Angle resolved color of bulk scattering media.
The angle resolved reflectance factor of matte samples is measured with a goniophotometer and simulated using radiative transfer theory. Both measurements and simulations display the same characteristic dependence of the reflectance factor on the observation angle. The angle resolved reflectance spectra are translated to CIELAB color coordinates and the angular color differences are found to be surprisingly large. A chromatic adaptation that is dependent on the observation angle is suggested, in which a nonabsorbing opaque medium is used as the reference white, and the angular color differences are then reduced. Furthermore, the use of an undyed paper as the reference white is evaluated. The angular lightness differences are then reduced further, but the angular differences in chroma are still large. It is suggested that smaller variations in perceived color could be explained by angle dependent chromatic adaptation and a limited sensitivity of the human visual system to changes in chroma.


Improving inpatient venous thromboembolism prophylaxis.
The number and types of inpatients given inadequate prophylaxis for venous thromboembolism (VTE) are not known; patients receive less than appropriate prophylaxis with some frequency. Initially we evaluated VTE prophylaxis at a community hospital by comparing prophylaxis patterns in adult inpatients for whom some prophylaxis was indicated. Patients were categorized as medical, general surgery, and orthopedic, then categorized as "appropriate," "suboptimal," or "none" in terms of VTE prophylaxis. After initial data collection, we performed an intervention on medical patients using a VTE risk assessment tool; a printed evaluation containing the VTE risk assessment score with related VTE prophylaxis regimens was placed in the patients' charts, after which prophylaxis patterns were compared between preintervention and postintervention medical patients. Initial data collected from 116 medical, 110 general surgery, and 72 orthopedic patients (n = 298) showed that there was a significant association between diagnosis category and level of observed appropriate VTE prophylaxis (P < 0.0001). Fifty-six medical patients (48%) received no prophylaxis, compared to 40 (36%) general surgery patients and 12 (17%) orthopedic patients. In the second phase, 74 medical patients on whom the intervention was performed were compared to 116 preintervention medical patients (n = 190). The findings showed that intervention status had a significant association with level of appropriate VTE prophylaxis (P < 0.0001). An increase in appropriate VTE prophylaxis was observed after a system-level intervention.


Gestational weight gain charts for different body mass index groups for women in Europe, North America, and Oceania.
Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4-17.4) for underweight women, 14.5 kg (11.5-17.7) for normal weight women, 13.9 kg (10.1-17.9) for overweight women, and 11.2 kg (7.0-15.7), 8.7 kg (4.3-13.4) and 6.3 kg (1.9-11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.


Disturbances of the Basic Self and Prodromal Symptoms Among Young Adolescents From the Community: A Pilot Population-Based Study.
Recent findings have provided preliminary support for the notion that basic self-disturbances (SD) are related to prodromal symptoms among nonpsychotic help-seeking adolescents. As a sizable proportion of adolescents who are at risk do not seek help, this study attempts to assess the extent to which these findings can be generalized to the entire population of adolescents who are at risk for psychosis. The concurrent relationship between SD and prodromal symptoms was explored in a sample of 100 non-help-seeking adolescents (age 13-15) from the community. SD were assessed with the Examination of Anomalous Self-Experience (EASE); prodromal symptoms and syndromes were assessed with the Structured Interview for Prodromal Syndromes (SIPS); psychosocial functioning was assessed with the "Social and Role Global Functioning Scales"; and level of distress with the Mood and Anxiety States Questionnaire (MASQ). SD significantly correlated with sub-clinical psychotic symptoms (r = .70, P < .0001). This correlation was significantly stronger than those of SD with mood symptoms and social functioning. Finally, SD was the single best concurrent predictor of prodromal symptoms and syndromes. These results provide preliminary support for the generalizability of the association between SD and prodromal symptoms for the entire population of adolescents who are clinically at high risk for psychosis. In addition, they further support the notion that this association is both specific and unique.


Mechanical properties of a collagen fibril under simulated degradation.
Collagen fibrils are a very important component in most of the connective tissue in humans. An important process associated with several physiological and pathological states is the degradation of collagen. Collagen degradation is usually mediated by enzymatic and non-enzymatic processes. In this work we use molecular dynamics simulations to study the influence of simulated degradation on the mechanical properties of the collagen fibril. We applied tensile stress to the collagen fiber at different stages of degradation. We compared the difference in the fibril mechanical priorities due the removal of enzymatic crosslink, surface degradation and volumetric degradation. As anticipated, our results indicated that, regardless of the degradation scenario, fibril mechanical properties is reduced. The type of degradation mechanism (crosslink, surface or volumetric) expressed differential effect on the change in the fibril stiffness. Our simulation results showed dramatic change in the fibril stiffness with a small amount of degradation. This suggests that the hierarchical structure of the fibril is a key component for the toughness and is very sensitive to changes in the organization of the fibril. The overall results are intended to provide a theoretical framework for the understanding the mechanical behavior of collagen fibrils under degradation.


Treacle controls the nucleolar response to rDNA breaks via TOPBP1 recruitment and ATR activation.
Induction of DNA double-strand breaks (DSBs) in ribosomal DNA (rDNA) repeats is associated with ATM-dependent repression of ribosomal RNA synthesis and large-scale reorganization of nucleolar architecture, but the signaling events that regulate these responses are largely elusive. Here we show that the nucleolar response to rDNA breaks is dependent on both ATM and ATR activity. We further demonstrate that ATM- and NBS1-dependent recruitment of TOPBP1 in the nucleoli is required for inhibition of ribosomal RNA synthesis and nucleolar segregation in response to rDNA breaks. Mechanistically, TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of the nucleolar phosphoprotein Treacle. Our data thus reveal an important cooperation between TOPBP1 and Treacle in the signaling cascade that triggers transcriptional inhibition and nucleolar segregation in response to rDNA breaks.


Identification of gene microarray expression profiles in patients with chronic graft-versus-host disease following allogeneic hematopoietic cell transplantation.
Chronic graft-versus-host disease (GVHD) results in significant morbidity and mortality, limiting the benefit of allogeneic hematopoietic cell transplantation (HCT). Peripheral blood gene expression profiling of the donor immune repertoire following HCT may provide associated genes and pathways thereby improving the pathophysiologic understanding of chronic GVHD. We profiled 70 patients and identified candidate genes that provided mechanistic insight in the biologic pathways that underlie chronic GVHD. Our data revealed that the dominant gene signature in patients with chronic GVHD represented compensatory responses that control inflammation and included the interleukin-1 decoy receptor, IL-1 receptor type II, and genes that were profibrotic and associated with the IL-4, IL-6 and IL-10 signaling pathways. In addition, we identified three genes that were important regulators of extracellular matrix. Validation of this discovery phase study will determine if the identified genes have diagnostic, prognostic or therapeutic implications.


Inhibition of calcineurin by FK506 protects against polyglutamine-huntingtin toxicity through an increase of huntingtin phosphorylation at S421.
Huntington's disease (HD) is caused by an abnormal expanded polyglutamine (polyQ) repeat in the huntingtin protein. Insulin-like growth factor-1 acting through the prosurvival kinase Akt mediates the phosphorylation of huntingtin at S421 and inhibits the toxicity of polyQ-expanded huntingtin in cell culture, suggesting that compounds enhancing phosphorylation are of therapeutic interest. However, it is not clear whether phosphorylation of S421 is crucial in vivo. Using a rat model of HD based on lentiviral-mediated expression of a polyQ-huntingtin fragment in the striatum, we demonstrate here that phosphorylation of S421 is neuroprotective in vivo. We next demonstrate that calcineurin (CaN), a calcium/calmodulin-regulated Ser/Thr protein phosphatase, dephosphorylates S421 in vitro and in cells. Inhibition of calcineurin activity, either by overexpression of the dominant-interfering form of CaN or by treatment with the specific inhibitor FK506, favors the phosphorylation of S421, restores the alteration in huntingtin S421 phosphorylation in HD neuronal cells, and prevents polyQ-mediated cell death of striatal neurons. Finally, we show that administration of FK506 to mice increases huntingtin S421 phosphorylation in brain. Collectively, these data highlight the importance of CaN in the modulation of S421 phosphorylation and suggest the potential use of CaN inhibition as a therapeutic approach to treat HD.


