MitoVariome: a variome database of human mitochondrial DNA.
Mitochondrial sequence variation provides critical information for studying human evolution and variation. Mitochondrial DNA provides information on the origin of humans, and plays a substantial role in forensics, degenerative diseases, cancers, and aging process. Typically, human mitochondrial DNA has various features such as HVSI, HVSII, single-nucleotide polymorphism (SNP), restriction enzyme sites, and short tandem repeat (STR). We present a variome database (MitoVariome) of human mitochondrial DNA sequences. Queries against MitoVariome can be made using accession numbers or haplogroup/continent. Query results are presented not only in text but also in HTML tables to report extensive mitochondrial sequence variation information. The variation information includes repeat pattern, restriction enzyme site polymorphism, short tandem repeat, disease information as well as single nucleotide polymorphism. It also provides a graphical interface as Gbrowse displaying all variations at a glance. The web interface also provides the tool for assigning haplogroup based on the haplogroup-diagnostic system with complete human mitochondrial SNP position list and for retrieving sequences that users query against by using accession numbers. MitoVariome is a freely accessible web application and database that enables human mitochondrial genome researchers to study genetic variation in mitochondrial genome with textual and graphical views accompanied by assignment function of haplogrouping if users submit their own data. Hence, the MitoVariome containing many kinds of variation features in the human mitochondrial genome will be useful for understanding mitochondrial variations of each individual, haplogroup, or geographical location to elucidate the history of human evolution.


Prognostic Value and Therapeutic Perspectives of Coronary CT Angiography: A Literature Review.
Coronary stenosis severity is both a powerful and a still debated predictor of prognosis in coronary artery disease. Coronary computed tomographic angiography (CCTA) has emerged as a noninvasive technique that enables anatomic visualization of coronary artery disease (CAD). CCTA with newer applications, plaque characterization and physiologic/functional evaluation, allows a comprehensive diagnostic and prognostic assessment of otherwise low-intermediate subjects for primary prevention. CCTA measures the overall plaque burden, differentiates plaque subtypes, and identifies high-risk plaque with good reproducibility. Research in this field may also advance towards an era of personalized risk prediction and individualized medical therapy. It has been demonstrated that statins may delay plaque progression and change some plaque features. The potential effects on plaque modifications induced by other medical therapies have also been investigated. Although it is not currently possible to recommend routinely serial scans to monitor the therapeutic efficacy of medical interventions, the plaque modulation, as a part of risk modification, appears a feasible strategy. In this review we summarize the current evidence regarding vulnerable plaque and effects of lipid lowering therapy on morphological features of CAD. We also discuss the potential ability of CCTA to characterize coronary atherosclerosis, stratify prognosis of asymptomatic subjects, and guide medical therapy.


Effect of steroids on edema and sodium uptake of the brain during focal ischemia in rats.
Steroids reduce permeability of the blood-brain barrier and inhibit active sodium transport by brain capillaries in vitro. Since the rate of edema formation during the early stages of ischemia is related to the rate of sodium transport from blood to brain, this study was designed to determine whether steroids reduce ischemic edema formation by inhibiting blood-brain barrier sodium transport. Dexamethasone was compared with progesterone since the latter is a more potent inhibitor of sodium transport in isolated capillaries. Sprague-Dawley rats were treated with vehicle (n = 22) or 2 mg/kg of either dexamethasone (n = 22) or progesterone (n = 17) 1 hour before occlusion of the middle cerebral artery. After 4 hours of ischemia, brain water content and blood-brain barrier permeability to [3H] alpha-aminoisobutyric acid and sodium-22 were determined. In controls, mean +/- SEM water content of tissue in the center of the ischemic zone was 82.4 +/- 0.2%. Brain edema was significantly reduced following pretreatment with either dexamethasone (80.6 +/- 0.1%, p less than 0.001) or progesterone (81.5 +/- 0.3%, p less than 0.05). There was also a significant reduction in blood-brain barrier permeability to alpha-aminoisobutyric acid in normal brain following either treatment (e.g., 2.21 +/- 0.19 and 1.37 +/- 0.10 microliters/g/min, p less than 0.001, for control and dexamethasone treatments, respectively), but no effect on the permeability to sodium (e.g., 1.19 +/- 0.05 and 1.12 +/- 0.11 microliters/g/min for control and dexamethasone treatments, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)


The relationship between amyloid structure and cytotoxicity.
Self-assembly of proteins and peptides into amyloid structures has been the subject of intense and focused research due to their association with neurodegenerative, age-related human diseases and transmissible prion diseases in humans and mammals. Of the disease associated amyloid assemblies, a diverse array of species, ranging from small oligomeric assembly intermediates to fibrillar structures, have been shown to have toxic potential. Equally, a range of species formed by the same disease associated amyloid sequences have been found to be relatively benign under comparable monomer equivalent concentrations and conditions. In recent years, an increasing number of functional amyloids have also been found. These developments show that not all amyloid structures are generically toxic to cells. Given these observations, it is important to understand why amyloid structures may encode such varied toxic potential despite sharing a common core molecular architecture. Here, we discuss possible links between different aspects of amyloidogenic structures and assembly mechanisms with their varied functional effects. We propose testable hypotheses for the relationship between amyloid structure and its toxic potential in the context of recent reports on amyloid sequence, structure, and toxicity relationships.


Regulatory T cells in transplantation: transferring mouse studies to the clinic.
Switching the balance from rejection of major histocompatibility-mismatched grafts toward long-term tolerance of donor grafts, with the need for minimal immunosuppressive drugs, is a major transplantation goal. Regulatory T cells (Treg) can induce and maintain antigen-specific immune tolerance and facilitate allogeneic graft survival successfully in animals. This review will focus on the valuable insights experimental mouse models have given us into the effects of currently used immunosuppressive reagents on Treg, the Treg transcription factor forkhead box P3, and strategies to expand or induce alloantigen-reactive Treg in vivo and in vitro. These have facilitated the translation of strategies for promoting transplantation tolerance towards a new clinical era.


Mechanical Properties of Nonwoven Reinforced Thermoplastic Polyurethane Composites.
Reinforcement of flexible fibre reinforced plastic (FRP) composites with standard textile fibres is a potential low cost solution to less critical loading applications. The mechanical behaviour of FRPs based on mechanically bonded nonwoven preforms composed of either low or high modulus fibres in a thermoplastic polyurethane (TPU) matrix were compared following compression moulding. Nonwoven preform fibre compositions were selected from lyocell, polyethylene terephthalate (PET), polyamide (PA) as well as para-aramid fibres (polyphenylene terephthalamide; PPTA). Reinforcement with standard fibres manifold improved the tensile modulus and strength of the reinforced composites and the relationship between fibre, fabric and composite's mechanical properties was studied. The linear density of fibres and the punch density, a key process variable used to consolidate the nonwoven preform, were varied to study the influence on resulting FRP mechanical properties. In summary, increasing the strength and degree of consolidation of nonwoven preforms did not translate to an increase in the strength of resulting fibre reinforced TPU-composites. The TPU composite strength was mainly dependent upon constituent fibre stress-strain behaviour and fibre segment orientation distribution.


Environmental Heat Exposure and Heat-Related Symptoms in United States Coast Guard Deepwater Horizon Disaster Responders.
The response to the 2010 Deepwater Horizon oil spill was impacted by heat. We evaluated the association between environmental heat exposure and self-reported heat-related symptoms in US Coast Guard Deepwater Horizon disaster responders. Utilizing climate data and postdeployment survey responses from 3648 responders, we assigned heat exposure categories based on both wet bulb globe temperature (WBGT) and heat index (HI) measurements (median, mean, maximum). We calculated prevalence ratios (PRs) and 95% confidence intervals (CIs) via adjusted Poisson regression models with robust error variance to estimate associations with reported heat-related symptoms. We also evaluated the association between use of personal protective equipment (PPE) and heat-related symptoms. Those in the highest WBGT median-based heat exposure category had increased prevalence of heat-related symptoms compared to those in the lowest category (PR=2.22 [95% CI: 1.61, 3.06]), and there was a significant exposure-response trend (P<.001). Results were similar for exposure categories based on WBGT and HI metrics. Analyses stratified by use of PPE found significantly stronger associations between environmental heat exposure and heat-related symptoms in those who did not use PPE (PR=2.23 [95% CI: 1.10, 4.51]) than in those who did (PR=1.64 [95% CI: 1.14, 2.36]). US Coast Guard Deepwater Horizon disaster responders who experienced higher levels of environmental heat had higher prevalences of heat-related symptoms. These symptoms may impact health, safety, and mission effectiveness. As global climate change increases the frequency of disasters and weather extremes, actions must be taken to prevent heat-related health impacts among disaster responders. (Disaster Med Public Health Preparedness. 2019;13:561-569).


Ancient Demographics Determine the Effectiveness of Genetic Purging in Endangered Lizards.
The purging of deleterious alleles has been hypothesized to mitigate inbreeding depression, but its effectiveness in endangered species remains debatable. To understand how deleterious alleles are purged during population contractions, we analyzed genomes of the endangered Chinese crocodile lizard (Shinisaurus crocodilurus), which is the only surviving species of its family and currently isolated into small populations. Population genomic analyses revealed four genetically distinct conservation units and sharp declines in both effective population size and genetic diversity. By comparing the relative genetic load across populations and conducting genomic simulations, we discovered that seriously deleterious alleles were effectively purged during population contractions in this relict species, although inbreeding generally enhanced the genetic burden. However, despite with the initial purging, our simulations also predicted that seriously deleterious alleles will gradually accumulate under prolonged bottlenecking. Therefore, we emphasize the importance of maintaining a minimum population capacity and increasing the functional genetic diversity in conservation efforts to preserve populations of the crocodile lizard and other endangered species.


