasticity.


Conspicuous accumulation of transcription elongation repressor hrp130/CA150 on the intron-rich Balbiani ring 3 gene.
Chromosomal puffs on the polytene chromosomes in the dipteran Chironomus tentans offer the possibility of comparing the appearance of RNA-binding proteins at different transcription sites. We raised a monoclonal antibody that recognized a 130 kDa protein, designated hrp130. Immunocytological analysis of isolated chromosomes showed that hrp130 is heavily accumulated in a specific puff, called Balbiani ring 3; only occasionally is hrp130 abundant in one or two additional puffs on other chromosomes. The immunolabeling was sensitive to RNase treatment, suggesting that hrp130 is associated with nascent ribonucleoproteins. As shown by immunoelectron microscopy hrp130 is distributed along the active BR3 genes. The full sequence of hrp130 was determined by cDNA cloning. The protein comprises 1028 amino acids and contains three WW domains in the N-terminal half and six FF domains in the C-terminal half of the molecule. The protein is conserved from Caenorhabditis elegans to mammals; the human homolog is known as the transcription elongation repressor CA150. We propose that the abundance of hrp130/CA150 in BR3 is connected with the exceptionally high level of splicing in this locus and that hrp130/CA150 adjusts the transcription rate to the numerous splicing events taking place along the gene to ensure proper splicing.


How to manage plant biomass originated from phytotechnologies? Gathering perceptions from end-users.
A questionnaire survey was carried out in four European countries to gather end-user's perceptions of using plants from phytotechnologies in combustion and anaerobic digestion (AD). Nine actors of the wood energy sector from France, Germany, and Sweden, and eleven AD platform operators from France, Germany, and Austria were interviewed. Questions related to installation, input materials, performed analyses, phytostabilization, and phytoextraction were asked. Although the majority of respondents did not know phytotechnologies, results suggested that plant biomass from phytomanaged areas could be used in AD and combustion, under certain conditions. As a potential benefit, phytomanaged plants would not compete with plants grown on agricultural lands, contaminated lands being not suitable for agriculture production. Main limitations would be related to additional controls in process' inputs and end-products and installations that might generate additional costs. In most cases, the price of phytotechnologies biomass was mentioned as a driver to potentially use plants from metal-contaminated soils. Plants used in phytostabilization or phytoexclusion were thought to be less risky and, consequently, benefited from a better theoretical acceptance than those issued from phytoextraction. Results were discussed according to national regulations. One issue was related to the regulatory gap concerning the status of the plant biomass produced on contaminated land.


Assessing the cost-effectiveness of finding cases of hepatitis C infection in UK migrant populations and the value of further research.
Hepatitis C (HCV) infection can cause cirrhosis, liver cancer and death in the absence of treatment. Many people living in the UK but born overseas are believed to be infected with HCV although many are unlikely to know they are infected. The aim of this study is to assess the potential for a case-finding approach to be cost-effective and to estimate the value of further research. An economic evaluation and value of information analysis was undertaken by developing a model of HCV disease progression and by populating it with evidence from the published literature. They were performed from a UK National Health Services cost perspective, and outcomes were expressed in terms of quality-adjusted life-years (QALYs). The comparator intervention was defined as the background rate of testing (i.e. no intervention). The base case results generated an incremental cost-effectiveness ratio (ICER) of about £23,200 per additional QALY. However, the ICER was shown to be particularly sensitive to HCV seroprevalence, the intervention effect / cost and the probability of treatment uptake. The value of information analysis suggested that approximately £4 million should be spent on further research. This evaluation demonstrates that testing UK migrants for HCV could be cost-effective. However, further research, particularly to refine estimates of the probability of treatment uptake once identified, the utility associated with sustained virological response and the cost of the intervention, would help to increase the robustness of this conclusion.


Speciation in kleptoparasites of oak gall wasps often correlates with shifts into new tree habitats, tree organs, or gall morphospace.
Host shifts to new plant species can drive speciation for plant-feeding insects, but how commonly do host shifts also drive diversification for the parasites of those same insects? Oak gall wasps induce galls on oak trees and shifts to novel tree hosts and new tree organs have been implicated as drivers of oak gall wasp speciation. Gall wasps are themselves attacked by many insect parasites, which must find their hosts on the correct tree species and organ, but which also must navigate the morphologically variable galls with which they interact. Thus, we ask whether host shifts to new trees, organs, or gall morphologies correlate with gall parasite diversification. We delimit species and infer phylogenies for two genera of gall kleptoparasites, Synergus and Ceroptres, reared from a variety of North American oak galls. We find that most species were reared from galls induced by just one gall wasp species, and no parasite species was reared from galls of more than four species. Most kleptoparasite divergence events correlate with shifts to non-ancestral galls. These shifts often involved changes in tree habitat, gall location, and gall morphology. Host shifts are thus implicated in driving diversification for both oak gall wasps and their kleptoparasitic associates.