A molecular basis for synexin-driven, calcium-dependent membrane fusion.
Membranes of secretory vesicles fuse with each other and with plasma membranes during exocytosis in many different cell types. The probable role of calcium in the process is now widely accepted, and it is possible that at least one cytosolic mediator of calcium action is synexin. Synexin is a 47,000 Mr calcium-binding protein, initially discovered in the bovine adrenal medulla, which binds to granule membranes and to inner aspects of chromaffin cell plasma membranes. Synexin causes chromaffin granules to aggregate, and such aggregates can be caused to fuse in the additional presence of arachidonic acid. Synexin also mediates the direct fusion of liposomes and chromaffin granule ghosts. To understand better the mechanisms of membrane fusion promoted by synexin we have attempted to define the primary sequence of the protein. Our initial efforts were directed towards purification of bovine synexin in sufficient amounts to allow us to sequence tryptic peptides. However, as the project progressed we also directed our attention to human synexin, preparing peptides from this protein as well. From analysis of bovine peptides we learned that the synexin molecule might be closely related to a class of proteins including lipocortin I, calpactin (p36), endonexin II, protein II and calelectrin 67K. Complete analysis of a human synexin cDNA clone revealed strong homology with bovine synexin. The analysis also showed that synexin contained a unique, long, highly hydrophobic N-terminal leader sequence followed by a characteristic four-fold repeat homologous with those found in other members of the synexin gene family. The highly hydrophobic character of synexin seems consistent with information previously obtained that synexin is able to insert directly into the interior of bilayers prepared not only from purified phosphatidylserine but also from biological membranes. The evidence for such insertions is a dramatic increase in the capacitance of the membrane, formed at the tip of a patch pipette, when calcium-activated synexin is applied to the bilayer. Additional evidence is the fact that synexin also forms calcium-selective channels when the protein is applied to the cytosolic aspect of the plasmalemma when that side is also exposed to calcium at sub-millimolar concentrations. Thus, the synexin molecule not only enters the membrane, but also spans it. From these and other data we have developed the concept that the fusion process may involve synexin forming a 'hydrophobic bridge' between two fusing membranes. Lipid movement across this bridge may then be the material basis for final fusion.(ABSTRACT TRUNCATED AT 400 WORDS)


Duration and dosing of Proton Pump Inhibitors associated with high incidence of chronic kidney disease in population-based cohort.
Proton Pump Inhibitors (PPIs) have been associated with chronic kidney disease (CKD). Our objective was to quantify the association between PPI use and incident CKD in a population-based cohort. We used a population-based retrospective cohort, including people aged 15 years or over, between January 1, 2005 and December 31, 2012. PPI use was measured in a follow-up session by recording prescriptions. Incident CKD was defined as an estimated glomerular filtration rate < 60 ml/ min/1.73 m2 and/or urinary albumin level to creatinine level ≥ 30 mg/g, in two or more determinations over a period of at least 3 months of the follow-up. Proton Pump Inhibitor use was associated with incident CKD in analysis adjusted for different clinical variables (Hazard Ratio (HR) 1.18; 95% CI 1.04-1.51) in individuals who used PPI in the basal visit (HR 1.37; 95% CI 1.25-1.50) and in those who started to use PPI during the follow-up. High doses of PPI increased the risk of incident CKD (HR 1.92; 95%CI 1.00-6.19) for any type of exposure to PPIs (HR 2.40; 95%CI 1.65-3.46) and for individuals who used high doses throughout the follow-up. This risk of incident CKD increased after three months' exposure to PPIs, (HR1.78; 95% CI 1.39-2.25) between the third and sixth months and (HR 1.30; 95%CI 1.07-1.72) after the sixth month. PPI use is associated with a higher risk of incident CKD. This association is greater for high doses and becomes apparent after three months' exposure.


Prevailing over Adversity: Factors Counteracting the Long-Term Negative Health Influences of Social and Material Disadvantages in Youth.
Disadvantaged circumstances in youth tend to translate into poor health development. However, the fact that this is not always the case has been seen as indicative of differential resilience. The current study highlights factors outside the context of the family with the potential to counteract the long-term negative influences of social and material adversity in adolescence on general health status. This study was based on two waves of questionnaire data from the Northern Swedish Cohort. From the wave in 1981 (age 16), indicators of social and material conditions as well as factors related to school, peers, and spare time were derived. From the wave in 2008 (age 43), information about self-rated health was used. Ordinal logistic regression models (n = 908) showed that adversity in youth was associated with poorer self-rated health in midlife among men and women alike, net of health status at baseline. However, having an advantaged situation with regard to school, peers, or spare time appeared to protect against the detrimental influences of disadvantaged circumstances in the family context on subsequent health. This suggests that health-promoting interventions may benefit from focusing on contexts outside the family in their effort to strengthen processes of resilience among disadvantaged youths.


Long-term effects of neonatal hypoxia-ischemia on structural and physiological integrity of the eye and visual pathway by multimodal MRI.
Neonatal hypoxia-ischemia is a major cause of brain damage in infants and may frequently present visual impairments. Although advancements in perinatal care have increased survival, the pathogenesis of hypoxic-ischemic injury and the long-term consequences to the visual system remain unclear. We hypothesized that neonatal hypoxia-ischemia can lead to chronic, MRI-detectable structural and physiological alterations in both the eye and the brain's visual pathways. Eight Sprague-Dawley rats underwent ligation of the left common carotid artery followed by hypoxia for 2 hours at postnatal day 7. One year later, T2-weighted MRI, gadolinium-enhanced MRI, chromium-enhanced MRI, manganese-enhanced MRI, and diffusion tensor MRI (DTI) of the visual system were evaluated and compared between opposite hemispheres using a 7-Tesla scanner. Within the eyeball, systemic gadolinium administration revealed aqueous-vitreous or blood-ocular barrier leakage only in the ipsilesional left eye despite comparable aqueous humor dynamics in the anterior chamber of both eyes. Binocular intravitreal chromium injection showed compromised retinal integrity in the ipsilesional eye. Despite total loss of the ipsilesional visual cortex, both retinocollicular and retinogeniculate pathways projected from the contralesional eye toward ipsilesional visual cortex possessed stronger anterograde manganese transport and less disrupted structural integrity in DTI compared with the opposite hemispheres. High-field, multimodal MRI demonstrated in vivo the long-term structural and physiological deficits in the eye and brain's visual pathways after unilateral neonatal hypoxic-ischemic injury. The remaining retinocollicular and retinogeniculate pathways appeared to be more vulnerable to anterograde degeneration from eye injury than retrograde, transsynaptic degeneration from visual cortex injury.


8. Hereditary angioedema.
Hereditary angioedema is an episodic swelling disorder with autosomal dominant inheritance. Attacks are characterized by brawny, self-limited, nonpruritic edema of the deep dermal layers of the skin that most often involve the hands and feet. They usually begin in childhood and become more severe after puberty. Patients also have episodic attacks of severe abdominal pain caused by edema of the gastrointestinal mucosa. Swelling attacks are life threatening when they involve the airway. Estrogens exacerbate attacks, and in some patients attacks are precipitated by trauma or psychologic stress. The disease is caused by a mutation in one of the 2 copies of the gene for the plasma protein C1 inhibitor, with the product of 1 gene unable to control generation of bradykinin. Eighty-five percent of patients have low antigenic levels of C1 inhibitor, and 15% have normal levels of poorly functioning protein. Most patients have decreased plasma complement protein C4 levels. Impeded androgens and, less frequently, epsilon-aminocaproic acid are currently the mainstays of chronic treatment. These agents or fresh frozen plasma are also used for prophylaxis. At this time, acute therapy is mostly supportive. There are currently ongoing multiple trials of new therapeutic agents. In half a century, a life-threatening disease has become one that is manageable and rarely causes death.


Temperature sensitivity and cell division defects in an Escherichia coli strain with mutations in yghB and yqjA, encoding related and conserved inner membrane proteins.
Ludox density gradients were used to enrich for Escherichia coli mutants with conditional growth defects and alterations in membrane composition. A temperature-sensitive mutant named Lud135 was isolated with mutations in two related, nonessential genes: yghB and yqjA. yghB harbors a single missense mutation (G203D) and yqjA contains a nonsense mutation (W92TGA) in Lud135. Both mutations are required for the temperature-sensitive phenotype: targeted deletion of both genes in a wild-type background results in a strain with a similar phenotype and expression of either gene from a plasmid restores growth at elevated temperatures. The mutant has altered membrane phospholipid levels, with elevated levels of acidic phospholipids, when grown under permissive conditions. Growth of Lud135 under nonpermissive conditions is restored by the presence of millimolar concentrations of divalent cations Ca(2+), Ba(2+), Sr(2+), or Mg(2+) or 300 to 500 mM NaCl but not 400 mM sucrose. Microscopic analysis of Lud135 demonstrates a dramatic defect at a late stage of cell division when cells are grown under permissive conditions. yghB and yqjA belong to the conserved and widely distributed dedA gene family, for which no function has been reported. The two open reading frames encode predicted polytopic inner membrane proteins with 61% amino acid identity. It is likely that YghB and YqjA play redundant but critical roles in membrane biology that are essential for completion of cell division in E. coli.


Genomic analysis of single cells from human basal cell cancer using laser-assisted capture microscopy.
In this study, we show that direct mutational analysis of genomic DNA can be performed on single somatic cells extracted from a frozen, immunohistochemically stained tissue section using laser-assisted capture microscopy. Eighty-nine single tumor cells were separately dissected from one case of human basal cell cancer (BCC) and p53 mutations were analyzed by direct semi-automated sequencing of PCR fragments. Amplification was obtained for at least one of the two analyzed exons from approximately 50% of the single tumor cells. Identical p53 mutations were found in widely spread areas of the tumor, suggesting a clonal proliferation originating from one cell. Interestingly, comparison between results of immunohistochemistry and genetic analysis of the single cells revealed the same p53 mutations irrespective of the p53 immunoreactivity. We propose that this approach has a great potential to allow investigation of genotypic differences in single cells and more specifically to resolve important and fundamental questions determining cancer heterogeneity.


SRSF1 and PTBP1 Are trans-Acting Factors That Suppress the Formation of a CD33 Splicing Isoform Linked to Alzheimer's Disease Risk.
A single nucleotide polymorphism (SNP) in exon 2 of the CD33 gene is associated with reduced susceptibility to late-onset Alzheimer's disease (AD) and causal for elevated mRNA lacking exon 2. In contrast to full-length CD33, transcripts lacking exon 2 result in CD33 protein unable to suppress activation responses in myeloid cells, including microglia. Currently, little is known about the regulation of CD33 exon 2 splicing. Using functional genomics and proteomic approaches, we found that SRSF1 and PTBP1 act as splicing enhancers to increase CD33 exon 2 inclusion in mRNA. Binding of PTBP1 to RNA sequences proximal to the intron 1-exon 2 splice junction is altered by the SNP and represents a potential mechanism behind the SNP-genotype dependent alternative splicing. Our studies also reveal that binding of SRSF1 to the CD33 RNA is not altered by the SNP genotype. Instead, a putative SRSF1 binding sequence at the 3' end of exon 2 directs CD33 exon 2 inclusion into the mRNA, indicating that PTBP1 and SRSF1 promote full-length isoform expression through different mechanisms. Our findings shed light on molecular interactions that regulate CD33 exon 2 splicing, ultimately impacting receptor expression on the cell surface. These data aid in the understanding of CD33's regulation of microglial signaling underpinning the AD genetic associations.