All-dielectric integration of dielectric resonator antenna and photonic crystal waveguide.
Two-dimensional photonic crystal waveguides can support guided modes with low loss. Interfacing such a guided mode with free-space propagation modes is crucial for photonic integrated circuits. Here we propose a dielectric resonator antenna (DRA) fully integrated with a photonic crystal waveguide for endfire radiation. High radiation efficiency can be achieved from the DRA that relies on oscillating displacement currents in a low-loss dielectric material. The antenna is designed to operate at a high-order resonance for high gain. The reflection loss at the interface between the two components is minimized via a matching air hole, the mechanism of which is qualitatively described via temporal coupled-mode theory. As a proof of concept, the all-dielectric integrated structure is realized on a single intrinsic silicon wafer to operate at terahertz frequencies. The antenna footprint is only about one square operational wavelength. The experimental validation confirms the maximum gain of over 10.6 dBi with 3-dB angular beam widths of 29.0 degrees and 45.7 degrees in orthogonal dimensions. The impedance bandwidth obtained from simulation is 6%, spanning 311 to 331 GHz. Given a suitable low-loss dielectric material, this all-dielectric structure holds potential for scaling to infrared and visible light frequencies.


The pathology and clinical features of early recurrent membranous glomerulonephritis.
We assessed the earliest manifestations of recurrent membranous glomerulonephritis (MGN) in renal allografts. Clinical, laboratory and pathologic data were reviewed in 21 patients at the initial biopsy within 4 months post-transplant with evidence of MGN and on follow-up biopsies, compared to a biopsy control group of eight transplants without recurrent MGN. The mean time of first biopsy with pathologic changes was 2.7 months. In each earliest biopsy, immunofluorescence (IF) showed granular glomerular basement membrane (GBM) staining for C4d, IgG, kappa and lambda. IF for C3 was negative or showed trace staining in 16/21. On each MGN biopsy positive by IF, 14/19 showed absence of deposits or rare tiny subepithelial deposits by electron microscopy (EM). At the earliest biopsy, the mean proteinuria was 1.1 g/day; 16 patients had <1 g/day proteinuria. Follow-up was available in all patients (mean 35 months posttransplant). A total of 13 patients developed >1 g/day proteinuria; 12 were treated with: rituximab (n = 8), ACEI and increased prednisone dose (n = 2), ACEI or ARB only (n = 2). All patients showed reduction in proteinuria after treatment. A total of 11/16 patients showed progression of disease by EM on follow-up biopsy. Recognition of early allograft biopsy features aids in diagnosis of recurrent MGN before patients develop significant proteinuria.


Role of interlekin-35 as a biomarker in patients with newly diagnosed Hashimoto's thyroiditis.
Interleukin-35 (IL-35), an interleukin-12 (IL-12) cytokine family member, is shown to be a potent immunosuppressive and anti-inflammatory cytokine. Inducible regulatory T cells (Tregs) produce IL-35 that mediates the immune inhibitory function of Tregs. Growing evidence revealed that upregulation of IL-35 expression may play a critical role in the prevention of autoimmune diseases in various experimental autoimmunity models and vice versa. Hashimoto's thyroiditis (HT) is considered to be a Treg cell-related autoimmune disease with loss of self-tolerance. One hundred-twenty eight subjects, newly diagnosed hypothyroid HT patients [56 overt (Group 1), 72 subclinical hypothyroid (Group 2)] and 38 healthy controls (Group 3) were enrolled in the study. The levels of serum IL-35 were determined by enzyme-linked immunosorbent assay (ELISA). Serum IL-35 levels were lower in the HT group when compared with subclinical HT group [304.5 (834.6) pg/ml vs. 636.1 (1542.0) pg/ml, p=0.004] and control cases [304.5 (834.6) pg/ml vs. 1064.7 (2526.8) pg/ml, p<0.001]. Serum IL-35 levels were inversely associated with thyroid stimulating hormone (TSH; rs=-0.396, p<0.001) and anti-thyroid peroxidase antibodies (TPOAb; rs=-0.571, p<0.001) in whole group. Serum IL-35 were negatively associated with TSH (rs=-0.264, p=0.003) and TPOAb (rs=-0.735, p<0.001) in patients with Hashimoto's thyroiditis (Group 1 + Group 2). The results suggest that IL-35 may play a role in the pathogenesis of HT.


Association of Accelerometer-Measured Physical Activity Level With Risks of Hospitalization for 25 Common Health Conditions in UK Adults.
Higher physical activity levels are associated with lower risks of cancer, cardiovascular disease, and diabetes, but associations with many common and less severe health conditions are not known. These conditions impose large health care burdens and reduce quality of life. To investigate the association between accelerometer-measured physical activity and the subsequent risk of hospitalization for 25 common reasons for hospitalization and to estimate the proportion of these hospitalizations that might have been prevented if participants had higher levels of physical activity. This prospective cohort study used data from a subset of 81 717 UK Biobank participants aged 42 to 78 years. Participants wore an accelerometer for 1 week (between June 1, 2013, and December 23, 2015) and were followed up over a median (IQR) of 6.8 (6.2-7.3) years; follow-up for the current study ended in 2021 (exact date varied by location). Mean total and intensity-specific accelerometer-measured physical activity. Hospitalization for the most common health conditions. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% CIs for mean accelerometer-measured physical activity (per 1-SD increment) and risks of hospitalization for 25 conditions. Population-attributable risks were used to estimate the proportion of hospitalizations for each condition that might be prevented if participants increased their moderate to vigorous physical activity (MVPA) by 20 minutes per day. Among 81 717 participants, the mean (SD) age at accelerometer assessment was 61.5 (7.9) years; 56.4% were female, and 97.0% self-identified as White. Higher levels of accelerometer-measured physical activity were associated with lower risks of hospitalization for 9 conditions: gallbladder disease (HR per 1 SD, 0.74; 95% CI, 0.69-0.79), urinary tract infections (HR per 1 SD, 0.76; 95% CI, 0.69-0.84), diabetes (HR per 1 SD, 0.79; 95% CI, 0.74-0.84), venous thromboembolism (HR per 1 SD, 0.82; 95% CI, 0.75-0.90), pneumonia (HR per 1 SD, 0.83; 95% CI, 0.77-0.89), ischemic stroke (HR per 1 SD, 0.85; 95% CI, 0.76-0.95), iron deficiency anemia (HR per 1 SD, 0.91; 95% CI, 0.84-0.98), diverticular disease (HR per 1 SD, 0.94; 95% CI, 0.90-0.99), and colon polyps (HR per 1 SD, 0.96; 95% CI, 0.94-0.99). Positive associations were observed between overall physical activity and carpal tunnel syndrome (HR per 1 SD, 1.28; 95% CI, 1.18-1.40), osteoarthritis (HR per 1 SD, 1.15; 95% CI, 1.10-1.19), and inguinal hernia (HR per 1 SD, 1.13; 95% CI, 1.07-1.19), which were primarily induced by light physical activity. Increasing MVPA by 20 minutes per day was associated with reductions in hospitalization ranging from 3.8% (95% CI, 1.8%-5.7%) for colon polyps to 23.0% (95% CI, 17.1%-28.9%) for diabetes. In this cohort study of UK Biobank participants, those with higher physical activity levels had lower risks of hospitalization across a broad range of health conditions. These findings suggest that aiming to increase MVPA by 20 minutes per day may be a useful nonpharmaceutical intervention to reduce health care burdens and improve quality of life.


How do public health professionals view and engage with research? A qualitative interview study and stakeholder workshop engaging public health professionals and researchers.
With increasing financial pressures on public health in England, the need for evidence of high relevance to policy is now stronger than ever. However, the ways in which public health professionals (PHPs) and researchers relate to one another are not necessarily conducive to effective knowledge translation. This study explores the perspectives of PHPs and researchers when interacting, with a view to identifying barriers to and opportunities for developing practice that is effectively informed by research. This research focused on examples from two responsive research schemes, which provide university-based support for research-related enquiries from PHPs: the NIHR SPHR Public Health Practitioner Evaluation Scheme1 and the responsive research service AskFuse2. We examined enquiries that were submitted to both between 2013 and 2015, and purposively selected eight enquiries for further investigation by interviewing the PHPs and researchers involved in these requests. We also identified individuals who were eligible to make requests to the schemes but chose not to do so. In-depth interviews were conducted with six people in relation to the PHPES scheme, and 12 in relation to AskFuse. The interviews were transcribed and analysed using thematic framework analysis. Verification and extension of the findings were sought in a stakeholder workshop. PHPs recognised the importance of research findings for informing their practice. However, they identified three main barriers when trying to engage with researchers: 1) differences in timescales; 2) limited budgets; and 3) difficulties in identifying appropriate researchers. The two responsive schemes addressed some of these barriers, particularly finding the right researchers to work with and securing funding for local evaluations. The schemes also supported the development of new types of evidence. However, other barriers remained, such as differences in timescales and the resources needed to scale-up research. An increased mutual awareness of the structures and challenges under which PHPs and researchers work is required. Opportunities for frequent and meaningful engagement between PHPs and researchers can help to overcome additional barriers to co-production of evidence. Collaborative models, such as the use of researchers embedded in practice might facilitate this; however, flexible research funding schemes are needed to support these models.


Genetic and Environmental Influences on Traits of Gender Identity Disorder: A Study of Japanese Twins Across Developmental Stages.
The present study examined: (1) gender and age differences of mean gender identity disorder (GID) trait scores in Japanese twins; (2) the validity of the prenatal hormone transfer theory, which predicts that, in dizygotic (DZ) twin pairs, twins with an opposite-gender co-twin more frequently exhibit GID traits than twins with a same-gender co-twin; and (3) the magnitude of genetic and environmental influences on GID traits as a function of age and gender. Data from 1450 male twin pairs, 1882 female twin pairs, and 1022 DZ male-female pairs ranging from 3 to 26 years of age were analyzed. To quantify individual variances in GID traits, each participant completed four questionnaire items based on criteria for GID from the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR). Our most important findings were: (1) Japanese females exhibited GID traits more frequently than males and Japanese children exhibited GID traits less frequently than adolescents and adults (among females, the prevalence was 1.6 % in children, 10 % in adolescents, and 12 % in adults; among males, the prevalence was 0.5, 2, and 3 %, respectively); (2) the data did not support the prenatal hormone transfer theory for GID traits; and (3) a large part of the variance for GID traits in children was accounted for by familial factors; however, the magnitude was found to be greater in children than in adolescents or adults, particularly among females. This study suggests that although the prevalence is likely to increase, familial effects are likely to decrease as individuals age.