Genomic signatures among Oncorhynchus nerka ecotypes to inform conservation and management of endangered Sockeye Salmon.
Conservation of life history variation is an important consideration for many species with trade-offs in migratory characteristics. Many salmonid species exhibit both resident and migratory strategies that capitalize on benefits in freshwater and marine environments. In this study, we investigated genomic signatures for migratory life history in collections of resident and anadromous Oncorhynchus nerka (Kokanee and Sockeye Salmon, respectively) from two lake systems, using ~2,600 SNPs from restriction-site-associated DNA sequencing (RAD-seq). Differing demographic histories were evident in the two systems where one pair was significantly differentiated (Redfish Lake, FST = 0.091 [95% confidence interval: 0.087 to 0.095]) but the other pair was not (Alturas Lake, FST = -0.007 [-0.008 to -0.006]). Outlier and association analyses identified several candidate markers in each population pair, but there was limited evidence for parallel signatures of genomic variation associated with migration. Despite lack of evidence for consistent markers associated with migratory life history in this species, candidate markers were mapped to functional genes and provide evidence for adaptive genetic variation within each lake system. Life history variation has been maintained in these nearly extirpated populations of O. nerka, and conservation efforts to preserve this diversity are important for long-term resiliency of this species.


Tuning the localized surface plasmon resonance in Cu(2-x)Se nanocrystals by postsynthetic ligand exchange.
Nanoparticles exhibiting localized surface plasmon resonances (LSPR) are valuable tools traditionally used in a wide field of applications including sensing, imaging, biodiagnostics and medical therapy. Plasmonics in semiconductor nanocrystals is of special interest because of the tunability of the carrier densities in semiconductors, and the possibility to couple the plasmonic resonances to quantum confined excitonic transitions. Here, colloidal Cu2-xSe nanocrystals were synthesized, whose composition was shown by Rutherford backscattering analysis and electron dispersive X-ray spectroscopy, to exhibit Cu deficiency. The latter results in p-type doping causing LSPRs, in the present case around a wavelength of 1100 nm, closely matching the indirect band gap of Cu2-xSe. By partial exchange of the organic ligands to specific electron trapping or donating species the LSPR is fine-tuned to exhibit blue or red shifts, in total up to 200 nm. This tuning not only provides a convenient tool for post synthetic adjustments of LSPRs to specific target wavelength but the sensitive dependence of the resonance wavelength on surface charges makes these nanocrystals also interesting for sensing applications, to detect analytes dressed by functional groups.


Resource format preferences across the medical curriculum.
This research study sought to determine the formats (print or electronic) of articles and book chapters most-preferred by first-year medical students, third-year medical students entering clinical clerkships, and incoming residents and to determine if these preferences change during the course of the medical curriculum. These trends will enable academic health sciences libraries to make appropriate collection development decisions to best cater to their user populations. First-year medical students, third-year medical students, and incoming medical residents were asked to complete a paper survey from September 2014 to June 2015. The survey consisted of five multiple-choice questions, with two questions given space for optional short answers. Quantitative and qualitative responses were collected and calculated using Microsoft Excel. First-year students, third-year students, and incoming residents all preferred to read journal articles and book chapters in print, except in cases where the article or book chapter is under ten pages in length. Although print is preferred, demand for electronic articles and book chapters increases as students progress from undergraduate medical education into residency. The only category where a majority of incoming residents chose an electronic resource was which format they would give to a colleague, if the article or book chapter was critical to the care of an individual patient. The preference for print resources is strong across the medical curriculum, although residents show an increased preference for electronic materials when compared to first- and third-year students. Academic health sciences libraries should take these preferences into account when making decisions regarding collection development.