In vivo suppression of hormone-refractory prostate cancer growth by inositol hexaphosphate: induction of insulin-like growth factor binding protein-3 and inhibition of vascular endothelial growth factor.
Diet composition is an important etiologic factor in prostate cancer (PCA) growth and has significant impact on clinical PCA appearance. Because inositol hexaphosphate (IP6) is a dietary phytochemical present in cereals, soy, legumes, and fiber-rich foods, we evaluated efficacy of IP6 against PCA growth and associated molecular events. DU145 cells were injected into nude mice, and animals were fed normal drinking water or 1 or 2% IP6 in drinking water for 12 weeks. Body weight, diet, water consumption, and tumor sizes were monitored. Tumors were immunohistochemically analyzed for proliferating cell nuclear antigen, terminal deoxynucleotidyl transferase-mediated nick end labeling, and CD31. Tumor-secreted insulin-like growth factor binding protein (IGFBP)-3 and vascular endothelial growth factor (VEGF) were quantified in plasma by ELISA. IP6 feeding resulted in suppression of hormone-refractory human prostate tumor growth without any adverse effect on body weight gain, diet, and water consumption during entire study. At the end of study, tumor growth inhibition by 1 and 2% IP6 feeding was 47 and 66% (P = 0.049-0.012) in terms of tumor volume/mouse and 40 and 66% (P = 0.08-0.003) in terms of tumor weight/mouse, respectively. Tumor xenografts from IP6-fed mice showed significantly (P < 0.001) decreased proliferating cell nuclear antigen-positive cells but increased apoptotic cells. Tumor-secreted IGFBP-3 levels were also increased up to 1.7-fold in IP6-fed groups. Additionally, IP6 strongly decreased tumor microvessel density and inhibited tumor-secreted VEGF levels. IP6 suppresses hormone-refractory PCA growth accompanied by inhibition of tumor cell proliferation and angiogenesis and increased apoptosis. IP6-caused increase in IGFBP-3 and decrease in VEGF might have a role in PCA growth control.


Regional diagnosis of lymphoedema and selection of sites for lymphaticovenular anastomosis using elastography.
To evaluate the use of ultrasound elastography as a basis for determining the most appropriate sites for lymphaticovenular anastomosis (LVA) for treatment of lymphoedema. Preoperative elastography and LVA were performed in 11 patients (11 legs) with leg lymphoedema, including two cases of primary oedema and nine of secondary oedema. The mean number of LVAs applied per leg was 4.4 (range 3-7). The mean reduction in the leg circumference was 91.7%, and 10 of the 11 cases (90.0%) were improved. Hardness was reduced from a mean of 1.6 before surgery to 0.9 after surgery, and improvement was also noted in 10 cases (90.9%). The severity of oedema was determined in five regions in each leg, and was classified as elastography stage (ES) 0 in 11 regions, ES1 in 23, ES2 in 15, and ES3 in six. These results demonstrate the value of ultrasound elastography for the diagnosis of early-stage lymphoedema and determination of LVA sites. This is the first report of diagnosis of lymphoedema using elastography and the findings suggest that this procedure followed by LVA could be used as a new therapeutic method for early-stage lymphoedema.


Safety and effectiveness of tacrolimus add-on therapy for rheumatoid arthritis patients without an adequate response to biological disease-modifying anti-rheumatic drugs (DMARDs): Post-marketing surveillance in Japan.
Post-marketing surveillance (PMS) was conducted to assess the safety and effectiveness of tacrolimus (TAC) add-on therapy for patients with rheumatoid arthritis (RA) and an inadequate response to biological disease-modifying anti-rheumatic drugs (DMARDs). Patients with RA from 180 medical sites across Japan were registered centrally with an electronic investigation system. The observational period was 24 weeks from the first day of TAC administration concomitantly with biological DMARDs. Safety and effectiveness populations included 624 and 566 patients, respectively. Patients were predominantly female (81.1%), with a mean age of 61.9 years. Overall, 125 adverse drug reactions (ADRs) occurred in 94 patients (15.1%), and 15 serious ADRs occurred in 11 patients (1.8%). These incidences were lower compared with previously reported incidences after TAC treatment in PMS, and all of the observed ADRs were already known. A statistically significant improvement was observed in the primary effectiveness variable of Simplified Disease Activity Index after TAC treatment; 62.7% of patients achieved remission or low disease activity at week 24. TAC is well tolerated and effective when used as an add-on to biological DMARDs in Japanese patients with RA who do not achieve an adequate response to biological DMARDs in a real-world clinical setting.


Retrospective analysis of the role and performance of family medicine versus emergency medical services in the pre-hospital management of patients with AMI in Banja Luka.
The aim of this study was to investigate the differences in pre-hospital care of patients with acute myocardial infarction between emergency medical services and family medicine. This retrospective descriptive study included patients treated for acute myocardial infarction at the University Clinical Centre of Banja Luka, in the period from 1st January to 31st December 2011. The patients were divided into two groups: patients who received a hospital referral from the family medicine service and those who received one from the emergency medical service. The majority of patients (54.8%) received pre-hospital care from emergency medical services, while in 24.8% of cases the care was provided by family medicine physicians. The analysis showed that the time that passed from the onset of symptoms to the visit to the health institution of first medical contact was shorter in the emergency medical service (p<0.001). The average time from the onset of symptoms to arrival at the family practice was 24 hours, and to the emergency service 2 hours. The patients who established their first medical contact with the emergency service reported more severe symptoms than the ones who visited a family practice over the same period of time. The severity of symptoms affected the patients' decisions to seek help in a timely manner and to choose the facility of first medical contact. Interventions to decrease delay must focus on improving public awareness of acute myocardial infarction symptoms and increasing their knowledge of the benefits of early medical contact and treatment. Continuing education of family practitioners in this field is required.


A 10-year comparison of anterior cruciate ligament reconstructions with hamstring tendon and patellar tendon autograft: a controlled, prospective trial.
There are no controlled, prospective studies comparing the 10-year outcomes of anterior cruciate ligament (ACL) reconstruction using patellar tendon (PT) and 4-strand hamstring tendon (HT) autografts. Comparable results are possible with HT and PT autografts. Cohort study; Level of evidence, 2. One hundred eighty ACL-deficient knees that met inclusion criteria underwent ACL reconstruction (90 HT autograft, 90 PT autograft) by one surgeon and were treated with an accelerated rehabilitation program. All knees were observed in a prospective fashion with subjective, objective, and radiographic evaluation at 2, 5, 7, and 10-year intervals. At 10 years, there were no differences in graft rupture rates (7/90 PT vs. 12/90 HT, P = .24). There were 20 contralateral ACL ruptures in the PT group, compared with 9 in the HT group (P = .02). In all patients, graft rupture was associated with instrumented laxity >2 mm at 2 years (P = .001). Normal or near-normal function of the knee was reported in 97% of patients in both groups. In the PT group, harvest-site symptoms (P = .001) and kneeling pain (P = .01) were more common than in the HT group. More patients reported pain with strenuous activities in PT knees than in HT knees (P = .05). Radiographic osteoarthritis was more common in PT knees than the HT-reconstructed knees (P = .04). The difference, however, was composed of patients with mild osteoarthritis. Other predictors of radiographic osteoarthritis were <90% single-legged hop test at 1 year and the need for further knee surgery. An "ideal" outcome, defined as an overall International Knee Documentation Committee grade of A or B and a radiographic grade of A at 10 years after ACL reconstruction, was associated with <3 mm of instrumented laxity at 2 years, the absence of additional surgery in the knee, and HT grafts. It is possible to obtain excellent results with both HT and PT autografts. We recommend HT reconstructions to our patients because of decreased harvest-site symptoms and radiographic osteoarthritis.


Measuring the Impact of Delayed Cerebral Ischemia on Neuropsychological Outcome After Aneurysmal Subarachnoid Hemorrhage-Protocol of a Swiss Nationwide Observational Study (MoCA-DCI Study).
The exact relationship between delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) and neuropsychological impairment remains unknown, as previous studies lacked a baseline examination after aneurysm occlusion but before the DCI-period. Neuropsychological evaluation of acutely ill patients is often applied in a busy intensive care unit (ICU), where distraction represents a bias to the obtained results. To evaluate the relationship between DCI and neuropsychological outcome after aSAH by comparing the Montreal Cognitive Assessment (MoCA) results in aSAH patients with and without DCI at 3 mo with a baseline examination before the DCI-period (part 1). To determine the reliability of the MoCA, when applied in an ICU setting (part 2). Prospective, multicenter, and observational study performed at all Swiss neurovascular centers. For part 1, n = 240 consecutive aSAH patients and for part 2, n = 50 patients with acute brain injury are recruited. Part 1: Effect size of the relationship between DCI and neuropsychological outcome (MoCA). Part 2: Reliability measures for the MoCA. The institutional review boards approved this study on July 4, 2017 under case number BASEC 2017-00103. After completion, the results will be offered to an international scientific journal for peer-reviewed publication. This study determines the exact impact of DCI on the neuropsychological outcome after aSAH, unbiased by confounding factors such as early brain injury or patient-specific characteristics. The study provides unique insights in the neuropsychological state of patients in the early period after aSAH.