Transplantation of high panel-reactive antibody left ventricular assist device patients without crossmatch using on-bypass pheresis and alemtuzumab.
Highly sensitized (HS) left ventricular assist device (LVAD) patients with high panel-reactive antibody (PRA) levels present a challenge. Alemtuzumab, a potent depleting agent for T and B lymphocytes (months to years), and plasmapheresis, offer an opportunity for heart transplantation to these patients who might die of VAD complications on the transplant waiting list. This study compared rates of acute rejection and survival of a HS LVAD cohort with a contemporaneous control group after heart transplant. Clinical courses of 31 consecutive patients who underwent transplantation between January 2006 and January 2011 were reviewed. Eight patients with a T or B PRA of 70 or more (HS+) received non-crossmatched, ABO-compatible hearts using intraoperative plasmapheresis and alemtuzumab induction. Controls (HS-) received basiliximab induction. Acute rejection was defined as International Society for Heart and Lung Transplantation grades 2R or higher, or antibody-mediated rejection. The difference in survival between HS+ and HS- groups at 1 year (100% vs 94%) or at a mean follow-up of 2.3 and 2.4 years (75% vs 70%) was not significant. Retrospective lymphocytotoxic crossmatches were positive in 7 of 8 HS+ patients (6 T+ and B+, 1 B+) vs none in the HS- group (p < 0.001). There was a trend toward increased risk of cellular rejection per 100 patient-days beyond 1 year in the HS+ group (p = 0.07). Risk of humoral rejection was significantly increased in the HS+ group (38% vs 4%; p = 0.04). Heart transplantation with plasmapheresis and alemtuzumab in HS LVAD patients, most with a positive crossmatch, does not compromise midterm survival. The expected higher rates of rejection, especially beyond the first postoperative year, demand adjustments in surveillance strategies and immunosuppressive management.


Challenges in Maintaining the Hemostatic Balance in Children Undergoing Extracorporeal Membrane Oxygenation: A Systematic Literature Review.
Background: Despite advances in technology and clinical experience, the incidence of hemostatic complications, including bleeding and thrombosis, remains high in children supported with extracorporeal membrane oxygenation (ECMO). These hemostatic complications are important to prevent, since they are associated with increased morbidity and mortality. This systematic literature review aims to outline the most important risk factors for hemostatic complications in children undergoing ECMO treatment, to summarize the reported alternative anticoagulant drugs used in pediatric ECMO and to describe studied associations between coagulation tests and hemostatic complications. Methods: A literature search was performed in Embase, Medline, Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and Google Scholar in February 2020. Included studies were studies evaluating children (<18 years old) treated with ECMO, and studies evaluating risk factors for hemostatic complications, alternative anticoagulants, or the association between coagulation tests and hemostatic complications. Results: Out of 1,152 articles, 35 studies were included. Thirteen out of 49 risk factors were investigated in three or more studies. Most consistent results were found regarding ECMO duration and pH. However, evidence for risk factors was equivocal in the majority of studies, which is explained by the variability of populations studied, definitions of hemostatic complications, ECMO circuits, anticoagulation protocols, transfusion triggers and monitoring of anticoagulation. Five studies described alternative anticoagulants, including bivalirudin (n = 3), argatroban (n = 1) and FUT (n = 1). Higher anti-factor Xa levels were associated with less clotting events in one of nine studies, investigating the association between tests and hemostatic complications. Two studies revealed an association between anti-factor Xa assay-based protocols and a decreased number of transfusions, bleedings and need for circuit change. Conclusion: Studies regarding risk factors showed conflicting results and a few retrospective studies reported the use of new anticoagulants and data on coagulation tests in relation to hemostatic complications. To decrease hemostatic complications in ECMO children, prospective multicenter studies are needed with clear bleeding and thrombotic definitions, and the best possible standardization of ECMO circuits used, anticoagulation protocols, and transfusion triggers.


Prevalence of depression after TBI in a prospective cohort: The SHEFBIT study.
The objective is to measure the prevalence of depression after traumatic brain injury (TBI) and the features associated with increased risk in a cohort that reflects clinical practice. Prospective TBI admissions to a large Teaching Hospital Emergency Department were recruited over a 2-year period. Assessments for depression and other psychosocial and global outcomes were completed at 3 months post-injury. Comparisons were made with demographic and injury features of interest to establish any associations of depression risk. Out of 827 individuals, 774 (94%) successfully attended follow-up. A percentage of 56.3 had depression using a HADS-D >8. Depressed individuals had higher levels of post-concussion symptoms and worse psychosocial and global outcome ratings. In multivariable analysis, features associated with depression were TBI severity, previous psychiatric history, alcohol intoxication at time of injury, female gender and nonwhite ethnicity. Those with a normal CT scan showed higher risk than those with only mild abnormality and were comparable to those with much more marked CT changes. The 3-month prevalence of depression after TBI is very high and associated with several injury and demographic features. Future long-term follow-up of this cohort aims to confirm the features that increase risk; this may allow the earlier targeting of susceptible individuals for depression interventions.


In vivo uncoating and efficient expression of foreign mRNAs packaged in TMV-like particles.
The ribonucleocapsids of many plant viruses are extremely stable. The protein coat protects the RNA genome against degradation during the accumulation and spread of progeny virions. Chimeric single-stranded RNA molecules were transcribed in vitro from recombinant plasmids and later encapsidated, in vitro, into ribonucleoprotein particles (pseudoviruses) 60 nanometers long that resembled tobacco mosaic virus. Transcripts encoding an assayable enzyme, chloramphenicol acetyltransferase (CAT), were packaged into pseudovirus particles to assess the utility of this single-stranded RNA delivery system in a wide range of cell types. In all cases, packaged CAT messenger RNA was uncoated and transiently expressed. Significantly higher levels of CAT activity were detected with packaged than with naked CAT messenger RNA after inoculation of plant protoplasts in the presence of polyethylene glycol or abrasive inoculation of intact leaf surfaces. Structural events that lead to the uncoating and expression of CAT messenger RNA showed no cell specificity. This observation may support the view that the comparatively restricted host range of a true plant virus results from events that occur later during the infection cycle.


Dynamic discharge characteristics of low pressure receptors in the rat.
An in vitro preparation was used to examine the discharge of low pressure receptors in response to a pulsatile pressure stimulus. Both slowly adapting and rapidly adapting receptors were examined. After an increase in the mean level and/or dP/dt of a pulsatile pressure input, the discharge of slowly adapting receptors reached a steady state level within 2 minutes. An increase in mean pressure, with constant pulsatile amplitude and dP/dt, produced a sustained increase in the number of spikes/cycle, in the average number of spikes/second, and in the average frequency during the burst within the cycle. In slowly adapting receptors, an increase in dP/dt at a constant mean pressure and pulsatile amplitude produced a decrease in the number of spikes/cycle and an increase in both the average number of spikes/second and the frequency during the burst. Rapidly adapting receptors showed very different characteristics, responding to a pulsatile pressure input above threshold with an irregular discharge which averages approximately 1 spike/cycle at all mean pressure levels. Although rapidly adapting receptors transiently increased their discharge in response to an increase in mean pressure, within 60 seconds discharge returned to the pre-increase level. Rapidly adapting receptors continued to discharge with an average of 1 spike/cycle as dP/dt was increased. Since dP/dt was raised by increasing the frequency of the pulsatile input, the number of spikes/second increased. In the steady state, slowly adapting receptors transmit information reflecting mean pressure levels. They are also sensitive to the rate of change of pressure. Rapidly adapting receptors, on the other hand, are insensitive to mean pressure but do respond to the frequency of the stimulus.


High-flux solar-driven thermochemical dissociation of CO2 and H2O using nonstoichiometric ceria.
Because solar energy is available in large excess relative to current rates of energy consumption, effective conversion of this renewable yet intermittent resource into a transportable and dispatchable chemical fuel may ensure the goal of a sustainable energy future. However, low conversion efficiencies, particularly with CO(2) reduction, as well as utilization of precious materials have limited the practical generation of solar fuels. By using a solar cavity-receiver reactor, we combined the oxygen uptake and release capacity of cerium oxide and facile catalysis at elevated temperatures to thermochemically dissociate CO(2) and H(2)O, yielding CO and H(2), respectively. Stable and rapid generation of fuel was demonstrated over 500 cycles. Solar-to-fuel efficiencies of 0.7 to 0.8% were achieved and shown to be largely limited by the system scale and design rather than by chemistry.


[Blepharospasm and acupuncture--initial results of a treatment trial].
Blepharospasm is a dystonia of the orbicularis muscle. The background is still unknown, but it appears together with organic and psychic diseases. The therapy with botulinum toxine is symptomatically but efficient. Because of the relaxing effect on the psychological and autonomous nervous disorders we performed a pilot study with acupuncture. There was a neurological observation first, then a ophthalmologic examination of the ocular surface. Blepharospasm was measured by the Visual Analogue Scale (VAS), the social disorders by the Elston-Score. We performed acupuncture treatment 10 times once weekly. The used points were local points with higher sensitivity, and points with empiric relaxation effect. 5 patients were included. The mean of Elston score was 3 before acupuncture and 4 after acupuncture. The VAS increased from 33.3 to 69/100 points. But there were fluctuations of dystonias. In conclusion acupuncture maybe a good method for this difficult disease additionally.