The desalting/salting pathway: a route to form metastable aggregates with tuneable morphologies and lifetimes.
We investigate the formation/re-dissociation mechanisms of hybrid complexes made from negatively charged PAA2k coated γ-Fe2O3 nanoparticles (NP) and positively charged polycations (PDADMAC) in aqueous solution in the regime of very high ionic strength (I). When the building blocks are mixed at large ionic strength (1 M NH4Cl), the electrostatic interaction is screened and complexation does not occur. If the ionic strength is then lowered down to a targeted ionic strength Itarget, there is a critical threshold Ic = 0.62 M at which complexation occurs, that is independent of the charge ratio Z and the pathway used to reduce salinity (drop-by-drop mixing or fast mixing). If salt is added back up to 1 M, the transition is not reversible and persistent out-of-equilibrium aggregates are formed. The lifetimes of such aggregates depends on Itarget: the closer Itarget to Ic is, the more difficult it is to dissolve the aggregates. Such peculiar behavior is driven by the inner structure of the complexes that are formed after desalting. When Itarget is far below Ic, strong electrostatic interactions induce the formation of dense, compact and frozen aggregates. Such aggregates can only poorly reorganize further on with time, which makes their dissolution upon resalting almost reversible. Conversely, when Itarget is close to Ic more open aggregates are formed due to weaker electrostatic interactions upon desalting. The system can thus rearrange with time to lower its free energy and reach more stable out-of-equilibrium states which are very difficult to dissociate back upon resalting, even at very high ionic strength.


Is burnout separable from depression in cluster analysis? A longitudinal study.
Whether burnout and depression represent distinct pathologies is unclear. The aim of this study was to examine whether burnout and depressive symptoms manifest themselves separately from each other or are so closely intertwined as to reflect the same phenomenon. A two-wave longitudinal study involving 627 French schoolteachers (73 % female) was conducted. Burnout was assessed with the Maslach Burnout Inventory and depression with the 9-item depression module of the Patient Health Questionnaire. Burnout and depressive symptoms clustered both at baseline and follow-up. Cluster membership at time 1 (T1) predicted cases of burnout and depression at time 2 (T2), controlling for gender, age, length of employment, lifetime history of depression, and antidepressant intake. Changes in burnout and depressive symptoms from T1 to T2 were found to overlap. Teachers with increasing burnout experienced increases in depression and teachers with decreasing burnout experienced decreases in depression. In addition, emotional exhaustion, the core of burnout, was more strongly associated with depression than with depersonalization, the second dimension of burnout, underlining an inconsistency in the conceptualization of the burnout syndrome. Our results are consistent with recent findings showing qualitative and quantitative symptom overlap of burnout with depression. The close interconnection of burnout and depression questions the relevance of a nosological distinction between the two entities. Emotional exhaustion and depersonalization, the two main dimensions of burnout, may be better conceptualized as depressive responses to adverse occupational environments than as components of a separate entity.


The clinical surface anatomy anomalies of the palmaris longus muscle in the Black African population of Zimbabwe and a proposed new testing technique.
The presence of the palmaris longus muscle (PLM) is highly variable. Rates of absence vary from 0.6% in the Korean population to as high as 63.9% in the Turkish population. The tendon of PLM may be absent on one or both forearms, may have duplicated tendons on one forearm or may be laterally shifted to the extent that the tendon of the PLM lies superficial to that of flexor carpi radialis muscle. Among Black American populations, in which there is usually mixed ancestry, rates of absence are 3.5%. Only two studies have been performed on Black African populations: in Republic of Congo and Uganda, and each showed widely differing rates of absence of 3.0% and 14.6%, respectively. In this study, a total of 890 Black Zimbabwean subjects in Harare aged between 8 and 13 years, were examined for clinical surface anatomy anomalies of the tendon of PLM. The results showed that the tendon of the PLM was absent unilaterally in 0.9% of the population, and bilaterally absent in 0.6% with an overall rate of absence of 1.5%. Other variations noted were a laterally shifted PLM in 1.1% of subjects and duplicated tendons on one forearm, which was the least prevalent anomaly, in 0.2% of subjects. The author proposes a new technique to test the tendon of PLM, which combines resisted thumb abduction and resisted wrist flexion. The proposed technique capitalizes on the role of the PLM as an important abductor of the thumb.


Invited review: Genomic selection for small ruminants in developed countries: how applicable for the rest of the world?
Improved management and use of estimated breeding values in breeding programmes, have resulted in rapid genetic progress for small ruminants (SR) in Europe and other developed countries. The development of single nucleotide polymorphisms chips opened opportunities for genomic selection (GS) in SR in these countries. Initially focused on production traits (growth and milk), GS has been extended to functional traits (reproductive performance, disease resistance and meat quality). The GS systems have been characterized by smaller reference populations compared with those of dairy cattle and consisting mostly of cross- or multi-breed populations. Molecular information has resulted in gains in accuracy of between 0.05 and 0.27 and proved useful in parentage verification and the identification of QTLs for economically important traits. Except for a few established breeds with some degree of infrastructure, the basic building blocks to support conventional breeding programmes in small holder systems are lacking in most developing countries. In these systems, molecular data could offer quick wins in undertaking parentage verification and genetic evaluations using G matrix, and determination of breed composition. The development of next-generation molecular tools has prompted investigations on genome-wide signatures of selection for mainly adaptive and reproduction traits in SR in developing countries. Here, the relevance of the developments and application of GS and other molecular tools in developed countries to developing countries context is examined. Worth noting is that in the latter, the application of GS in SR will not be a 'one-size fits all' scenario. For breeds with some degree of conventional genetic improvement, classical GS may be feasible. In small holder systems, where production is key, community-based breeding programmes can provide the framework to implement GS. However, in fragile growth systems, for example those found in marginal environments, innovative GS to maximize adaptive diversity will be required. A cost-benefit analysis should accompany any strategy of implementing GS in these systems.