The predatory behaviour of the thylacine: Tasmanian tiger or marsupial wolf?
The extinct thylacine (Thylacinus cynocephalus) and the extant grey wolf (Canis lupus) are textbook examples of convergence between marsupials and placentals. Craniodental studies confirm the thylacine's carnivorous diet, but little attention has been paid to its postcranial skeleton, which would confirm or refute rare eyewitness reports of a more ambushing predatory mode than the pack-hunting pursuit mode of wolves and other large canids. Here we show that thylacines had the elbow morphology typical of an ambush predator, and propose that the 'Tasmanian tiger' vernacular name might be more apt than the 'marsupial wolf'. The 'niche overlap hypothesis' with dingoes (Canis lupus dingo) as a main cause of thylacine extinction in mainland Australia is discussed in the light of this new information.


Toward preclinical predictive drug testing for metabolism and hepatotoxicity by using in vitro models derived from human embryonic stem cells and human cell lines - a report on the Vitrocellomics EU-project.
Drug-induced liver injury is a common reason for drug attrition in late clinical phases, and even for post-launch withdrawals. As a consequence, there is a broad consensus in the pharmaceutical industry, and within regulatory authorities, that a significant improvement of the current in vitro test methodologies for accurate assessment and prediction of such adverse effects is needed. For this purpose, appropriate in vivo-like hepatic in vitro models are necessary, in addition to novel sources of human hepatocytes. In this report, we describe recent and ongoing research toward the use of human embryonic stem cell (hESC)-derived hepatic cells, in conjunction with new and improved test methods, for evaluating drug metabolism and hepatotoxicity. Recent progress on the directed differentiation of human embryonic stem cells to the functional hepatic phenotype is reported, as well as the development and adaptation of bioreactors and toxicity assay technologies for the testing of hepatic cells. The aim of achieving a testing platform for metabolism and hepatotoxicity assessment, based on hESC-derived hepatic cells, has advanced markedly in the last 2-3 years. However, great challenges still remain, before such new test systems could be routinely used by the industry. In particular, we give an overview of results from the Vitrocellomics project (EU Framework 6) and discuss these in relation to the current state-of-the-art and the remaining difficulties, with suggestions on how to proceed before such in vitro systems can be implemented in industrial discovery and development settings and in regulatory acceptance.


Characterizing chronic pain phenotypes in multiple sclerosis: a nationwide survey study.
Chronic pain is highly prevalent in multiple sclerosis (MS). Pain heterogeneity may contribute to poor treatment outcomes. The aim of this study was to characterize pain phenotypes distributions in persons with MS and compare pain phenotypes in terms of pain intensity, frequency of chronic overlapping pain conditions, and use and analgesic effects of different classes of pain medications. Data were collected through a national web-based survey with measures of neuropathic (painDETECT) and nociplastic pain (Fibromyalgia Survey Criteria), chronic overlapping pain conditions, and pain medication use and pain relief. In a sample of N = 842 adults with chronic pain and MS, the largest proportion (41%) showed evidence of nociceptive pain, 27% had mixed neuropathic/nociplastic pain, 23% had nociplastic pain, and 9% had neuropathic pain. Nociplastic pain was associated with significantly higher pain intensity and frequency of chronic overlapping pain conditions. Across all pain types, high frequency of pain medication use along with poor-modest pain relief was reported. Cannabis use for pain was more common, and pain relief ratings were higher among those with nociplastic pain, relative to nociceptive pain. Although NSAID use was highest among those with nociplastic pain (80%), pain relief ratings for NSAIDs were highest among those with nociceptive pain. These findings underscore the need for multidimensional assessment of pain in MS with greater emphasis on the identification of pain phenotype. An improved characterization of pain as a multifaceted condition in MS could inform therapeutic approaches.


Interplay of TRIM28 and DNA methylation in controlling human endogenous retroelements.
Reverse transcription-derived sequences account for at least half of the human genome. Although these retroelements are formidable motors of evolution, they can occasionally cause disease, and accordingly are inactivated during early embryogenesis through epigenetic mechanisms. In the mouse, at least for endogenous retroviruses, important mediators of this process are the tetrapod-specific KRAB-containing zinc finger proteins (KRAB-ZFPs) and their cofactor TRIM28. The present study demonstrates that KRAB/TRIM28-mediated regulation is responsible for controlling a very broad range of human-specific endogenous retroelements (EREs) in human embryonic stem (ES) cells and that it exerts, as a consequence, a marked effect on the transcriptional dynamics of these cells. It further reveals reciprocal dependence between TRIM28 recruitment at specific families of EREs and DNA methylation. It finally points to the importance of persistent TRIM28-mediated control of ERE transcriptional impact beyond their presumed inactivation by DNA methylation.


Data management and sharing in neuroimaging: Practices and perceptions of MRI researchers.
Neuroimaging methods such as magnetic resonance imaging (MRI) involve complex data collection and analysis protocols, which necessitate the establishment of good research data management (RDM). Despite efforts within the field to address issues related to rigor and reproducibility, information about the RDM-related practices and perceptions of neuroimaging researchers remains largely anecdotal. To inform such efforts, we conducted an online survey of active MRI researchers that covered a range of RDM-related topics. Survey questions addressed the type(s) of data collected, tools used for data storage, organization, and analysis, and the degree to which practices are defined and standardized within a research group. Our results demonstrate that neuroimaging data is acquired in multifarious forms, transformed and analyzed using a wide variety of software tools, and that RDM practices and perceptions vary considerably both within and between research groups, with trainees reporting less consistency than faculty. Ratings of the maturity of RDM practices from ad-hoc to refined were relatively high during the data collection and analysis phases of a project and significantly lower during the data sharing phase. Perceptions of emerging practices including open access publishing and preregistration were largely positive, but demonstrated little adoption into current practice.


Characteristics of L-PRP preparations for treating Achilles tendon rupture within the PATH-2 study.
Platelet-rich plasma (PRP) is an autologous preparation that has been claimed to improve healing and mechanobiological properties of tendons both in vitro and in vivo. In this sub-study from the PATH-2 (PRP in Achilles Tendon Healing-2) trial, we report the cellular and growth factor content and quality of the Leukocyte-rich PRP (L-PRP) (N = 103) prepared using a standardized commercial preparation method across 19 different UK centers. Baseline whole blood cell counts (red cells, leukocyte and platelets) demonstrated that the two groups were well-matched. L-PRP analysis gave a mean platelet count of 852.6 x 109/L (SD 438.96), a mean leukocyte cell count of 15.13 x 109/L (SD 10.28) and a mean red blood cell count of 0.91 x 1012/L (SD 1.49). The activation status of the L-PRP gave either low or high expression levels of the degranulation marker CD62p before and after ex-vivo platelet activation respectively. TGF-β, VEGF, PDGF, IGF and FGFb mean concentrations were 131.92 ng/ml, 0.98 ng/ml, 55.34 ng/ml, 78.2 ng/ml and 111.0 pg/ml respectively with expected correlations with both platelet and leukocyte counts. While PATH-2 results demonstrated that there was no evidence L-PRP is effective for improving clinical outcomes at 24 weeks after Achilles tendon rupture, our findings support that the majority of L-PRP properties were within the method specification and performance.


Synthesis and Characterization of Collagen Scaffolds Reinforced by Eggshell Derived Hydroxyapatite for Tissue Engineering.
In this work, we synthesized porous nanohydroxyapatite/collagen composite scaffold (nHA-COL), which resemble extracellular matrices in bone and cartilage tissues. Nano hydroxyapatite (nHA) was successfully nucleated in to the collagen matrix using hen eggshell as calcium biogenic source. Porosity was evaluated by apparent and theoretical density measurement. Porosity of all scaffolds was in the range of 95-98%. XRD and TEM analyses show the purity and size of nucleated HA around 10 nm and selected area electron diffraction (SAED) analysis reveals the polycrystalline nature of nucleated HA. SEM analysis reveals (i) all the scaffolds have interconnected pores with an average pore diameter of 130 micron and (ii) aggregates of hydroxyapatite were strongly embedded in the collagen matrix for both composite scaffolds compared with pure collagen scaffold. EDS analysis shows the Ca/P stoichiometric ratio around 1.67 and FTIR reveals the chemical interaction between the collagen molecule and HA particles. The testing of mechanical properties evidenced that incorporation of HA resulted in up to a two-fold increase in compressive modulus with high reinforcement level (-7 kPa for 50HA-50COL) compared to pure collagen scaffold.


Effective low dosage of mepivacaine in ultrasound-guided axillary nerve block: a double-blinded, randomized clinical trial of efficacy in patients undergoing distal upper extremity surgery.
To evaluate two low-dose volumes (20 mL or 30 mL) of 1.5% mepivacaine solution used for ultrasound-guided axillary blockade for outpatients undergoing distal upper limb surgery. Prospective, double-blinded randomized study. Outpatient surgical setting of a university-affiliated hospital. 64 adult, ASA physical status 1, 2, and 3 patients, aged 28-46 years, scheduled for upper limb surgery. Patients were randomized to two groups to receive either 20 mL of 1.5% mepivacaine solution (n=31) or 30 mL of 1.5% mepivacaine solution (n=33) for ultrasound-guided axillary plexus blockade. Block duration, proportion of surgical and functional successful blocks, onset of sensory and motor blockade measured from 0 to 30 minutes following final needle extraction, total amount of preoperative sedative (midazolam), and intraoperative propofol administered were recorded. Following axillary plexus blockade, neither patient group showed any statistically significant difference in the percentage of functionally successful blockade (30 mL, 100%: 20 mL, 97%; P = 0.48), surgically successful blockade (30 mL, 100%; 20 mL, 94%; P = 0.23), cumulative sensory or motor blockade surgical time, block performance time, preoperative midazolam use, or intraoperative propofol use. Low volumes (30 mL or 20 mL) of 1.5% mepivacaine provides satisfactory anesthesia for ambulatory distal upper limb surgery with no significant difference in clinical outcomes.