The value of a 1-day multidisciplinary robot surgery training for novice robot surgeons.
To fulfil the need for a basic level of competence in robotic surgery (Brinkman et al., Surg Endosc Other Interv Tech 31(1):281-287, 2017; Dutch Health inspectorate (Inspectie voor de gezondheidszorg), Insufficient carefulness at the introduction of surgical robots (in Dutch: Onvoldoende zorgvuldigheid bij introductie van operatierobots), Igz, Utrecht, 2010), the NIVEL (Netherlands Institute for Healthcare Research) developed the 'Basic proficiency requirements for the safe use of robotic surgery' (BPR). Based on the BPR a 1-day robotic surgery training was organised to answer the following research questions: (1) Are novice robot surgeons able to accurately self-assess their knowledge and dexterity skills? (2) Is it possible to include the teaching of all BPRs in a 1-day training? Based on the BPR, a robot surgery course was developed for residents and specialists (surgery, gynaecology and urology). In preparation, the participants completed an online e-module. The 1-day training consisted of a practical part on robot set-up, a theoretical section, and hands-on exercises on virtual reality robot simulators. Multiple online questionnaire was filled out by the participants at the end of the training to evaluate the perceived educational value of the course and to self-assess the degree to which BPRs were reached. 20 participants completed the training during the conference of the Dutch Association for Endoscopic Surgery (NVEC) in 2017. Participants indicated nearly all competency requirements were mastered at the end of the training. The competency requirements not mastered were, however, critical requirements for the safe use of the surgical robot. Skill simulation results show a majority of participants are unable to reach a proficient simulation score in basic skill simulation exercises. Results show novice robot surgeons are too positive in the self-assessment of their own dexterity skills after a 1-day training. Self-assessment revealed uncertainty of the obtained knowledge level on requirements for the safe use of the surgical robot. Basic courses on robotic training should inform trainees about their results to enhance learning and inform them of their competence levels.


The contribution of emotional partners to sexual risk taking and violence among female sex workers in Mombasa, Kenya: a cohort study.
To assess sexual risk-taking of female sex workers (FSWs) with emotional partners (boyfriends and husbands), compared to regular and casual clients. Experiences of violence and the degree of relationship control that FSWs have with emotional partners are also described. Cohort study with quarterly follow-up visit over 12-months. Four hundred HIV-uninfected FSWs older than 16 years were recruited from their homes and guesthouses in Mombasa, Kenya. A structured questionnaire assessed participant characteristics and study outcomes at each visit, and women received risk-reduction counselling, male and female condoms, and HIV testing. Four or more unprotected sex acts in the past week were reported by 21.3% of women during sex with emotional partners, compared to 5.8% with regular and 4.8% with casual clients (P<0.001). Total number of unprotected sex acts per week was 5-6-fold higher with emotional partners (603 acts with 259 partners) than with regular or casual clients (125 acts with 456, and 98 acts with 632 clients, respectively; P<0.001). Mostly, perceptions of "trust" underscored unprotected sex with emotional partners. Low control over these relationships, common to many women (36.9%), was linked with higher partner numbers, inconsistent condom use, and being physically forced to have sex by their emotional partners. Half experienced sexual or physical violence in the past year, similarly associated with partner numbers and inconsistent condom use. High-risk sexual behaviour, low control and frequent violence in relationships with emotional partners heighten FSWs' vulnerability and high HIV risk, requiring targeted interventions that also encompass emotional partners.


The Best Interest Standard: Same Name but Different Roles in Pediatric Bioethics and Child Rights Frameworks.
This article explores the intersection of pediatric bioethics and child rights by examining the best interest standard as it operates within the pediatric bioethics framework in the United States and the child rights framework based on the UN 1989 Convention on the Rights of the Child (CRC). While the "best interest of the child" standard is central to both pediatric bioethics and the child rights community, it operates only as a guidance principle, and not as an intervention principle, in decision-making within U.S. pediatric bioethics, whereas it operates as both a guidance and intervention principle in the child rights community. The differences in how the best interest standard is operationalized lead to different roles for the family, the state, and the minor in decision-making processes and outcomes. We examine the recent case of Charlie Gard to illustrate some of these differences.


How important is self-consistency for the dDsC density dependent dispersion correction?
The treatment of dispersion interactions is ubiquitous but computationally demanding for seamless ab initio approaches. A highly popular and simple remedy consists in correcting for the missing interactions a posteriori by adding an attractive energy term summed over all atom pairs to standard density functional approximations. These corrections were originally based on atom pairwise parameters and, hence, had a strong touch of empiricism. To overcome such limitations, we recently proposed a robust system-dependent dispersion correction, dDsC, that is computed from the electron density and that provides a balanced description of both weak inter- and intramolecular interactions. From the theoretical point of view and for the sake of increasing reliability, we here verify if the self-consistent implementation of dDsC impacts ground-state properties such as interaction energies, electron density, dipole moments, geometries, and harmonic frequencies. In addition, we investigate the suitability of the a posteriori scheme for molecular dynamics simulations, for which the analysis of the energy conservation constitutes a challenging tests. Our study demonstrates that the post-SCF approach in an excellent approximation.


Change of redox status and modulation by thiol replenishment in retinal photooxidative damage.
Cellular or tissue reduction-oxidation (redox) is crucial in various diseases. The present study was conducted to analyze how tissue redox status is affected by photooxidative stress and whether the exogenous thiol antioxidant N-acetylcysteine (NAC) affects photooxidative stress-induced retinal damage. Mice were intraperitoneally injected with either NAC (250 mg/kg) or phosphate-buffered saline (PBS) and exposed to white fluorescent light (8000 lux) for 2 hours. Levels of thioredoxin (TRX), glutaredoxin (GRX), and glutathione (GSH), endogenous regulators of redox; 4-hydroxy-2-nonenal (HNE)-modified protein, a marker of lipid peroxidation; and nuclear factor (NF)-kappaB, a redox-sensitive transcription factor in retinal samples, was measured by immunohistochemistry and Western blot or enzymatic recycling assay. Light-induced retinal damage estimated by electroretinography and quantitative immunohistochemistry for 8-hydroxy-2-deoxyguanosine (8OHdG index), a marker of oxidative stress-induced DNA damage, was compared in NAC- and PBS-treated mice. Upregulation of TRX and HNE-modified protein, decrease of GSH, and nuclear translocation of NF-kappaB were noted after light exposure in PBS-treated mice. These changes were suppressed in NAC-treated mice compared with PBS-treated mice. GRX was not upregulated after light exposure in any mice. The a- and b-wave amplitudes were significantly higher, and the 8OHdG index was significantly lower after light exposure in NAC-treated mice than in PBS-treated mice. Retinal redox status is altered by intense light and is normalized partially by the effect of NAC on TRX and GSH tissue levels. Manipulation of the tissue redox state by exogenous thiol replenishment may be a useful strategy to prevent retinal photooxidative damage.


Neural correlates of 'pessimistic' attitude in depression.
Preparing for potentially threatening events in the future is essential for survival. Anticipating the future to be unpleasant is also a cognitive key feature of depression. We hypothesized that 'pessimism'-related emotion processing would characterize brain activity in major depression.MethodDuring functional magnetic resonance imaging, depressed patients and a healthy control group were cued to expect and then perceive pictures of known emotional valences--pleasant, unpleasant and neutral--and stimuli of unknown valence that could have been either pleasant or unpleasant. Brain activation associated with the 'unknown' expectation was compared with the 'known' expectation conditions. While anticipating pictures of unknown valence, activation patterns in depressed patients within the medial and dorsolateral prefrontal areas, inferior frontal gyrus, insula and medial thalamus were similar to activations associated with expecting unpleasant pictures, but not with expecting positive pictures. The activity within a majority of these areas correlated with the depression scores. Differences between healthy and depressed persons were found particularly for medial and dorsolateral prefrontal and insular activations. Brain activation in depression during expecting events of unknown emotional valence was comparable with activation while expecting certainly negative, but not positive events. This neurobiological finding is consistent with cognitive models supposing that depressed patients develop a 'pessimistic' attitude towards events with an unknown emotional meaning. Thereby, particularly the role of brain areas associated with the processing of cognitive and executive control and of the internal state is emphasized in contributing to major depression.


Dietary molasses increases ruminal pH and enhances ruminal biohydrogenation during milk fat depression.
Feeding high-concentrate diets has the potential to cause milk fat depression, but several studies have suggested that dietary sugar can increase milk fat yield. Two experiments were conducted to evaluate the ability of dietary molasses to prevent milk fat depression in the presence of a 65% concentrate diet. In trial 1, molasses replaced corn grain at 0, 2.5, or 5% of diet dry matter in diets fed to 12 second-lactation Holstein cows (134±37 d in milk) in a 3×3 Latin square design. Trial 1 demonstrated that replacing up to 5% of dietary dry matter from corn with molasses had positive effects on de novo fatty acid synthesis, increasing the yield of short- and medium-chain fatty acids during diet-induced milk fat depression. Increasing inclusion rate of molasses increased milk fat concentration, but decreased milk yield and milk protein yield. Trial 2 used 7 ruminally cannulated, multiparous, late-lactation Holstein cows (220±18 d in milk) to evaluate effects of dietary molasses on ruminal parameters and milk composition, and also to assess whether increased metabolizable protein supply would alter these responses. Cows were randomly assigned to a dietary treatment sequence in a crossover split plot design with 0 and 5% molasses diets. Dietary treatments were fed for 28 d, with 16 d for diet adaptation, and the final 12 d for 2 abomasal infusion periods in a crossover arrangement. Abomasal infusions of water or AA (5 g of l-Met/d+15 g of l-Lys-HCl/d+5 g of l-His-HCl-H(2)O/d) were administered 3 times daily for 5 d, with 2 d between infusion periods. Administration of AA had no effect on concentration or yield of any milk components. Addition of molasses increased milk fat concentration (2.71 vs. 2.94±0.21%), but had no effect on yields of milk fat or protein. Dietary molasses decreased total volatile fatty acid concentration (141 vs. 133±4.6mM), decreased the molar proportion of propionate, and increased the molar proportion of butyrate in ruminal fluid. Molasses also increased ruminal pH (5.73 vs. 5.87±0.06), decreased the yield of trans-10 C18:1, and increased the yield of trans-11 C18:1 in milk fat. These data provide evidence that molasses may promote mammary de novo fatty acid synthesis in cows fed high-energy rations by moderating ruminal pH and altering ruminal fatty acid biohydrogenation pathways.