Prognoses and improvement for head and neck cancers diagnosed in Europe in early 2000s: The EUROCARE-5 population-based study.
Head and neck (H&N) cancers are a heterogeneous group of malignancies, affecting various sites, with different prognoses. The aims of this study are to analyse survival for patients with H&N cancers in relation to tumour location, to assess the change in survival between European countries, and to investigate whether survival improved over time. We analysed about 250,000 H&N cancer cases from 86 cancer registries (CRs). Relative survival (RS) was estimated by sex, age, country and stage. We described survival time trends over 1999-2007, using the period approach. Model based survival estimates of relative excess risks (RERs) of death were also provided by country, after adjusting for sex, age and sub-site. Five-year RS was the poorest for hypopharynx (25%) and the highest for larynx (59%). Outcome was significantly better in female than in male patients. In Europe, age-standardised 5-year survival remained stable from 1999-2001 to 2005-2007 for laryngeal cancer, while it increased for all the other H&N cancers. Five-year age-standardised RS was low in Eastern countries, 47% for larynx and 28% for all the other H&N cancers combined, and high in Ireland and the United Kingdom (UK), and Northern Europe (62% and 46%). Adjustment for sub-site narrowed the difference between countries. Fifty-four percent of patients was diagnosed at advanced stage (regional or metastatic). Five-year RS for localised cases ranged between 42% (hypopharynx) and 74% (larynx). This study shows survival progresses during the study period. However, slightly more than half of patients were diagnosed with regional or metastatic disease at diagnosis. Early diagnosis and timely start of treatment are crucial to reduce the European gap to further improve H&N cancers outcome.


Synthesis and characterisation of ruthenium dihydrogen complexes and their reactivity towards B-H bonds.
In this paper the synthesis and characterisation of ruthenium dihydrogen complexes bearing rigid aliphatic PNP pincer-type ligands are described. As one result hydride complexes were synthesised in good to high yields by a one-pot direct hydrogenation reaction. As another finding the dihydrogen complex, stabilised with a N-Me group in the ligand frame, can be converted with dimethylamine borane into a rare σ-boron complex [RuH2(BH3)(Me-PNP)] with rapid B-N decoupling. Additionally, we present the first mass spectrometric analysis of the synthesised σ-complexes via liquid injection field desorption/ionisation technique (LIFDI-MS).


Molecular rotors report on changes in live cell plasma membrane microviscosity upon interaction with beta-amyloid aggregates.
Amyloid deposits of aggregated beta-amyloid Aβ(1-42) peptides are a pathological hallmark of Alzheimer's disease. Aβ(1-42) aggregates are known to induce biophysical alterations in cells, including disruption of plasma membranes. We investigated the microviscosity of plasma membranes upon interaction with oligomeric and fibrillar forms of Aβ(1-42). Viscosity-sensing fluorophores termed molecular rotors were utilised to directly measure the microviscosities of giant plasma membrane vesicles (GPMVs) and plasma membranes of live SH-SY5Y and HeLa cells. The fluorescence lifetimes of membrane-inserting BODIPY-based molecular rotors revealed a decrease in bilayer microviscosity upon incubation with Aβ(1-42) oligomers, while fibrillar Aβ(1-42) did not significantly affect the microviscosity of the bilayer. In addition, we demonstrate that the neuroprotective peptide H3 counteracts the microviscosity change induced by Aβ(1-42) oligomers, suggesting the utility of H3 as a neuroprotective therapeutic agent in neurodegenerative disorders and indicating that ligand-induced membrane stabilisation may be a possible mechanism of neuroprotection during neurodegenerative disorders such as Alzheimer's disease.