Increasing human motor skill acquisition by driving theta-gamma coupling.
Skill learning is a fundamental adaptive process, but the mechanisms remain poorly understood. Some learning paradigms, particularly in the memory domain, are closely associated with gamma activity that is amplitude modulated by the phase of underlying theta activity, but whether such nested activity patterns also underpin skill learning is unknown. Here, we addressed this question by using transcranial alternating current stimulation (tACS) over sensorimotor cortex to modulate theta-gamma activity during motor skill acquisition, as an exemplar of a non-hippocampal-dependent task. We demonstrated, and then replicated, a significant improvement in skill acquisition with theta-gamma tACS, which outlasted the stimulation by an hour. Our results suggest that theta-gamma activity may be a common mechanism for learning across the brain and provides a putative novel intervention for optimizing functional improvements in response to training or therapy.


Modular Architecture and Unique Teichoic Acid Recognition Features of Choline-Binding Protein L (CbpL) Contributing to Pneumococcal Pathogenesis.
The human pathogen Streptococcus pneumoniae is decorated with a special class of surface-proteins known as choline-binding proteins (CBPs) attached to phosphorylcholine (PCho) moieties from cell-wall teichoic acids. By a combination of X-ray crystallography, NMR, molecular dynamics techniques and in vivo virulence and phagocytosis studies, we provide structural information of choline-binding protein L (CbpL) and demonstrate its impact on pneumococcal pathogenesis and immune evasion. CbpL is a very elongated three-module protein composed of (i) an Excalibur Ca2+-binding domain -reported in this work for the very first time-, (ii) an unprecedented anchorage module showing alternate disposition of canonical and non-canonical choline-binding sites that allows vine-like binding of fully-PCho-substituted teichoic acids (with two choline moieties per unit), and (iii) a Ltp_Lipoprotein domain. Our structural and infection assays indicate an important role of the whole multimodular protein allowing both to locate CbpL at specific places on the cell wall and to interact with host components in order to facilitate pneumococcal lung infection and transmigration from nasopharynx to the lungs and blood. CbpL implication in both resistance against killing by phagocytes and pneumococcal pathogenesis further postulate this surface-protein as relevant among the pathogenic arsenal of the pneumococcus.


Abnormal lipid metabolism after renal transplantation.
The evidence that lipid disorders in patients following renal transplantation play a major role in the pathogenesis of atherosclerosis and chronic renal allograft rejection is circumstantial. The high rate of clinical vascular disease and cardiovascular complications in renal transplant recipients, the high prevalence of an atherogenic dyslipidemia and the evidence from the statin regression trials in the general population suggest that lipid lowering treatment is beneficial in patients after renal transplantation. In addition, animal models and observational studies in patients have demonstrated correlations between plasma lipid levels and both acute and chronic rejection. Animal transplant models and clinical trials in heart transplant patients also suggest that statin treatment decreases the incidence of chronic rejection. However, the mechanisms behind this protective effect remain unsolved and no conclusive data exist proving that statins directly inhibit the development of chronic rejection. However, sufficient evidence exists to consider the use of these agents in the posttransplant setting for their possible effects on cardiovascular complications.


Resolving the structure of interactomes with hierarchical agglomerative clustering.
Graphs provide a natural framework for visualizing and analyzing networks of many types, including biological networks. Network clustering is a valuable approach for summarizing the structure in large networks, for predicting unobserved interactions, and for predicting functional annotations. Many current clustering algorithms suffer from a common set of limitations: poor resolution of top-level clusters; over-splitting of bottom-level clusters; requirements to pre-define the number of clusters prior to analysis; and an inability to jointly cluster over multiple interaction types. A new algorithm, Hierarchical Agglomerative Clustering (HAC), is developed for fast clustering of heterogeneous interaction networks. This algorithm uses maximum likelihood to drive the inference of a hierarchical stochastic block model for network structure. Bayesian model selection provides a principled method for collapsing the fine-structure within the smallest groups, and for identifying the top-level groups within a network. Model scores are additive over independent interaction types, providing a direct route for simultaneous analysis of multiple interaction types. In addition to inferring network structure, this algorithm generates link predictions that with cross-validation provide a quantitative assessment of performance for real-world examples. When applied to genome-scale data sets representing several organisms and interaction types, HAC provides the overall best performance in link prediction when compared with other clustering methods and with model-free graph diffusion kernels. Investigation of performance on genome-scale yeast protein interactions reveals roughly 100 top-level clusters, with a long-tailed distribution of cluster sizes. These are in turn partitioned into 1000 fine-level clusters containing 5 proteins on average, again with a long-tailed size distribution. Top-level clusters correspond to broad biological processes, whereas fine-level clusters correspond to discrete complexes. Surprisingly, link prediction based on joint clustering of physical and genetic interactions performs worse than predictions based on individual data sets, suggesting a lack of synergy in current high-throughput data.


In vitro evaluation of the ciliary beat frequency of the rat nasal epithelium using a high-speed digital imaging system.
Mucociliary clearance (MC) is an important factor in determining nasal drug absorption and the ciliary beat of ciliated epithelial cells of the nasal mucosa is the driving force of MC. However, the relationship between MC and ciliary beat frequency (CBF) is still ambiguous. The purpose of this study was to establish an evaluation method of CBF as an index of mucociliary function and examine the relationship between MC and CBF. A sequence of images of ciliary beating of an excised rat nasal septum was captured using a high-speed digital video camera. CBF (beats per second, Hz) was determined from periodic changes in the contrast value of a specific location in a sequence of images. CBF under control conditions was 8.49±0.38 Hz, which is similar to values reported for cultured human nasal epithelial cells and rat tracheal cells. β-Adrenergic and cholinergic antagonists decreased CBF, while β-adrenergic agonists and acetylcholine increased CBF. These results were similar with those observed for MC in our previous study. It was found that CBFs were significantly and linearly correlated with MC, indicating that MC is directly regulated by CBF and that this evaluation system allows the quantitative determination of nasal mucociliary function.


Implementing guidelines for venous thromboembolism prophylaxis in a large Italian teaching hospital: lights and shadows.
Venous thromboembolism (VTE) remains a serious complication in hospitalized patients, in spite of several published guidelines (GL) on its prevention. The objective of this study (part of the TRiPSS-2 project) was to evaluate the impact of a locally adapted GL, supported by a multifaceted implementation strategy, in improving VTE prophylaxis in a large teaching hospital. A before and after controlled study was used to evaluate the impact of the recommendations on the appropriateness of prophylaxis. We evaluated the medical charts of two random samples, each of 250 patients, discharged in the first semester of the years 2000 and 2002. The hospital incidence of VTE (1996-2004) was also monitored, through the discharge summaries. Among high risk patients, appropriateness of prophylaxis increased both in medical (from 25% to 41.7%, p=0.0075) and in surgical patients (from 63.7% to 97.1%, p=0.0004). A parallel sharp increase (by 6-8 times) of consumption of elastic stockings was documented. In both medical and surgical patients the incidence of VTE decreased markedly and sustainedly in 2002-2004, with an adjusted odds ratio of 0.68 (95% confidence interval: 0.62-0.75). However, the use of lower than recommended doses of heparins and the increased use of prophylaxis in low risk patients represent unsolved problems. Implementing locally adapted GL may be highly effective in improving appropriateness of prophylaxis and in reducing the incidence of VTE; however a careful evaluation of changes is recommended in order to identify unsolved problems or undesired effects.


Defect-enriched tunability of electronic and charge-carrier transport characteristics of 2D borocarbonitride (BCN) monolayers from ab initio calculations.
Development of inexpensive and efficient photo- and electro-catalysts is vital for clean energy applications. Electronic and structural properties can be tuned by the introduction of defects to achieve the desirable electrocatalytic activity. Using first-principles molecular dynamics simulations, the structural, dynamical, and electronic properties of 2D borocarbonitride (h-BCN) sheets have been investigated, highlighting how anti-site defects in B and N doped graphene significantly influence the bandgap, and thereby open up new avenues to tune the chemical behavior of the 2D sheets. In the present work, all of the monolayers investigated display direct bandgaps, which reduce from 0.99 eV to 0.24 eV with increasing number of anti-site defects. The present results for the electronic structure and findings for bandgap engineering open up applications of BCN monolayers in optoelectronic devices and solar cells. The influence of the anti-site distribution of B and N atoms on the ultra-high hole/electron mobility and conductivity is discussed based on density functional theory coupled with the Boltzmann transport equation. The BCN defect monolayer is predicted to have carrier mobilities three times higher than that of the pristine sheet. The present results demonstrate that BN doped graphene monolayers are likely to be useful in the next-generation 2D field-effect transistors.


A systematic review of the impact of the use of social networking sites on body image and disordered eating outcomes.
A large body of literature has demonstrated mass media effects on body image and disordered eating. More recently, research in this area has turned to 'new' forms of media, such as the Internet, and particularly Social Networking Sites (SNSs). A systematic search for peer-reviewed articles on SNS use and body image and eating disorders resulted in 20 studies meeting specific inclusion criteria. As a whole, these articles demonstrated that use of SNSs is associated with body image and disordered eating. Specific SNS activities, such as viewing and uploading photos and seeking negative feedback via status updates, were identified as particularly problematic. A small number of studies also addressed underlying processes and found that appearance-based social comparison mediated the relationship between SNS use and body image and eating concerns. Gender was not found to be a moderating factor. It was concluded that, although there is a good deal of correlational research supporting the maladaptive effect of SNS use on body image and disordered eating, more longitudinal and experimental studies are needed.


Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.
Psoriasis is an immune-mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. The relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis. To compare the efficacy and safety of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their efficacy and safety. For this update of the living systematic review, we updated our searches of the following databases monthly to October 2021: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation). We conducted duplicate study selection, data extraction, risk of bias assessment and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs). We assessed the certainty of NMA evidence for the two primary outcomes and all comparisons using CINeMA, as very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety). This update includes an additional 19 studies, taking the total number of included studies to 167, and randomised participants to 58,912, 67.2% men, mainly recruited from hospitals. Average age was 44.5 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (57%). We assessed a total of 20 treatments. Most (140) trials were multicentric (two to 231 centres). One-third of the studies (57/167) had high risk of bias; 23 unclear risk, and most (87) low risk. Most studies (127/167) declared funding by a pharmaceutical company, and 24 studies did not report a funding source. Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions, except anti-IL23. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23 and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents. For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 50.19, 95% CI 20.92 to 120.45), bimekizumab (RR 30.27, 95% CI 25.45 to 36.01), ixekizumab (RR 30.19, 95% CI 25.38 to 35.93), risankizumab (RR 28.75, 95% CI 24.03 to 34.39). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab, ixekizumab and risankizumab showed a higher proportion of patients reaching PASI 90 than other anti-IL17 drugs (secukinumab and brodalumab) and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab and brodalumab) and anti-IL23 drugs (risankizumab and guselkumab) except tildrakizumab showed a higher proportion of patients reaching PASI 90 than ustekinumab and three anti-TNF alpha agents (adalimumab, certolizumab and etanercept). Ustekinumab was superior to certolizumab; adalimumab and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with low- to moderate-certainty for all the comparisons (except methotrexate versus placebo, which was high-certainty). The findings therefore have to be viewed with caution. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions. Our review shows that, compared to placebo, the biologics infliximab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.5 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was low to moderate quality. More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long-term information on the safety of treatments included in this review, an evaluation of non-randomised studies and postmarketing reports from regulatory agencies is needed. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.


Heart and neural tube defects in transgenic mice overexpressing the Cx43 gap junction gene.
Transgenic mice were generated containing a cytomegaloviral promoter driven construct (CMV43) expressing the gap junction polylpeptide connexin 43. RNA and protein analysis confirmed that the transgene was being expressed. In situ hybridization analysis of embryo sections revealed that transgene expression was targeted to the dorsal neural tube and in subpopulations of neural crest cells. This expression pattern was identical to that seen in transgenic mice harboring other constructs driven by the cytomegaloviral promoter (Kothary, R., Barton, S. C., Franz, T., Norris, M. L., Hettle, S. and Surani, M. A. H. (1991) Mech. Develop. 35, 25-31; Koedood, M., Fitchel, A., Meier, P. and Mitchell, P. (1995) J. Virol. 69, 2194-2207), and corresponded to a subset of the endogenous Cx43 expression domains. Significantly, dye injection studies showed that transgene expression resulted in an increase in gap junctional communication. Though viable and fertile, these transgenic mice exhibited reduced postnatal viability. Examination of embryos at various stages of development revealed developmental perturbations consisting of cranial neural tube defects (NTD) and heart malformations. Interestingly, breeding of the CMV43 transgene into the Cx43 knockout mice extended postnatal viability of mice homozygote for the Cx43 knockout allele, indicating that the CMV43 trangsene may partially complement the Cx43 deletion. Both the Cx43 knockout and the CMV43 transgenic mice exhibit heart defects associated with malformations in the conotruncus, a region of the heart in which neural crest derivatives are known to have important roles during development. Together with our results indicating neural-crest-specific expression of the transgene in our CMV-based constructs, these observations strongly suggest a role for Cx43-mediated gap junctional communication in neural crest development. Furthermore, these observations indicate that the precise level of Cx43 function may be of critical importance in downstream events involving these migratory cell populations. As such, the CMV43 mouse may represent a powerful new model system for examining the role of extracardiac cell populations in cardiac morphogenesis and other developmental processes.


Causal attributions of dementia among Korean American immigrants.
To better understand conceptualizations of dementia, this study explored causal attributions of dementia among 209 Korean Americans, using a self-administered questionnaire in Korean. Findings show that Korean Americans endorsed various causal attributions. Factor analysis yielded 3 dimensions of their attributions including psychological, physical/environmental, and cognitive/social. Bivariate analyses showed that younger age and higher education were related to more physical/environmental attributions, and younger age was related to more cognitive/social attributions. The study provides an understanding of causal attributions of dementia that practitioners need to understand to provide culturally competent practice and highlights a need to customize public education messages by specific ethnic groups.


Histologic study of testis injury after bisphenol A exposure in mice.
The health effects of bisphenol A (BPA) have become a great concern in recent years. In this study, the reproductive toxicity of BPA was investigated. Male CD-1 mice were orally administrated with BPA (0, 100, 300 and 600 mg kg-1 body weight) for 56 consecutive days. Results showed that relative testis weight to total body weight was significantly lower in the high-dose group ( p < 0.01, p < 0.05). Microscopic examination under light and transmission electron microscopes showed disorders of spermatogenesis after BPA exposure, including rough basal lamina of seminiferous tubules and damage of tight junctions between Sertoli cells. Further study by terminal-deoxynucleoitidyl transferase-mediated nick end labelling assay showed a significant induction of apoptosis in the testis tissue of the BPA groups ( p < 0.01). Immunohistochemical study found that the expression of androgen-binding protein (ABP) was significantly decreased in BPA-treated mice ( p < 0.01). Our results indicated that impairment of the basal lamina of seminiferous tubules and tight junctions may contribute to BPA-induced cell injury. A decrease in the level of ABP could be the possible mechanism for the reproductive toxicity of BPA. These findings provided direct evidence and novel insight into the reproductive toxicity of BPA and may have implications for understanding the toxicity of other endocrine disruptors.


Calcitonin Gene-Related Peptide-Targeted Therapies for Migraine and Cluster Headache: A Review.
Calcitonin gene-related peptide (CGRP) is a signaling neuropeptide released from activated trigeminal sensory afferents in headache and facial pain disorders. There are a handful of CGRP-targeted therapies currently in phase 3 studies for migraine acute treatment or prevention. Currently, 4 monoclonal antibodies targeting either the CGRP ligand or receptor are being studied for migraine prevention: ALD403 (eptinezumab), AMG 334 (erenumab), LY2951742 (galcanezumab), and TEV-48125 (fremanezumab). Meanwhile, 1 small-molecule CGRP receptor antagonist (ubrogepant, MK-1602) is currently in phase 3 studies for the acute treatment of migraine. Two of these anti-CGRP monoclonal antibodies are in clinical trials for cluster headache prevention as well. Several other small-molecular CGRP receptor antagonists are in earlier stages of development for acute migraine treatment or prevention. In this review, we will discuss the growing body of clinical trials studying CGRP-targeted therapies for migraine and cluster headache.


Global gene expression profiling and cluster analysis in Xenopus laevis.
We have undertaken a large-scale microarray gene expression analysis using cDNAs corresponding to 21,000 Xenopus laevis ESTs. mRNAs from 37 samples, including embryos and adult organs, were profiled. Cluster analysis of embryos of different stages was carried out and revealed expected affinities between gastrulae and neurulae, as well as between advanced neurulae and tadpoles, while egg and feeding larvae were clearly separated. Cluster analysis of adult organs showed some unexpected tissue-relatedness, e.g. kidney is more related to endodermal than to mesodermal tissues and the brain is separated from other neuroectodermal derivatives. Cluster analysis of genes revealed major phases of co-ordinate gene expression between egg and adult stages. During the maternal-early embryonic phase, genes maintaining a rapidly dividing cell state are predominantly expressed (cell cycle regulators, chromatin proteins). Genes involved in protein biosynthesis are progressively induced from mid-embryogenesis onwards. The larval-adult phase is characterised by expression of genes involved in metabolism and terminal differentiation. Thirteen potential synexpression groups were identified, which encompass components of diverse molecular processes or supra-molecular structures, including chromatin, RNA processing and nucleolar function, cell cycle, respiratory chain/Krebs cycle, protein biosynthesis, endoplasmic reticulum, vesicle transport, synaptic vesicle, microtubule, intermediate filament, epithelial proteins and collagen. Data filtering identified genes with potential stage-, region- and organ-specific expression. The dataset was assembled in the iChip microarray database, , which allows user-defined queries. The study provides insights into the higher order of vertebrate gene expression, identifies synexpression groups and marker genes, and makes predictions for the biological role of numerous uncharacterized genes.