Sublethal photic stress and the motility of RPE phagosomes and melanosomes.
To determine whether sublethal oxidative stress to the retinal pigment epithelium by visible light treatment affects the translocation of organelles, notably phagosomes and melanosomes. Isolated porcine melanosomes were phagocytized by ARPE-19 cells, then cultures were treated with blue light to generate reactive oxygen intermediates (ROIs) by endogenous retinal pigment epithelial (RPE) chromophores throughout the cytoplasm. Other melanosomes were preloaded with a photosensitizer before phagocytosis, and cells were light treated to generate ROIs specifically at the granule surface. Phagosome movement was analyzed by live cell imaging. Also analyzed were phagocytized black latex beads, phagocytized melanosomes pretreated to simulate age-related melanin photobleaching, and endogenous RPE melanosomes in primary cultures of porcine retinal pigment epithelium. Sublethal blue light treatment slowed the movement of some, but not all, phagocytized melanosomes. All phagosomes slowed when ROIs were generated near the organelles through a photosensitized reaction. Melanosome photobleaching, which makes granules more photoreactive, increased the effects of blue light. Blue light treatment also slowed the motility of phagosomes containing latex beads and endogenous pigment granules. Blue light-induced stress impairs phagosome motility in RPE cells but affects individual organelles differently, suggesting that the effects of mild oxidative injury vary with subcellular location. The mechanisms underlying slowed motility are at least partially local because slowing can be induced by a photosensitized reaction in the subdomain of the organelle and the magnitude of the slowing is greater when the phagosome contents are photoreactive. Photic stress may impair the movement and positioning of RPE organelles, which would have widespread consequences for maintaining a functionally efficient subcellular organization.


Long-term intake of vitamins and carotenoids and odds of early age-related cortical and posterior subcapsular lens opacities.
Proper nutrition appears to protect against cataracts. Few studies have related nutrition to the odds of developing cortical or posterior subcapsular (PSC) cataracts. We assessed the relation between usual nutrient intakes and age-related cortical and PSC lens opacities. We studied 492 nondiabetic women aged 53-73 y from the Nurses' Health Study cohort who were without previously diagnosed cataracts. Usual nutrient intake was calculated as the average intake from 5 food-frequency questionnaires collected over a 13-15-y period before the eye examination. Duration of vitamin supplement use was determined from 7 questionnaires collected during this same period. We defined cortical opacities as grade > or = 0.5 and subcapsular opacities as grade > or =0.3 of the Lens Opacities Classification System III. Some lenses had more than one opacity. No nutrient measure was related to prevalence of opacities in the full sample, but significant interactions were seen between age and vitamin C intake (P = 0.02) for odds of cortical opacities and between smoking status and folate (P = 0.02), alpha-carotene (P = 0.02), beta-carotene (P = 0.005), and total carotenoids (P = 0.02) for odds of PSC opacities. For women aged <60 y, a vitamin C intake > or = 362 mg/d was associated with a 57% lower odds ratio (0.43; 95% CI: 0.2, 0.93) of developing a cortical cataract than was an intake <140 mg/d, and use of vitamin C supplements for > or = 10 y was associated with a 60% lower odds ratio (0.40; 0.18, 0.87) than was no vitamin C supplement use. Prevalence of PSC opacities was related to total carotenoid intake in women who never smoked (P = 0.02). Our results support a role for vitamin C in diminishing the risk of cortical cataracts in women aged <60 y and for carotenoids in diminishing the risk of PSC cataracts in women who have never smoked.


Quantitative comparison of cortical surface reconstructions from MP2RAGE and multi-echo MPRAGE data at 3 and 7 T.
The Magnetization-Prepared 2 Rapid Acquisition Gradient Echo (MP2RAGE) method achieves spatially uniform contrast across the entire brain between gray matter and surrounding white matter tissue and cerebrospinal fluid by rapidly acquiring data at two points during an inversion recovery, and then combining the two volumes so as to cancel out sources of intensity and contrast bias, making it useful for neuroimaging studies at ultrahigh field strengths (≥7T). To quantify the effectiveness of the MP2RAGE method for quantitative morphometric neuroimaging, we performed tissue segmentation and cerebral cortical surface reconstruction of the MP2RAGE data and compared the results with those generated from conventional multi-echo MPRAGE (MEMPRAGE) data across a group of healthy subjects. To do so, we developed a preprocessing scheme for the MP2RAGE image data to allow for automatic cortical segmentation and surface reconstruction using FreeSurfer and analysis methods to compare the positioning of the surface meshes. Using image volumes with 1mm isotropic voxels we found a scan-rescan reproducibility of cortical thickness estimates to be 0.15 mm (or 6%) for the MEMPRAGE data and a slightly lower reproducibility of 0.19 mm (or 8%) for the MP2RAGE data. We also found that the thickness estimates were systematically smaller in the MP2RAGE data, and that both the interior and exterior cortical boundaries estimated from the MP2RAGE data were consistently positioned within the corresponding boundaries estimated from the MEMPRAGE data. Therefore several measureable differences exist in the appearance of cortical gray matter and its effect on automatic segmentation methods that must be considered when choosing an acquisition or segmentation method for studies requiring cortical surface reconstructions. We propose potential extensions to the MP2RAGE method that may help to reduce or eliminate these discrepancies.


Automating ChIP-seq experiments to generate epigenetic profiles on 10,000 HeLa cells.
Chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq) is a technique of choice for studying protein-DNA interactions. ChIP-seq has been used for mapping protein-DNA interactions and allocating histones modifications. The procedure is tedious and time consuming, and one of the major limitations is the requirement for high amounts of starting material, usually millions of cells. Automation of chromatin immunoprecipitation assays is possible when the procedure is based on the use of magnetic beads. Successful automated protocols of chromatin immunoprecipitation and library preparation have been specifically designed on a commercially available robotic liquid handling system dedicated mainly to automate epigenetic assays. First, validation of automated ChIP-seq assays using antibodies directed against various histone modifications was shown, followed by optimization of the automated protocols to perform chromatin immunoprecipitation and library preparation starting with low cell numbers. The goal of these experiments is to provide a valuable tool for future epigenetic analysis of specific cell types, sub-populations, and biopsy samples.


The Effectiveness of EMLA as a Primary Dressing on Painful Chronic Leg Ulcers: A Pilot Randomized Controlled Trial.
To evaluate the effectiveness of the eutectic mixture of local anesthetics (EMLA; Aspen Pharmacare, St. Leonards, New South Wales, Australia) as a primary dressing on painful chronic leg ulcers. A pilot randomized controlled trial. The study was conducted across 6 community nursing procedure clinics located in a community nursing service in New South Wales, Australia. Sixty participants with painful chronic leg ulcers of varied etiology were recruited into the study. Participants were randomly assigned to an intervention (daily EMLA use for 4 weeks as a primary dressing) or a standard wound care group. The effectiveness of EMLA on wound-related pain intensity before, during, and after dressing change. Mean pain scores were similar between the 2 groups at baseline (P = .84). During dressing change, mean pain scores across the 4-week intervention period were significantly lower in the intervention compared with the control group (intervention group: mean, 3.39 [SD, 2.16]; control group: mean, 4.82 [SD, 2.27]; P = .02). Mean pain scores after dressing change were also significantly lower for the intervention group over the 4-week intervention period (intervention group: mean, 2.71 [SD, 1.94]; control group: mean, 3.92 [SD, 2.03]; P = .03). Data from this pilot study suggest that EMLA as a primary dressing may be effective in reducing chronic leg ulcer pain during and after dressing change and warrant further evaluation.


A bacterially expressed single-chain Fv construct from the 2B4 T-cell receptor.
A single-chain Fv construct of the 2B4 T-cell receptor has been made and expressed in Escherichia coli as bacterial inclusion bodies. After solubilization in 6 M guanidine hydrochloride and formation of mixed disulfides with glutathione, the protein was refolded by diluting out the denaturant and allowing intramolecular disulfide bridges to form by disulfide exchange. Approximately 65-100 mg of refolded protein was obtained from 1 liter of bacterial culture, an appreciable fraction of which was monomeric in nondenaturing solvents. This protein bound to three monoclonal antibodies specific for allotypic or idiotypic determinants on the native 2B4 variable region but did not bind several other anti-T-cell-receptor monoclonal antibodies that lacked such specificity. These experiments show that T-cell-receptor variable regions, like the V regions of antibodies, can form a well-behaved single-chain Fv molecule and provide large amounts of recombinant single-chain Fv T-cell receptor that can be used to study T-cell function.


Cue configuration effects in acquisition and extinction of a cocaine-induced place preference.
A pervasive finding in animal models of substance abuse is that associations form quickly between contexts and drugs of abuse, such as cocaine. Studies of conditioned place preference (CPP) demonstrate that animals approach cues previously paired with cocaine. This is a commonly used preparation, but the configuration of the CPP apparatus differs across laboratories. Two common apparatus configurations for CPP are one compartment (in which the animal has access to the entire apparatus and spatial cues are irrelevant) or two compartments (in which access is restricted to one half of the apparatus and spatial cues are relevant). We compared the effects of acquisition and extinction of cocaine-induced CPP as a function of configuration. During CPP acquisition, C57BL/6J mice received cocaine paired with one tactile floor (conditioned stimulus; CS+) and saline paired with the other (CS-). CS+ and CS- trials occurred on alternate days in one of three configurations: one-compartment (exposure to the entire apparatus during CS+ or CS-), two-compartment consistent position (exposure to CS+ or CS- in adjacent, spatially distinct compartments), or two-compartment alternating position (exposure to CS+ or CS- in adjacent compartments that alternated spatial locations across days). A stronger preference for the CS+ floor occurred in two- versus one-compartment groups, with the strongest preference observed when cocaine was paired with alternating chamber positions. In contrast, greater loss of preference occurred after extinction in a one-compartment procedure, regardless of one- or two-compartment acquisition history. These findings suggest that a two-compartment configuration facilitated acquisition but attenuated extinction of a cocaine-induced CPP. The use of different CPP configurations may distinguish the underlying substrates and relevant cues for acquisition and extinction processes in cocaine abuse.