Radiofrequency ablation of idiopathic left ventricular tachycardia at the site of earliest activation as determined by noncontact mapping.
The most effective method for guiding radiofrequency (RF) ablation of idiopathic left ventricular tachycardia (ILVT) has yet to be determined. We investigated the use of noncontact mapping in five patients with this condition. The multielectrode array was positioned in the left ventricular apex via the retrograde approach. Isopotential color maps of ILVT were examined to determine the site of earliest endocardial activation. The ablation catheter was steered to the target site using the locator signal. Pace mapping was performed and contact electrograms examined for diastolic potentials. RF energy was applied to the target site. Sustained ventricular tachycardia was induced in 2 patients and nonsustained ventricular tachycardia in 3. The site of earliest activation was at the apical septum in 3, the inferior apex in 1, and the base of the inferior wall in 1. Mean timing was 21 +/- 10 msec before onset of the surface QRS. Diastolic activity was visualized with noncontact mapping at the base of the septum in 1 patient. A Purkinje potential was seen at the ablation site in only 1 patient. No diastolic activity was seen in the remaining 3 patients. Tachycardia was successfully terminated in all 5 patients with a median of four RF applications. No patient suffered a recurrence after 9.6 +/- 4.7 months of follow-up. By identifying the precise site of earliest activation during ILVT, noncontact mapping has been shown to be an effective and safe method for guiding RF ablation.


Minimum dose of fludarabine for the maximal modulation of 1-beta-D-arabinofuranosylcytosine triphosphate in human leukemia blasts during therapy.
1-beta-d-Arabinofuranosylcytosine (ara-C), an effective drug for acute leukemias, must be phosphorylated to its 5'-triphosphate, ara-CTP, for activity. Our previous studies during therapy of acute myelogenous leukemia (AML) patients demonstrated that the accumulation of ara-CTP in circulating leukemia blasts was increased by a median of 2-fold when fludarabine (30 mg/m2/day over 30 min) was infused 4 h prior to intermediate dose ara-C. The augmentation was dependent on the cellular concentration of fludarabine triphosphate (F-ara-ATP). To determine the lowest dose of fludarabine needed for modulation of ara-C metabolism, the present study administered fludarabine at a test dose (15 mg/m2 over 30 min) followed by 2 g/m2 ara-C infused over 4 h. The next day, the fludarabine/ara-C couplet was repeated but with a standard dose (30 mg/m2) of fludarabine. There was a dose-dependent accumulation of F-ara-ATP in circulating leukemia blasts; the median peak concentrations were 33 and 41 microM with 15 and 30 mg/m2 of fludarabine, respectively. These intracellular levels of F-ara-ATP effectively increased ara-CTP accumulation to similar levels. To further titrate the dose of fludarabine, the next cohort of patients (n = 4) initially received fludarabine test doses of 7.5 or 5 mg/m2, followed by the 30 mg/m2 dose of fludarabine on the next day; each dose was infused 4 h prior to 2 g/m2 of ara-C. The peak levels of F-ara-ATP at 7.5 and 5 mg/m2 fludarabine were between 3 and 39 microM. The AML blasts that achieved >/=10 microM intracellular F-ara-ATP accumulated ara-CTP similar to the levels achieved after 30 mg/m2 of fludarabine. However, <10 microM intracellular F-ara-ATP resulted in less ara-CTP accumulation compared to that observed after the conventional dose of fludarabine. These data suggest that the modulation of the ara-CTP accumulation by fludarabine is dependent on the cellular concentration of F-ara-ATP, and that 15 mg/m2 fludarabine infused over 30 min consistently produces cellular F-ara-ATP levels that maximize ara-CTP accumulation in AML blasts. These findings point to the feasibility of intensifying the fludarabine-ara-C regimen by using fludarabine as a 15 mg/m2/dose twice daily with intermediate-dose ara-C.


Radiation exposures in Utah from Nevada Nuclear Tests.
The exposure of the population of Utah to external gamma-radiation from the fallout from nuclear weapons tests carried out between 1951 and 1958 at the Nevada Test Site has been reconstructed from recent measurements of residual cesium-137 and plutonium in soil. Although the highest exposures were found in the extreme southwest part of Utah, as expected, the residents of the populous northern valleys around Provo, Salt Lake City, and Ogden received a higher mean dose and a significantly greater population dose (person-rads) than did the residents of most counties closer to the test site. However, population doses from external exposure throughout Utah were far too low to result in any statistically observable health effects.