The streptococcal collagen-like protein-1 (Scl1) is a significant determinant for biofilm formation by group A Streptococcus.
Group A Streptococcus (GAS) is a human-specific pathogen responsible for a number of diseases characterized by a wide range of clinical manifestations. During host colonization GAS-cell aggregates or microcolonies are observed in tissues. GAS biofilm, which is an in vitro equivalent of tissue microcolony, has only recently been studied and little is known about the specific surface determinants that aid biofilm formation. In this study, we demonstrate that surface-associated streptococcal collagen-like protein-1 (Scl1) plays an important role in GAS biofilm formation. Biofilm formation by M1-, M3-, M28-, and M41-type GAS strains, representing an intraspecies breadth, were analyzed spectrophotometrically following crystal violet staining, and characterized using confocal and field emission scanning electron microscopy. The M41-type strain formed the most robust biofilm under static conditions, followed by M28- and M1-type strains, while the M3-type strains analyzed here did not form biofilm under the same experimental conditions. Differences in architecture and cell-surface morphology were observed in biofilms formed by the M1- and M41-wild-type strains, accompanied by varying amounts of deposited extracellular matrix and differences in cell-to-cell junctions within each biofilm. Importantly, all Scl1-negative mutants examined showed significantly decreased ability to form biofilm in vitro. Furthermore, the Scl1 protein expressed on the surface of a heterologous host, Lactococcus lactis, was sufficient to induce biofilm formation by this organism. Overall, this work (i) identifies variations in biofilm formation capacity among pathogenically different GAS strains, (ii) identifies GAS surface properties that may aid in biofilm stability and, (iii) establishes that the Scl1 surface protein is an important determinant of GAS biofilm, which is sufficient to enable biofilm formation in the heterologous host Lactococcus. In summary, the GAS surface adhesin Scl1 may have an important role in biofilm-associated pathogenicity.


Antibacterial Efficacy of Several Surgical Hand Preparation Products Used by Veterinary Students.
To compare the antibacterial efficacy of different surgical hand antisepsis protocols used by veterinary students. Prospective, randomized, controlled study. Third year veterinary students (n=45). The participants were randomly assigned to 4 of the following 12 hand preparation product/time combinations: nonabrasive hand scrub method with 4% chlorhexidine gluconate (CH); hand rub with a mixture of 30% 1-propanol and 45% 2-propanol solution (MPS), 70% 2-propanol solution (IPS), or 61% ethanol solution with 1% chlorhexidine gluconate (ES/CH), with a contact time of 1.5, 3, or 5 minutes. Antibacterial efficacy was assessed after surgical hand preparation and at the end of surgery. Log reductions of total bacterial colony forming unit (CFU)/mL and positive aerobic culture rates were compared using multivariable analysis of variance and multivariable logistic regression, respectively. After surgical hand preparation, CH and ES/CH provided significantly higher log CFU reduction and lower positive culture rate for Gram-positive and spore-forming bacteria compared to MPS and IPS. Increase in contact time did not provide significant improvement in bacterial reduction. At the end of surgery, ES/CH provided significantly higher log CFU reduction compared to IPS and lower positive culture rate for Gram-positive bacteria compared to CH, MPS, and IPS. Increase in contact time significantly improved log CFU reduction in ES/CH and MPS groups. In our population of veterinary students ES/CH hand rubs or CH scrubs were more effective in reducing bacterial CFU during surgical hand preparation than MPS or IPS.


Method for path imbalance measurement of the two-arm fiber-optic interferometer.
The path imbalance (PI) of the two-arm fiber-optic interferometric sensor is a substantial parameter; a precise value of millimeters is required. Currently the precision reflectometry and the millimeter optical time-domain reflectometry are used to measure the tiny optical path difference, but the performances of these measurements are limited from the length and the resolution of the PI. We propose a new method accomplished by interferometer to accurately measure millimeters to within a few decimeters of the PI.


Cyclic AMP-regulated AChR assembly is independent of AChR subunit phosphorylation by PKA.
Forskolin treatment of cells expressing Torpedo acetylcholine receptors leads to enhanced assembly efficiency of subunits, which correlates with increased phosphorylation of the gamma subunit. To determine the role of the two potential protein kinase A sites of the gamma subunit in receptor assembly, cell lines expressing different mutant receptors were established. Mouse fibroblast cell lines stably expressing wild-type Torpedo acetylcholine receptor alpha, beta, delta subunits plus one of three gamma subunit mutations (S353A, S354A, or S353,354A) were established to identify the protein kinase A phosphorylation sites of gamma in vivo, and to determine if increased phosphorylation of the gamma subunit leads to enhanced expression of receptors. We found that both serines (353, 354) in gamma are phosphorylated in vivo by protein kinase A, however, phosphorylation of either or both of these sites does not lead to increased assembly efficiency. We established a cell line expressing alpha, beta, and gamma(S353,354A) subunits only (no delta), and found that the presence of delta (or its phosphorylation) is also not necessary for the observed stimulation by forskolin. alpha beta gamma, alpha gamma, and beta gamma associations were stimulated by forskolin but alpha beta and alpha delta interactions were not. These data imply that the presence of gamma is necessary for forskolin action. We postulate that forskolin may stimulate acetylcholine receptor expression through a cellular protein that is involved in the folding and/or assembly of protein complexes, and that forskolin may regulate the action of such a protein through phosphorylation.


Definitive high-dose photon/proton radiotherapy for unresected mobile spine and sacral chordomas.
A retrospective review. The purpose of this study is to report the results of high-dose proton based definitive radiotherapy for unresected spinal chordomas. Spine chordoma is treated primarily by surgical resection. However, local recurrence rate is high. Adjuvant radiotherapy improves local control. In certain locations, such as high sacrum, resection may result in significant neurological dysfunction. We retrospectively reviewed 24 patients with newly diagnosed, previously untreated spinal chordomas (core biopsy only; no prior incision or resection) treated with high-dose definitive radiotherapy alone using protons and photons at our center from 1988 to 2009. Reasons for radiotherapy alone included medical inoperability (3) and concern for neurological dysfunction based on spine level (21). Median age was 69.5 years. Tumor locations included cervical (2), thoracic (1), lumbar (2), S1-S2 (17), and S3 or below (2). Median maximal tumor diameter was 6.6 cm (1.4-25.5), and median tumor volume was 198.3 cm (4.65-2061). Median total dose was 77.4 GyRBE (proton dose unit, gray relative biological effectiveness). Analysis at median follow-up of 56 months showed overall survival of 91.7% and 78.1%, chordoma specific survival of 95.7% and 81.5%, local progression free survival of 90.4% and 79.8% and metastases free survival of 86.5% and 76.3%, at 3 and 5 years respectively. Tumor volume more than 500 cm was correlated with worse overall survival. Long-term side effects included 8 sacral insufficiency fractures (none required surgical stabilization), 1 secondary malignancy, 1 foot drop, 1 erectile dysfunction, 1 perineal numbness, 2 worsening urinary/fecal incontinence, and 4 grade-2 rectal bleeding. None required new colostomy. All surviving patients remained ambulatory. These results support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected, mobile spine or sacrococcygeal chordomas.


The SURE-LET approach to image denoising.
We propose a new approach to image denoising, based on the image-domain minimization of an estimate of the mean squared error--Stein's unbiased risk estimate (SURE). Unlike most existing denoising algorithms, using the SURE makes it needless to hypothesize a statistical model for the noiseless image. A key point of our approach is that, although the (nonlinear) processing is performed in a transformed domain--typically, an undecimated discrete wavelet transform, but we also address nonorthonormal transforms--this minimization is performed in the image domain. Indeed, we demonstrate that, when the transform is a "tight" frame (an undecimated wavelet transform using orthonormal filters), separate subband minimization yields substantially worse results. In order for our approach to be viable, we add another principle, that the denoising process can be expressed as a linear combination of elementary denoising processes--linear expansion of thresholds (LET). Armed with the SURE and LET principles, we show that a denoising algorithm merely amounts to solving a linear system of equations which is obviously fast and efficient. Quite remarkably, the very competitive results obtained by performing a simple threshold (image-domain SURE optimized) on the undecimated Haar wavelet coefficients show that the SURE-LET principle has a huge potential.


Nuclear pore complex number and distribution throughout the Saccharomyces cerevisiae cell cycle by three-dimensional reconstruction from electron micrographs of nuclear envelopes.
The number of nuclear pore complexes (NPCs) in individual nuclei of the yeast Saccharomyces cerevisiae was determined by computer-aided reconstruction of entire nuclei from electron micrographs of serially sectioned cells. Nuclei of 32 haploid cells at various points in the cell cycle were modeled and found to contain between 65 and 182 NPCs. Morphological markers, such as cell shape and nuclear shape, were used to determine the cell cycle stage of the cell being examined. NPC number was correlated with cell cycle stage to reveal that the number of NPCs increases steadily, beginning in G1-phase, suggesting that NPC assembly occurs continuously throughout the cell cycle. However, accumulation of nuclear envelope observed during the cell cycle, indicated by nuclear surface area, is not continuous at the same rate, such that the density of NPCs per unit area of nuclear envelope peaks in apparent S-phase cells. Analysis of the nuclear envelope reconstructions also revealed no preferred NPC-to-NPC distance. However, NPCs were found in large clusters over regions of the nuclear envelope. Interestingly, clusters of NPCs were most pronounced in early mitotic nuclei and were found to be associated with the spindle pole bodies, but the functional significance of this association is unknown.


Pantoea ananatis Genetic Diversity Analysis Reveals Limited Genomic Diversity as Well as Accessory Genes Correlated with Onion Pathogenicity.
Pantoea ananatis is a member of the family Enterobacteriaceae and an enigmatic plant pathogen with a broad host range. Although P. ananatis strains can be aggressive on onion causing foliar necrosis and onion center rot, previous genomic analysis has shown that P. ananatis lacks the primary virulence secretion systems associated with other plant pathogens. We assessed a collection of fifty P. ananatis strains collected from Georgia over three decades to determine genetic factors that correlated with onion pathogenic potential. Previous genetic analysis studies have compared strains isolated from different hosts with varying diseases potential and isolation sources. Strains varied greatly in their pathogenic potential and aggressiveness on different cultivated Allium species like onion, leek, shallot, and chive. Using multi-locus sequence analysis (MLSA) and repetitive extragenic palindrome repeat (rep)-PCR techniques, we did not observe any correlation between onion pathogenic potential and genetic diversity among strains. Whole genome sequencing and pan-genomic analysis of a sub-set of 10 strains aided in the identification of a novel series of genetic regions, likely plasmid borne, and correlating with onion pathogenicity observed on single contigs of the genetic assemblies. We named these loci Onion Virulence Regions (OVR) A-D. The OVR loci contain genes involved in redox regulation as well as pectate lyase and rhamnogalacturonase genes. Previous studies have not identified distinct genetic loci or plasmids correlating with onion foliar pathogenicity or pathogenicity on a single host pathosystem. The lack of focus on a single host system for this phytopathgenic disease necessitates the pan-genomic analysis performed in this study.