The nonvisual illusion of self-touch: Misaligned hands and anatomical implausibility.
The self-touch illusion is elicited when the participant (with eyes closed) administers brushstrokes to a prosthetic hand while the examiner administers synchronous brushstrokes to the participant's other (receptive) hand. In three experiments we investigated the effects of misalignment on the self-touch illusion. In experiment 1 we manipulated alignment (0 degrees, 45 degrees, 90 degrees, 135 degrees, 180 degrees) of the prosthetic hand relative to the participant's receptive hand. The illusion was equally strong at 0 degrees and 45 degrees: the two conditions in which the prosthetic hand was in an anatomically plausible orientation. To investigate whether the illusion was diminished at 90 degrees (and beyond) by anatomical implausibility rather than by misalignment, in experiment 2 hand positioning was changed. The illusion was equally strong at 0 degrees, 45 degrees, and 90 degrees, but diminished at 135 degrees despite the prosthetic hand now being in an anatomically plausible orientation. Thus the illusion is diminished with misalignment of 135 degrees, irrespective of anatomical plausibility. Having demonstrated that the illusion was equally strong with the hands aligned (0 degrees) or misaligned by 45 degrees, in experiment 3 we demonstrated that participants did not detect a 45 degrees misalignment. Large degrees of misalignment prevent a compelling experience of the self-touch illusion, and the self-touch illusion prevents detection of small degrees of misalignment.


Accuracy of Measurements With the iCare HOME Rebound Tonometer.
To evaluate the accuracy of intraocular pressure (IOP) measurements obtained with the newly available iCare HOME (RTHOME) rebound tonometer compared with the iCare ONE (RTONE) tonometer and Goldmann applanation tonometry (GAT), and possible correlation with central corneal thickness (CCT). IOP measurements were obtained from 154 patients by an ophthalmologist (doc) using each of the above-mentioned tonometers. In addition, patients (pat) measured their own IOP with the RTHOME and RTONE. The means and SD of results obtained with the different tonometers were compared. Agreement between the tonometers was calculated using the Bland-Altman method. Mean IOPs for the right eyes only were 15.9±6.4 mm Hg (RTONEdoc), 15.8±6.4 mm Hg (RTONEpat), 15.0±5.9 mm Hg (RTHOMEdoc), 14.9±6.3 mm Hg (RTHOMEpat), and 15.8±4.4 mm Hg (GAT). Bland-Altman analysis revealed mean differences (bias) between RTONEdoc and RTHOMEdoc, between RTHOMEdoc and RTHOMEpat, and between RTHOMEdoc and GAT of 0.8, 0.1, and -0.8 mm Hg, respectively, with 95% limits of agreement of -3.5 to 5.2, -4.9 to 5.1, and -7.2 to 5.6 mm Hg, respectively. Linear regression of the comparisons revealed a proportional error over the range of pressures examined in the case of RTHOMEdoc versus GAT (slope=0.32, P<0.001). Considering the data from all eyes, the difference between RTHOMEdoc and GAT correlated significantly with the CCT (P=0.01). RTHOME readings correlate well with the GAT results although some limitations such as dependency of readings on CCT and increasing differences at lower and higher IOP levels need to be taken into account.


Myocardial Function during Ventilation with Lower versus Higher Positive End-Expiratory Pressure in Patients without ARDS.
The aim of this study was to investigate whether lower PEEP (positive end-expiratory pressure) had beneficial effects on myocardial function among intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) compared to higher PEEP. In this pre-planned substudy of a randomized controlled trial (RELAx), comparing lower to higher PEEP, 44 patients underwent transthoracic echocardiography. The exclusion criteria were known poor left ventricular function and severe shock requiring high dosages of norepinephrine. To create contrast, we also excluded patients who received PEEP between 2 cmH2O and 7 cmH2O in the two randomization arms of the study. The primary outcome was the right ventricular myocardial performance index (MPI), a measure of systolic and diastolic function. The secondary outcomes included systolic and diastolic function parameters. A total of 20 patients were ventilated with lower PEEP (mean ± SD, 0 ± 1 cmH2O), and 24 patients, with higher PEEP (8 ± 1 cmH2O) (mean difference, -8 cmH2O; 95% CI: -8.1 to -7.9 cmH2O; p = 0.01). The tidal volume size was low in both groups (median (IQR), 7.2 (6.3 to 8.1) versus 7.0 (5.3 to 9.1) ml/kg PBW; p = 0.97). The median right ventricular MPI was 0.32 (IQR, 0.26 to 0.39) in the lower-PEEP group versus 0.38 (0.32 to 0.41) in the higher-PEEP group; the median difference was -0.03; 95% CI: -0.11 to 0.03; p = 0.33. The other systolic and diastolic parameters were similar. In patients without ARDS ventilated with a low tidal volume, a lower PEEP had no beneficial effects on the right ventricular MPI.


Inherent variation in multiple shoe-sole test impressions.
Shoeprints left at crime scenes are seldom perfect. Many prints are distorted or contaminated by various materials. Noisy background often contributes to vagueness on the shoeprints as well. Test impressions made from the suspect's shoes in the laboratory are considered a genuine replication of the shoe-sole. This naïve attitude is far from being correct. Consecutive test impressions made in the laboratory under strict similar conditions revealed differences among the exemplars of the same sole. Some of them are minor, but some are major, and can mislead the less experienced practitioners during the comparison process. This article focuses on the inherent within source variability between controlled shoeprints made from the same shoe, as it appears on the RACs. To describe and analyze this variability, repeated test impressions were prepared, and datasets were created. Several RACs were marked on each test impression, using an expert assisting software tool (developed in the authors' lab). The variance in repeated test impressions is demonstrated and possible sources are discussed. This variance should be considered when trying to establish the degree of matching between individual characteristics.


Comparison of ice fog methods and monitoring of controlled nucleation success after freeze-drying.
Improving freeze-drying processes regarding drying time and batch homogeneity is subject of ongoing research work. In this context, controlled nucleation raised great expectations. However, practically we face some challenges, e.g. how to non-destructively monitor successfully performed controlled nucleation. The question if different controlled nucleation methods lead to comparable products, as not every method can easily be implemented in lab and production scale equipment, is also of high interest. Additionally, the optimal nucleation temperature for controlled nucleation is an open question. In our study, we addressed these challenges. We successfully evaluated frequency modulated spectroscopy as a fast and non-destructive method to monitor controlled nucleation success and batch homogeneity. We found that the better homogeneity generated by controlled nucleation during the freezing step did not sustain in the dried product. Lyophilizates produced by three different ice fog methods for controlled nucleation were characterized by comparable specific surface areas but differed in residual moisture content. To investigate the impact of the ice nucleation temperature (TN) on the resulting specific surface area, we performed controlled nucleation at -3 °C and -10 °C. We concluded that TN is not the only specific surface area determining factor and a high TN does not necessarily lead to larger pores but poses a higher risk of not-nucleating vials.


The Present Status of Global Mission Trips in Plastic Surgery Residency Programs.
The present status of global mission trips of all of the academic Plastic Surgery programs was surveyed. We aimed to provide information and guidelines for other interested programs on creating a global health elective in compliance with American Board of Plastic Surgery (ABPS) and Accreditation Council for Graduate Medical Education Residency Review Committee (ACGME/RRC) requirements. A free-response survey was sent to all of the Plastic Surgery Residency program directors inquiring about their present policy on international mission trips for residents and faculty. Questions included time spent in mission, cases performed, sponsoring organizations, and whether cases are being counted in their resident Plastic Surgery Operative Logs (PSOL). Thirty-one programs responded, with 23 programs presently sponsoring international mission trips. Thirteen programs support residents going on nonprogram-sponsored trips where the majority of these programs partner with outside organizations. Many programs do not count cases performed on mission trips as part of ACGME index case requirement. Application templates for international rotations to comply with ABPS and ACGME/RRC requirements were created to facilitate the participation of interested programs. Many Plastic Surgery Residency programs are sponsoring international mission trips for their residents; however, there is a lack of uniformity and administrative support in pursuing these humanitarian efforts. The creation of a dynamic centralized database will help interested programs and residents seek out the global health experience they desire and ensure standardization of the educational experience they obtain during these trips.


P-cadherin is a p63 target gene with a crucial role in the developing human limb bud and hair follicle.
P-cadherin is a member of the classical cadherin family that forms the transmembrane core of adherens junctions. Recently, mutations in the P-cadherin gene (CDH3) have been shown to cause two inherited diseases in humans: hypotrichosis with juvenile macular dystrophy (HJMD) and ectodermal dysplasia, ectrodactyly, macular dystrophy (EEM syndrome). The common features of both diseases are sparse hair and macular dystrophy of the retina, while only EEM syndrome shows the additional finding of split hand/foot malformation (SHFM). We identified five consanguineous Pakistani families with either HJMD or EEM syndrome, and detected pathogenic mutations in the CDH3 gene of all five families. In order to define the role of P-cadherin in hair follicle and limb development, we performed expression studies on P-cadherin in the mouse embryo, and demonstrated the predominant expression of P-cadherin not only in the hair follicle placode, but also at the apical ectodermal ridge (AER) of the limb bud. Based on the evidence that mutations in the p63 gene also result in hypotrichosis and SHFM, and that the expression patterns of p63 and P-cadherin overlap in the hair follicle placode and AER, we postulated that CDH3 could be a direct transcriptional target gene of p63. We performed promoter assays and ChIP, which revealed that p63 directly interacts with two distinct regions of the CDH3 promoter. We conclude that P-cadherin is a newly defined transcriptional target gene of p63, with a crucial role in hair follicle morphogenesis as well as the AER during limb bud outgrowth in humans, whereas it is not required for either in mice.