Effects of metabolic syndrome on language functions in aging.
This study explored effects of the metabolic syndrome (MetS) on language in aging. MetS is a constellation of five vascular and metabolic risk factors associated with the development of chronic diseases and increased risk of mortality, as well as brain and cognitive impairments. We tested 281 English-speaking older adults aged 55-84, free of stroke and dementia. Presence of MetS was based on the harmonized criteria (Alberti et al., 2009). Language performance was assessed by measures of accuracy and reaction time on two tasks of lexical retrieval and two tasks of sentence processing. Regression analyses, adjusted for age, education, gender, diabetes, hypertension, and heart disease, demonstrated that participants with MetS had significantly lower accuracy on measures of lexical retrieval (action naming) and sentence processing (embedded sentences, both subject and object relative clauses). Reaction time was slightly faster on the test of embedded sentences among those with MetS. MetS adversely affects the language performance of older adults, impairing accuracy of both lexical retrieval and sentence processing. This finding reinforces and extends results of earlier research documenting the negative influence of potentially treatable medical conditions (diabetes, hypertension) on language performance in aging. The unanticipated finding that persons with MetS were faster in processing embedded sentences may represent an impairment of timing functions among older individuals with MetS.


Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HPV vaccination in a randomized clinical trial in Costa Rica.
Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination. A total of 7,466 women 18-25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses. HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer. ClinicalTrials.gov, Registry number NCT00128661.


Compact electro-optic modulator on silicon-on-insulator substrates using cavities with ultra-small modal volumes.
We experimentally demonstrate a micron-size electro-optic modulator using a high-index-contrast silicon Fabry-Pérot resonator cavity. This compact device consists of a 1-D cavity formed within a single mode silicon channel waveguide and an embedded p-i-n junction on a silicon-oninsulator platform. The entire device is 6.0 microns in length. We demonstrate modulation depths as large as 5.87 dB at speeds of 250 Mbps limited only by fabrication imperfections, with optimized theoretical speeds of several Gbps.


Infections in solid organ transplant HIV-infected patients.
Solid organ transplantation (SOT) is an appropriate therapeutic option for HIV-infected patients with end-stage organ disease. Recent experience in North America and Europe indicates that 3- to 5-year survival in HIV/HCV-coinfected liver recipients is lower than that of HCV-monoinfected recipients. Conversely, 3- to 5-year survival of non-HCV-coinfected transplant patients (liver, kidney and heart) was similar to that of non-HIV-infected patients. Preliminary experience with lung transplantation and combined kidney and pancreas transplantation is also satisfactory. Infections in HIV-infected recipients during the post-transplant period are similar to those seen in non-HIV-infected patients, although the incidence rates of tuberculosis and fungal infections seem to be higher. HIV-infected patients who are being evaluated for SOT should follow the same recommendations as those used for non-HIV-infected patients in order to prevent infections during the pre-transplant period. After transplantation, HIV-infected SOT recipients must follow recommendations on post-SOT and anti-HIV immunization and on antimicrobial prophylaxis. The recommended antiretroviral regimen is one based on raltegravir or dolutegravir plus two nucleos(t)ide reverse transcriptase inhibitors (tenofovir + emtricitabine or abacavir + lamivudine), because it can prevent pharmacokinetic interactions between antiretroviral drugs, immunosuppressive drugs and some of the antimicrobial agents used to treat or prevent post-transplant infections. In this manuscript, we review current recommendations for preventing infections both before and after transplantation. We also analyse the incidence, aetiology and clinical characteristics of opportunistic and non-opportunistic bacterial, mycobacterial, fungal and viral infections in HIV-infected SOT recipients during the post-transplant period.


Mild cognitive impairment: cognitive screening or neuropsychological assessment?
To describe the neuropsychological profile of mild cognitive impairment subtypes (amnestic, non-amnestic and multiple-domain) of a clinical sample. We further address the diagnostic properties of the Mini-Mental State Examination and the Cambridge Cognitive Examination for the identification of the different mild cognitive impairment subtypes in clinical practice. Cross-sectional clinical and neuropsychological evaluation of 249 elderly patients attending a memory clinic at a university hospital in Sao Paulo, Brazil. The performance of patients with mild cognitive impairment was heterogeneous across the different subtests of the neuropsychological battery, with a trend towards an overall worse performance for amnestic (particularly multiple domain) mild cognitive impairment as compared to non-amnestic subtypes. Screening tests for dementia (Mini-Mental State Examination and Cambridge Cognitive Examination) adequately discriminated cases of mild Alzheimer's disease from controls, but they were not accurate to discriminate patients with mild cognitive impairment (all subtypes) from control subjects. The discrimination of mild cognitive impairment subtypes was possible only with the aid of a comprehensive neuropsychological assessment. It is necessary to develop new strategies for mild cognitive impairment screening in clinical practice.