A transient placental source of serotonin for the fetal forebrain.
Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1(-/-) (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.


Sleep: a health imperative.
Chronic sleep deficiency, defined as a state of inadequate or mistimed sleep, is a growing and underappreciated determinant of health status. Sleep deprivation contributes to a number of molecular, immune, and neural changes that play a role in disease development, independent of primary sleep disorders. These changes in biological processes in response to chronic sleep deficiency may serve as etiological factors for the development and exacerbation of cardiovascular and metabolic diseases and, ultimately, a shortened lifespan. Sleep deprivation also results in significant impairments in cognitive and motor performance which increase the risk of motor vehicle crashes and work-related injuries and fatal accidents. The American Academy of Sleep Medicine and the Sleep Research Society have developed this statement to communicate to national health stakeholders the current knowledge which ties sufficient sleep and circadian alignment in adults to health.


Selection within visual memory representations activates the oculomotor system.
Humans tend to create and maintain internal representations of the environment that help guiding actions during the everyday activities. Previous studies have shown that the oculomotor system is involved in coding and maintenance of locations in visual-spatial working memory. In these studies selection of the relevant location for maintenance in working memory took place on the screen (selecting the location of a dot presented on the screen). The present study extended these findings by showing that the oculomotor system also codes selection of location from an internal memory representation. Participants first memorized two locations and after a retention interval selected one location for further maintenance. The results show that saccade trajectories deviated away from the ultimately remembered location. Furthermore, selection of the location from the memorized representation produced sustained oculomotor preparation to it. The results show that oculomotor system is very flexible and plays an active role for coding and maintaining information selected within internal memory representations.


RNA Interference for Functional Genomics and Improvement of Cotton (Gossypium sp.).
RNA interference (RNAi), is a powerful new technology in the discovery of genetic sequence functions, and has become a valuable tool for functional genomics of cotton (Gossypium sp.). The rapid adoption of RNAi has replaced previous antisense technology. RNAi has aided in the discovery of function and biological roles of many key cotton genes involved in fiber development, fertility and somatic embryogenesis, resistance to important biotic and abiotic stresses, and oil and seed quality improvements as well as the key agronomic traits including yield and maturity. Here, we have comparatively reviewed seminal research efforts in previously used antisense approaches and currently applied breakthrough RNAi studies in cotton, analyzing developed RNAi methodologies, achievements, limitations, and future needs in functional characterizations of cotton genes. We also highlighted needed efforts in the development of RNAi-based cotton cultivars, and their safety and risk assessment, small and large-scale field trials, and commercialization.


Renal infarction due to polyarteritis nodosa in a patient with angioimmunoblastic T-cell lymphoma: a case report and a brief review of the literature.
Angioimmunoblastic T-cell lymphoma is one of the most common subtypes of peripheral T-cell lymphoma (15-20% of all cases), accounting for approximately 1-2% of all non-Hodgkin lymphomas. It often presents autoimmune phenomena including hemolytic anemia, thrombocytopenia, glomerulonephrities and circulating immune complexes. Polyarteritis nodosa is an autoimmune disease characterized by necrotizing vasculitis of medium vessels, which rarely develops in association with hematological malignant disorders. Herein we report the case of a 40-year-old man who underwent lymph node biopsy in the suspicious of sarcoidosis. On the basis of histological and immunohistochemical findings, the diagnosis of angioimmunoblastic T-cell lymphoma was performed. The patient was successfully treated with cytarabine-based regimen for 6 cycles. Three months after the initial diagnosis of angioimmunoblastic T-cell lymphoma, a whole body computed tomography showed a lesion in the lower pole of the left kidney. Renal cell carcinoma was suspected, thus a nephrectomy was carried out. The histological findings were compatible with polyarteritis nodosa. To the best of our knowledge, the association between polyarteritis nodosa and angioimmunoblastic T-cell lymphoma has been described only once. This relation may be secondary to the induction of an autoimmune phenomenon by the lymphoma with the formation of circulating immune complexes, leading to vessels walls injury. A careful evaluation is needed in the management of angioimmunoblastic T-cell lymphoma patients with signs of renal failure in order to avoid delay of treatment and organ damage.


Initial experience with a self-expanding retrievable stent for recanalization of large vessel occlusions in acute ischemic stroke.
Quicker recanalization results in better clinical outcomes in patients with acute ischemic strokes. We describe our experience with the use of a self-expanding, fully retrievable stent in acute intracranial occlusions. Patients who underwent intra-arterial procedures with a self-expanding, fully retrievable stent for acute ischemic strokes at our center in 2009 were included in this study. The primary outcome was recanalization [Thrombolysis in Myocardial Infarction (TIMI) grade 2/3] at end of procedure. Secondary endpoints were procedural interval times, incidence of vasospasm, rupture of vessels, device-related complications, groin complications, postprocedural intracerebral hemorrhage (ICH) on noncontrast CT, and all-cause mortality. Fourteen patients (mean age 62.1 years, range 34-81 years; six males) were included in the study. Sites of occlusion are as follows: M1 middle cerebral artery (MCA, n = 8), M2 MCA (n = 1), proximal basilar artery (n = 1), and distal basilar artery (n = 4). An additional device or technique was used in 9 of 14 patients prior to the use of the retrievable stent. Twelve out of 14 (85.7%) achieved TIMI 2-3 recanalization with 4 of 14 (28.6%) achieving TIMI 3. Eight of 14 (57.1%) patients had modified Rankin Scale (0-2) at 3 months or discharge. ICH on follow-up CT was noted in 28.6% (4 of 14) of patients. All-cause mortality was 2 of 14 (14.3%). Use of a novel self-expanding, fully retrievable stent resulted in fast and very high recanalization rates in acute ischemic strokes with intravascular occlusions.


Studies on the Interaction of the Histone Demethylase KDM5B with Tricarboxylic Acid Cycle Intermediates.
Methylation of lysine-4 of histone H3 (H3K4men) is an important regulatory factor in eukaryotic transcription. Removal of the transcriptionally activating H3K4 methylation is catalyzed by histone demethylases, including the Jumonji C (JmjC) KDM5 subfamily. The JmjC KDMs are Fe(II) and 2-oxoglutarate (2OG)-dependent oxygenases, some of which are associated with cancer. Altered levels of tricarboxylic acid (TCA) cycle intermediates and the associated metabolites D- and L-2-hydroxyglutarate (2HG) can cause changes in chromatin methylation status. We report comprehensive biochemical, structural and cellular studies on the interaction of TCA cycle intermediates with KDM5B, which is a current medicinal chemistry target for cancer. The tested TCA intermediates were poor or moderate KDM5B inhibitors, except for oxaloacetate and succinate, which were shown to compete for binding with 2OG. D- and L-2HG were moderate inhibitors at levels that might be relevant in cancer cells bearing isocitrate dehydrogenase mutations. Crystallographic analyses with succinate, fumarate, L-malate, oxaloacetate, pyruvate and D- and L-2HG support the kinetic studies showing competition with 2OG. An unexpected binding mode for oxaloacetate was observed in which it coordinates the active site metal via its C-4 carboxylate rather than the C-1 carboxylate/C-2 keto groups. Studies employing immunofluorescence antibody-based assays reveal no changes in H3K4me3 levels in cells ectopically overexpressing KDM5B in response to dosing with TCA cycle metabolite pro-drug esters, suggesting that the high levels of cellular 2OG may preclude inhibition. The combined results reveal the potential for KDM5B inhibition by TCA cycle intermediates, but suggest that in cells, such inhibition will normally be effectively competed by 2OG.


Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study.
We evaluated the safety and efficacy of intranasal bremelanotide in men with erectile dysfunction who did not respond to sildenafil. A total of 342 married men (28 to 59 years old) with erectile dysfunction who did not respond to sildenafil were randomly assigned to receive 10 mg bremelanotide as an intranasal spray (group 1, 172) 45 minutes to 2 hours prior to sexual stimulation, or a similar regimen of placebo (group 2, 170). Patients were asked to use at least 16 doses/attempts at home. They underwent preliminary assessment, including medical and sexual history, and self-administered International Index of Erectile Function. The efficacy of 2 treatments was assessed every 4 attempts during treatment and at the end of study, using responses to International Index of Erectile Function, and evaluation of mean intercourse satisfaction domain, mean weekly coitus episodes and adverse drug effects. Positive clinical results were seen in 51 (33.5%) patients in the bremelanotide group compared with 13 (8.5%) patients in the placebo group (p = 0.03). Patients in the bremelanotide group reported significantly greater intercourse satisfaction than those in placebo group (p = 0.03). More drug related adverse effects occurred in the bremelanotide group (p = 0.01). Bremelanotide can be an alternative treatment for erectile dysfunction with a potentially broad patient base. Further studies with different dosages and treatment regimens are necessary to draw final conclusions on the efficacy of this drug in erectile dysfunction.