Environmental toxicity studies using chickens as surrogates for wildlife: effects of injection day.
Domestic chicken embryos are frequently used for avian developmental toxicity studies of polyhalogenated aromatic hydrocarbons, which are often injected into eggs with oil-based vehicles. Injection times range from immediately prior to incubation (embryonic day zero, E0) to after 4 days of incubation (E4) and beyond. Because the majority of organogenesis in chicken embryos occurs during the first 4 days of development, injection after E0 may miss critical, sensitive, developmental periods. We evaluated whether differences in the day of vehicle administration would lead to differences in standard measures of embryotoxicity. We assessed embryotoxicity using mortality, organ somatic indices, teratogenesis, and behavior in hatchling chickens developmentally exposed to a high volume (1.0 microl/g egg) of corn oil vehicle, which was injected into the airsac at E0 or E4. The E0 vehicle group had 76.5% higher overall embryo mortality, embryos died earlier in development, and hatchlings took more than two times longer to right in a righting reflex test compared to the E4 vehicle group. Other behavioral results demonstrated that hatchling chickens from the E0 vehicle group performed differently from their respective no-inject controls, whereas hatchling chickens from the E4 vehicle group did not. The bursal somatic index differed statistically by injection day and weighed 23.7% more in the E0 vehicle group than the E4 vehicle group. These results suggest that the embryonic day of contaminant injection is an important consideration, particularly when using a high volume of vehicle to evaluate developmental toxicity of a contaminant on embryo mortality or behavior.


Strengths and challenges of longitudinal non-human primate neuroimaging.
Longitudinal non-human primate neuroimaging has the potential to greatly enhance our understanding of primate brain structure and function. Here we describe its specific strengths, compared to both cross-sectional non-human primate neuroimaging and longitudinal human neuroimaging, but also its associated challenges. We elaborate on factors guiding the use of different analytical tools, subject-specific versus age-specific templates for analyses, and issues related to statistical power.


A novel natural product compound enhances cAMP-regulated chloride conductance of cells expressing CFTR[delta]F508.
Cystic fibrosis (CF) results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a chloride channel localized at the plasma membrane of diverse epithelia. The most common mutation leading to CF, Delta F508, occurs in the first nucleotide-binding domain (NBD1) of CFTR. The Delta F508 mutation disrupts protein processing, leading to a decreased level of mutant channels at the plasma membrane and reduced transepithelial chloride permeability. Partial correction of the Delta F508 molecular defect in vitro is achieved by incubation of cells with several classes of chemical chaperones, indicating that further investigation of novel small molecules is warranted as a means for producing new therapies for CF. The yeast two-hybrid assay was used to study the effect of CF-causing mutations on the ability of NBD1 to self-associate and form dimers. A yeast strain demonstrating defective growth as a result of impaired NBD1 dimerization due to Delta F508 was used as a drug discovery bioassay for the identification of plant natural product compounds restoring mutant NBD1 interaction. Active compounds were purified and the chemical structures determined. The purified compounds were tested in epithelial cells expressing CFTR Delta F508 and the resulting effect on transepithelial chloride permeability was assessed using short-circuit chloride current measurements. Wild-type NBD1 of CFTR forms homodimers in a yeast two-hybrid assay. CF-causing mutations within NBD1 that result in defective processing of CFTR (Delta F508, Delta I507, and S549R) disrupted NBD1 interaction in yeast. In contrast, a CF-causing mutation that does not impair CFTR processing (G551D) had no effect on NBD1 dimerization. Using the yeast-based assay, we identified a novel limonoid compound (TS3) that corrected the Delta F508 NBD1 dimerization defect in yeast and also increased the chloride permeability of Fisher Rat Thyroid (FRT) cells stably expressing CFTR Delta F508. The establishment of a phenotype for the Delta F508 mutation in the yeast two-hybrid system yielded a simple assay for the identification of small molecules that interact with the mutant NBD1 and restore dimerization. The natural product compound identified using the system (TS3) was found to increase chloride conductance in epithelial cells to an extent comparable to genistein, a known CFTR activator. The yeast system will thus be useful for further identification of compounds with potential for CF drug therapy.


Mobile phones modulate response patterns of human brain activity.
Mobile phones emit a pulsed high-frequency electromagnetic field (PEMF) which may penetrate the scalp and the skull. Increasingly, there is an interest in the interaction of this pulsed microwave radiation with the human brain. Our investigations show that these electromagnetic fields alter distinct aspects of the brain's electrical response to acoustic stimuli. More precisely, our results demonstrate that aspects of the induced but not the evoked brain activity during PEMF exposure can be different from those not influenced by PEMF radiation. This effect appears in higher frequency bands when subjects process task-relevant target stimuli but was not present for irrelevant standard stimuli. As the induced brain activity in higher frequency bands has been proposed to be a correlate of coherent high-frequency neuronal activity, PEMF exposure may provide means to systematically alter the pattern fluctuations in neural mass activity.


High hydrostatic pressure adaptive strategies in an obligate piezophile Pyrococcus yayanosii.
Pyrococcus yayanosii CH1, as the first and only obligate piezophilic hyperthermophilic microorganism discovered to date, extends the physical and chemical limits of life on Earth. It was isolated from the Ashadze hydrothermal vent at 4,100 m depth. Multi-omics analyses were performed to study the mechanisms used by the cell to cope with high hydrostatic pressure variations. In silico analyses showed that the P. yayanosii genome is highly adapted to its harsh environment, with a loss of aromatic amino acid biosynthesis pathways and the high constitutive expression of the energy metabolism compared with other non-obligate piezophilic Pyrococcus species. Differential proteomics and transcriptomics analyses identified key hydrostatic pressure-responsive genes involved in translation, chemotaxis, energy metabolism (hydrogenases and formate metabolism) and Clustered Regularly Interspaced Short Palindromic Repeats sequences associated with Cellular apoptosis susceptibility proteins.


An attenuated total reflection (ATR) and Raman spectroscopic investigation into the effects of chloroquine on Plasmodium falciparum-infected red blood cells.
Attenuated Total Reflection Fourier Transform Infrared (ATR-FTIR) and Raman spectroscopy were used to compare chloroquine (CQ)-treated and untreated cultured Plasmodium falciparum-infected human red blood cells (iRBCs). The studies were carried out in parallel from the same starting cultures using both spectroscopic techniques, in duplicate. ATR FTIR spectra showed modifications in the heme vibrational bands as well as increases in the CH2/CH3 stretching bands in the 3100-2800 cm(-1) region of CQ-treated iRBCs consistent with an increase in lipid content. Other changes consisted of secondary structural variations including shifts in the amide I and II modes, along with changes in RNA and carbohydrate bands. Raman microspectroscopy of single red blood cells using 532 nm revealed subtle changes in the positions and intensity of ν37 of the core size region marker band and ν4 in the pyrrole ring-stretching region between untreated and CQ-treated iRBCs. Similar patterns in the corresponding relations were also observed in the non-fundamental (overtone region) between the control and treated cells. These differences were consistent with higher levels of oxygenated hemoglobin (oxyHb) in the treated cells as shown in a Principle Component Analysis (PCA) loadings plot. The results obtained demonstrate that vibrational spectroscopic techniques can provide insight into the effect of quinolines on iRBCs and thus may assist understanding the sensitivity and resistance of new and existing anti-malarial drugs.


The effects of high-impact and resistance exercise on urinary calcium excretion.
Although physical activity is known to improve bone mineralization, it is unclear whether this occurs through altered absorption and/or excretion. The purpose of this study was to investigate the effects of a high-impact and resistance-training exercise program versus a period of restricted physical activity on urinary calcium excretion. Ten healthy, moderately active men (27.0 +/- 5.8 yr) participated in a 3-wk randomized crossover study. Participants were assigned to complete either a period of daily participation in exercise including high-impact and resistance-training activities (EX) or a period of restriction in physical activity (NE) for 7 consecutive days. After a 1-wk washout period, participants completed the opposite trial. During both phases, participants consumed four 8-oz servings of low-fat (1%) milk daily and avoided other dietary and supplemental sources of calcium. Urine was collected throughout the final 72 hr of each study phase. Urinary calcium and sodium excretions were 14.7% +/- 17.1% and 15.8% +/- 9.9% lower (p < .05), respectively, during the EX phase than the NE phase. These results occurred despite participants consuming more (p < .05) sodium during the EX phase than the NE phase. These results suggest that healthy, moderately active men excrete significantly less urinary calcium concurrent with lower sodium excretion during a week of performing high-impact and resistance-training exercises versus a week of restricted physical activity. The reduction in urinary loss of calcium might be at least partially responsible for improved bone mineralization that has been observed during periods of greater physical activity.


Single dose dipyrone for acute postoperative pain.
Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought. To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain. The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010. Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs. Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected. Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls.Over 70% of participants experienced at least 50% pain relief over 4 to 6 hours with oral dipyrone 500 mg compared to 30% with placebo in five studies (288 participants; NNT 2.4 (1.9 to 3.2)). Fewer participants needed rescue medication with dipyrone (7%) than with placebo (34%; four studies, 248 participants). There was no difference in participants experiencing at least 50% pain relief with 2.5 g intravenous dipyrone and 100 mg intravenous tramadol (70% vs 65%; two studies, 200 participants). No serious adverse events were reported. Based on very limited information, single dose dipyrone 500 mg provides good pain relief to 70% of patients. For every five individuals given dipyrone 500 mg, two would experience this level of pain relief who would not have done with placebo, and fewer would need rescue medication, over 4 to 6 hours.


A comprehensive workflow for general-purpose neural modeling with highly configurable neuromorphic hardware systems.
In this article, we present a methodological framework that meets novel requirements emerging from upcoming types of accelerated and highly configurable neuromorphic hardware systems. We describe in detail a device with 45 million programmable and dynamic synapses that is currently under development, and we sketch the conceptual challenges that arise from taking this platform into operation. More specifically, we aim at the establishment of this neuromorphic system as a flexible and neuroscientifically valuable modeling tool that can be used by non-hardware experts. We consider various functional aspects to be crucial for this purpose, and we introduce a consistent workflow with detailed descriptions of all involved modules that implement the suggested steps: The integration of the hardware interface into the simulator-independent model description language PyNN; a fully automated translation between the PyNN domain and appropriate hardware configurations; an executable specification of the future neuromorphic system that can be seamlessly integrated into this biology-to-hardware mapping process as a test bench for all software layers and possible hardware design modifications; an evaluation scheme that deploys models from a dedicated benchmark library, compares the results generated by virtual or prototype hardware devices with reference software simulations and analyzes the differences. The integration of these components into one hardware-software workflow provides an ecosystem for ongoing preparative studies that support the hardware design process and represents the basis for the maturity of the model-to-hardware mapping software. The functionality and flexibility of the latter is proven with a variety of experimental results.