Pharmacological inhibition of a microRNA family in nonhuman primates by a seed-targeting 8-mer antimiR.
MicroRNAs (miRNAs) regulate many aspects of human biology. They target mRNAs for translational repression or degradation through base pairing with 3' untranslated regions, primarily via seed sequences (nucleotides 2 to 8 in the mature miRNA sequence). A number of individual miRNAs and miRNA families share seed sequences and targets, but differ in the sequences outside of the seed. miRNAs have been implicated in the etiology of a wide variety of human diseases and therefore represent promising therapeutic targets. However, potential redundancy of different miRNAs sharing the same seed sequence and the challenge of simultaneously targeting miRNAs that differ significantly in nonseed sequences complicate therapeutic targeting approaches. We recently demonstrated effective inhibition of entire miRNA families using seed-targeting 8-mer locked nucleic acid (LNA)-modified antimiRs in short-term experiments in mammalian cells and in mice. However, the long-term efficacy and safety of this approach in higher organisms, such as humans and nonhuman primates, have not been determined. We show that pharmacological inhibition of the miR-33 family, key regulators of cholesterol/lipid homeostasis, by a subcutaneously delivered 8-mer LNA-modified antimiR in obese and insulin-resistant nonhuman primates results in derepression of miR-33 targets, such as ABCA1, increases circulating high-density lipoprotein cholesterol, and is well tolerated over 108 days of treatment. These findings demonstrate the efficacy and safety of an 8-mer LNA-antimiR against an miRNA family in a nonhuman primate metabolic disease model, suggesting that this could be a feasible approach for therapeutic targeting of miRNA families sharing the same seed sequence in human diseases.


Exposure to in utero lipopolysaccharide induces inflammation in the fetal ovine skin.
Inflammation is a defensive process by which the body responds to both localized and systemic tissue damage by the induction of innate and adaptive immunity. Literature from human and animal studies links inappropriate in utero inflammation to preterm parturition and fetal injury. The pathways by which such inflammation may cause labor, however, are not fully understood. Any proinflammatory agonist in the amniotic fluid will contact the fetal skin, in its entirety, but a potential role of the fetal skin in the pathways to labor have not previously been explored. We hypothesized that the fetal skin would respond robustly to the presence of intra-amniotic lipopolysaccharide (LPS) in our ovine model of in utero inflammation. In vitro and in utero exposure of fetal ovine keratinocytes or fetal skin to Escherichia coli LPS reliably induced significant increases in interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), and IL-8 expression. We demonstrate that, in utero, this expression requires direct exposure with LPS suggesting that the inflammation is triggered directly in the skin itself, rather than as a secondary response to a systemic stimuli and that inflammation involves Toll-like receptor (TLR) regulation and neutrophil chemotaxis in concordance with an acute inflammatory reaction. We show that this response involves multiple inflammatory mediators, TLR regulation, and localized inflammatory cell influx characteristic of an acute inflammatory reaction. These novel data strongly suggests that the fetal skin acts as an important mediator of the fetal inflammatory response and as such may contribute to preterm birth.


Relationship of personality disorders to the course of major depressive disorder in a nationally representative sample.
The purpose of this study was to examine the effects of specific personality disorder comorbidity on the course of major depressive disorder in a nationally representative sample. Data were drawn from 1,996 participants in a national survey. Participants who met criteria for major depressive disorder at baseline in face-to-face interviews (in 2001-2002) were reinterviewed 3 years later (in 2004-2005) to determine persistence and recurrence. Predictors included all DSM-IV personality disorders. Control variables included demographic characteristics, other axis I disorders, family and treatment histories, and previously established predictors of the course of major depressive disorder. A total of 15.1% of participants had persistent major depressive disorder, and 7.3% of those who remitted had a recurrence. Univariate analyses indicated that avoidant, borderline, histrionic, paranoid, schizoid, and schizotypal personality disorders all elevated the risk for persistence. With axis I comorbidity controlled, all personality disorders except histrionic personality disorder remained significant. With all other personality disorders controlled, borderline and schizotypal disorders remained significant predictors. In final, multivariate analyses that controlled for age at onset of major depressive disorder, the number of previous episodes, duration of the current episode, family history, and treatment, borderline personality disorder remained a robust predictor of major depressive disorder persistence. Neither personality disorders nor other clinical variables predicted recurrence. In this nationally representative sample of adults with major depressive disorder, borderline personality disorder robustly predicted persistence, a finding that converges with recent clinical studies. Personality psychopathology, particularly borderline personality disorder, should be assessed in all patients with major depressive disorder, considered in prognosis, and addressed in treatment.