Separate influences of acoustic AM and FM sensitivity on the phonological decoding skills of impaired and normal readers.
Developmental dyslexia is associated with deficits in the processing of basic auditory stimuli. Yet it is unclear how these sensory impairments might contribute to poor reading skills. This study better characterizes the relationship between phonological decoding skills, the lack of which is generally accepted to comprise the core deficit in reading disabilities, and auditory sensitivity to amplitude modulation (AM) and frequency modulation (FM). Thirty-eight adult subjects, 17 of whom had a history of developmental dyslexia, completed a battery of psychophysical measures of sensitivity to FM and AM at different modulation rates, along with a measure of pseudoword reading accuracy and standardized assessments of literacy and cognitive skills. The subjects with a history of dyslexia were significantly less sensitive than controls to 2-Hz FM and 20-Hz AM only. The absence of a significant group difference for 2-Hz AM shows that the dyslexics do not have a general deficit in detecting all slow modulations. Thresholds for detecting 2-Hz and 240-Hz FM and 20-Hz AM correlated significantly with pseudoword reading accuracy. After accounting for various cognitive skills, however, multiple regression analyses showed that detection thresholds for both 2-Hz FM and 20-Hz AM were significant and independent predictors of pseudoword reading ability in the entire sample. Thresholds for 2-Hz AM and 240-Hz FM did not explain significant additional variance in pseudoword reading skill. It is therefore possible that certain components of auditory processing of modulations are related to phonological decoding skills, whereas others are not.


Splitting the nucleus: what's wrong with the tripartite ring model?
The segregation of sister DNA molecules at mitosis involves their traction to opposite poles by microtubules attached to kinetochores. By creating tension required to stabilize kinetochore microtubules, sister chromatid cohesion has a key role in ensuring that sister kinetochores attach to microtubules with opposing polarity, a process known as biorientation. Cohesion is mediated by a cohesin complex whose Smc1, Smc3, and kleisin subunits form a tripartite ring thought to hold sister DNAs together by entrapping them (the ring model). Sister chromatid disjunction at the onset of anaphase is triggered by a thiol protease called separase whose activation, only when all chromosomes have bioriented, opens the cohesin ring by cleaving its kleisin subunit. Separase is inhibited by the binding of an inhibitory chaperone called securin whose destruction at the hands of a ubiquitin protein ligase called the anaphase-promoting complex/cyclosome (APC/C) is essential for kleisin cleavage and sister chromatid disjunction. We describe microinjection experiments showing that cohesin cleavage and Cdk1 down-regulation are sufficient to drive formation of daughter nuclei in cells arrested in metaphase due to inactivation of the APC/C and describe chemical cross-linking experiments consistent with the ring model. How sister DNAs enter the cohesin ring and are retained inside for long periods of time after the completion of DNA replication remains poorly understood.


The HvNramp5 Transporter Mediates Uptake of Cadmium and Manganese, But Not Iron.
The Natural Resistance Associated Macrophage Protein (Nramp) represents a transporter family for metal ions in all organisms. Here, we functionally characterized a member of Nramp family in barley (Hordeum vulgare), HvNramp5. This member showed different expression patterns, transport substrate specificity, and cellular localization from its close homolog in rice (Oryza sativa), OsNramp5, although HvNramp5 was also localized to the plasma membrane. HvNramp5 was mainly expressed in the roots and its expression was not affected by Cd and deficiency of Zn, Cu, and Mn, but slightly up-regulated by Fe deficiency. Spatial expression analysis showed that the expression of HvNramp5 was higher in the root tips than that in the basal root regions. Furthermore, analysis with laser microdissection revealed higher expression of HvNramp5 in the outer root cell layers. HvNramp5 showed transport activity for both Mn2+ and Cd2+, but not for Fe2+ when expressed in yeast. Immunostaining with a HvNramp5 antibody showed that this protein was localized in the root epidermal cells without polarity. Knockdown of HvNramp5 in barley resulted in a significant reduction in the seedling growth at low Mn supply, but this reduction was rescued at high Mn supply. The concentration of Mn and Cd, but not other metals including Cu, Zn, and Fe, was decreased in both the roots and shoots of knockdown lines compared with the wild-type barley. These results indicate that HvNramp5 is a transporter required for uptake of Mn and Cd, but not for Fe, and that barley has a distinct uptake system from rice.


Scaffold: a novel carrier for cell and drug delivery.
Scaffolds are implants or injects, which are used to deliver cells, drugs, and genes into the body. Different forms of polymeric scaffolds for cell/drug delivery are available: (1) a typical three-dimensional porous matrix, (2) a nanofibrous matrix, (3) a thermosensitive sol-gel transition hydrogel, and (4) a porous microsphere. A scaffold provides a suitable substrate for cell attachment, cell proliferation, differentiated function, and cell migration. Scaffold matrices can be used to achieve drug delivery with high loading and efficiency to specific sites. Biomaterials used for fabrication of scaffold may be natural polymers such as alginate, proteins, collagens, gelatin, fibrins, and albumin, or synthetic polymers such as polyvinyl alcohol and polyglycolide. Bioceramics such as hydroxyapatites and tricalcium phosphates also are used. Techniques used for fabrication of a scaffold include particulate leaching, freeze-drying, supercritical fluid technology, thermally induced phase separation, rapid prototyping, powder compaction, sol-gel, and melt moulding. These techniques allow the preparation of porous structures with regular porosity. Scaffold are used successfully in various fields of tissue engineering such as bone formation, periodontal regeneration, repair of nasal and auricular malformations, cartilage development, as artificial corneas, as heart valves, in tendon repair ,in ligament replacement, and in tumors. They also are used in joint pain inflammation, diabetes, heart disease, osteochondrogenesis, and wound dressings. Their application of late has extended to delivery of drugs and genetic materials, including plasmid DNA, at a controlled rate over a long period of time. In addition, the incorporation of drugs (i.e., inflammatory inhibitors and/or antibiotics) into scaffolds may be used to prevent infection after surgery and other disease for longer duration. Scaffold also can be used to provide adequate signals (e.g., through the use of adhesion peptides and growth factors) to the cells, to induce and maintain them in their desired differentiation stage, and to maintain their survival and growth. The present review gives a detailed account of the need for the development of scaffolds along with the materials used and techniques adopted to manufacture scaffolds for tissue engineering and for prolonged drug delivery.


Mobile phone-based interventions for smoking cessation.
Access to mobile phones continues to increase exponentially globally, outstripping access to fixed telephone lines, fixed computers and the Internet. Mobile phones are an appropriate and effective option for the delivery of smoking cessation support in some contexts. This review updates the evidence on the effectiveness of mobile phone-based smoking cessation interventions. To determine whether mobile phone-based smoking cessation interventions increase smoking cessation in people who smoke and want to quit. For the most recent update, we searched the Cochrane Tobacco Addiction Group Specialised Register in April 2015. We also searched the UK Clinical Research Network Portfolio for current projects in the UK, and the ClinicalTrials.gov register for ongoing or recently completed studies. We searched through the reference lists of identified studies and attempted to contact the authors of ongoing studies. We applied no restrictions on language or publication date. We included randomised or quasi-randomised trials. Participants were smokers of any age who wanted to quit. Studies were those examining any type of mobile phone-based intervention for smoking cessation. This included any intervention aimed at mobile phone users, based around delivery via mobile phone, and using any functions or applications that can be used or sent via a mobile phone. Review authors extracted information on risk of bias and methodological details using a standardised form. We considered participants who dropped out of the trials or were lost to follow-up to be smoking. We calculated risk ratios (RR) and 95% confidence intervals (CI) for each included study. Meta-analysis of the included studies used the Mantel-Haenszel fixed-effect method. Where meta-analysis was not possible, we presented a narrative summary and descriptive statistics. This updated search identified 12 studies with six-month smoking cessation outcomes, including seven studies completed since the previous review. The interventions were predominantly text messaging-based, although several paired text messaging with in-person visits or initial assessments. Two studies gave pre-paid mobile phones to low-income human immunodeficiency virus (HIV)-positive populations - one solely for phone counselling, the other also included text messaging. One study used text messages to link to video messages. Control programmes varied widely. Studies were pooled according to outcomes - some providing measures of continuous abstinence or repeated measures of point prevalence; others only providing 7-day point prevalence abstinence. All 12 studies pooled using their most rigorous 26-week measures of abstinence provided an RR of 1.67 (95% CI 1.46 to 1.90; I(2) = 59%). Six studies verified quitting biochemically at six months (RR 1.83; 95% CI 1.54 to 2.19). The current evidence supports a beneficial impact of mobile phone-based smoking cessation interventions on six-month cessation outcomes. While all studies were good quality, the fact that those studies with biochemical verification of quitting status demonstrated an even higher chance of quitting further supports the positive findings. However, it should be noted that most included studies were of text message interventions in high-income countries with good tobacco control policies. Therefore, caution should be taken in generalising these results outside of this type of intervention and context.


A targeted genetic association study of epithelial ovarian cancer susceptibility.
Genome-wide association studies have identified several common susceptibility alleles for epithelial ovarian cancer (EOC). To further understand EOC susceptibility, we examined previously ungenotyped candidate variants, including uncommon variants and those residing within known susceptibility loci. At nine of eleven previously published EOC susceptibility regions (2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13), novel variants were identified that were more strongly associated with risk than previously reported variants. Beyond known susceptibility regions, no variants were found to be associated with EOC risk at genome-wide statistical significance (p <5x10(-8)), nor were any significant after Bonferroni correction for 17,000 variants (p< 3x10-6). A customized genotyping array was used to assess over 17,000 variants in coding, non-coding, regulatory, and known susceptibility regions in 4,973 EOC cases and 5,640 controls from 13 independent studies. Susceptibility for EOC overall and for select histotypes was evaluated using logistic regression adjusted for age, study site, and population substructure. Given the novel variants identified within the 2q31, 3q25, 5p15, 8q21, 8q24, 10p12, 17q12, 17q21.31, and 19p13 regions, larger follow-up genotyping studies, using imputation where necessary, are needed for fine-mapping and confirmation of low frequency variants that fall below statistical significance.