Targeting gut microbiome: A novel and potential therapy for autism.
Autism spectrum disorder (ASD) is a severely neurodevelopmental disorder that impairs a child's ability to communicate and interact with others. Children with neurodevelopmental disorder, including ASD, are regularly affected by gastrointestinal problems and dysbiosis of gut microbiota. On the other hand, humans live in a co-evolutionary association with plenty of microorganisms that resident on the exposed and internal surfaces of our bodies. The microbiome, refers to the collection of microbes and their genetic material, confers a variety of physiologic benefits to the host in many key aspects of life as well as being responsible for some diseases. A large body of preclinical literature indicates that gut microbiome plays an important role in the bidirectional gut-brain axis that communicates between the gut and central nervous system. Moreover, accumulating evidences suggest that the gut microbiome is involved in the pathogenesis of ASD. The present review introduces the increasing evidence suggesting the reciprocal interaction network among microbiome, gut and brain. It also discusses the possible mechanisms by which gut microbiome influences the etiology of ASD via altering gut-brain axis. Most importantly, it highlights the new findings of targeting gut microbiome, including probiotic treatment and fecal microbiota transplant, as novel and potential therapeutics for ASD diseases.


Sexual behavior and drug consumption among young adults in a shantytown in Lima, Peru.
Risky sexual behaviors of young adults have received increasing attention during the last decades. However, few studies have focused on the sexual behavior of young adults in shantytowns of Latin America. Specifically, studies on the association between sexual behaviors and other risk factors for sexually transmitted infections (STI) and HIV/AIDS transmission, such as the consumption of illicit drugs or alcohol are scarce in this specific context. The study participants were 393 men and 400 women between 18 and 30 years of age, from a shantytown in Lima, Peru. Data were obtained via survey: one section applied by a trained research assistant, and a self-reporting section. Logistic regression was used to estimate associations between use of any illicit drug, high-risk sexual behaviors and reported STI symptoms, adjusting for alcohol consumption level and various socio-demographic characteristics. Among men, age of sexual debut was lower, number of lifetime sexual partners was higher, and there were higher risk types of sexual partners, compared to women. Though consistent condom use with casual partners was low in both groups, reported condom use at last intercourse was higher among men than women. Also, a lifetime history of illicit drug consumption decreased the probability of condom use at last sexual intercourse by half. Among men, the use of illicit drugs doubled the probability of intercourse with a casual partner during the last year and tripled the probability of reported STI symptoms. Drug consumption is associated with high-risk sexual behaviors and reported STI symptoms in a Lima shantytown after controlling for alcohol consumption level. Development of prevention programs for risky sexual behaviors, considering gender differences, is discussed.


A convergent approach to biocompatible polyglycerol "click" dendrons for the synthesis of modular core-shell architectures and their transport behavior.
Dendrimers are an important class of polymeric materials for a broad range of applications in which monodispersity and multivalency are of interest. Here we report on a highly efficient synthetic route towards bifunctional polyglycerol dendrons on a multigram scale. Commercially available triglycerol (1), which is highly biocompatible, was used as starting material. By applying Williamson ether synthesis followed by an ozonolysis/reduction procedure, glycerol-based dendrons up to the fourth generation were prepared. The obtained products have a reactive core, which was further functionalized to the corresponding monoazido derivatives. By applying copper(I)-catalyzed 1,3-dipolar cycloaddition, so-called "click" coupling, a library of core-shell architectures was prepared. After removal of the 1,2-diol protecting groups, water-soluble core-shell architectures 24-27 of different generations were obtained in high yields. In the structure-transport relationship with Nile red we observe a clear dependence on core size and generation of the polyglycerol dendrons.


Structural organization in peptide fragments of cytochrome c by heme binding.
Prosthetic groups are often important structural organizers of proteins as well as essential functional components. Insertion of prosthetic groups is usually spontaneous, and implies an apoprotein that is partially preorganized to provide a recognition surface for specific binding. Cytochrome c is distinguished by having its heme attached by a dedicated heme lyase through thioether links to cysteine side-chains, and the apoprotein shows no evidence of preorganization under physiological conditions. Nevertheless, addition of heme to two short fragments of cytochrome c enhances helical structure substantially (from approximately 8% to approximately 22%), an effect that depends on iron ligation but not thioether linkage. The helical segments in the corresponding parts of the native holoprotein have little contact surface with heme, implying that the increased helical structure in the fragment complex may depend on tertiary interactions. The absence of the intervening polypeptide chain suggests that the complex represents a relatively independent folded subdomain.