Biomarker Research and Development for Coronavirus Disease 2019 (COVID-19): European Medical Research Infrastructures Call for Global Coordination.
An effective response to the coronavirus disease 2019 (COVID-19) pandemic requires a better understanding of the biology of the infection and the identification of validated biomarker profiles that would increase the availability, accuracy, and speed of COVID-19 testing. Here, we describe the strategic objectives and action lines of the European Alliance of Medical Research Infrastructures (AMRI), established to improve the research process and tackle challenges related to diagnostic tests and biomarker development. Recommendations include: the creation of a European taskforce for validation of novel diagnostic products, the definition and promotion of criteria for COVID-19 samples biobanking, the identification and validation of biomarkers as clinical endpoints for clinical trials, and the definition of immune biomarker signatures at different stages of the disease. An effective management of the COVID-19 pandemic is possible only if there is a high level of knowledge and coordination between the public and private sectors within a robust quality framework.


Strain-induced droplet retraction memory in a pickering emulsion.
We studied the deformation and relaxation of a water droplet covered with polystyrene latex particles (diameter ca. 200 nm) and embedded in an immiscible fluid after a large strain jump. We show that the presence of the solid particles at the droplet interface slows down the retraction kinetics in comparison with a pure water droplet and induces flow singularity not observed with pure water droplets. The terminal relaxation time of the retraction process, defined as the characteristic time required for the droplet to relax to its spherical equilibrium shape, increases linearly with the applied strain. This result implies a memory effect induced by the presence of solid particles at the droplet interface in a solid-stabilized or Pickering emulsion.


The Obesity-Linked Gene Nudt3 Drosophila Homolog Aps Is Associated With Insulin Signaling.
Several genome-wide association studies have linked the Nudix hydrolase family member nucleoside diphosphate-linked moiety X motif 3 (NUDT3) to obesity. However, the manner of NUDT3 involvement in obesity is unknown, and NUDT3 expression, regulation, and signaling in the central nervous system has not been studied. We performed an extensive expression analysis in mice, as well as knocked down the Drosophila NUDT3 homolog Aps in the nervous system, to determine its effect on metabolism. Detailed in situ hybridization studies in the mouse brain revealed abundant Nudt3 mRNA and protein expression throughout the brain, including reward- and feeding-related regions of the hypothalamus and amygdala, whereas Nudt3 mRNA expression was significantly up-regulated in the hypothalamus and brainstem of food-deprived mice. Knocking down Aps in the Drosophila central nervous system, or a subset of median neurosecretory cells, known as the insulin-producing cells (IPCs), induces hyperinsulinemia-like phenotypes, including a decrease in circulating trehalose levels as well as significantly decreasing all carbohydrate levels under starvation conditions. Moreover, lowering Aps IPC expression leads to a decreased ability to recruit these lipids during starvation. Also, loss of neuronal Aps expression caused a starvation susceptibility phenotype while inducing hyperphagia. Finally, the loss of IPC Aps lowered the expression of Akh, Ilp6, and Ilp3, genes known to be inhibited by insulin signaling. These results point toward a role for this gene in the regulation of insulin signaling, which could explain the robust association with obesity in humans.


How to Better Motivate Customers to Participate in the Self-Design Process: A Conceptual Model in Underlying Self-Congruence Mechanism.
The voluntary shift of responsibility from the producer to the consumer is one feature of self-design activities. Past research emphasizes the economic gains of such customer co-creation. However, the psychological mechanism underlying customer co-creation behavior is still not fully understood. Notably, the goal-driven self-congruence nature of customer co-creation is mostly ignored in the co-creation literature. The objective of this research is to firstly develop a conceptual understanding of how co-creation literature can be related to the self-congruence theory. Furthermore, this study also extends the original self-congruence theory by arguing the differential role of actual and ideal self-congruence on the relationship between self-congruence and customers' willingness to participate in the co-creation process. Two laboratory experiments were conducted to examine whether self-congruence plays a prominent role in motivating customers to participate in the self-design process. Specifically, both the actual self-congruence and ideal self-congruence are positively related to customers' willingness to participate in the self-design process is hypothesized. Moreover, it is expected that product styles and different consumption situations may strengthen the relationship between actual/ideal self-congruence and customers' willingness to participate in the self-design process. Theoretical and practical implications are also discussed.


[Are ultrasonic images in diabetics different?].
The authors evaluated the results assembled in 5397 patients where between Jan. 1 1999 and Oct. 31 2000 sonographic examinations of the abdominal cavity and retroperitoneum were made with the objective to assess whether there are any statistically significant differences of results in diabetic patients, as compared with a group without this disease. The group of patients was divided into a sub-group of 4287 patients without diabetes and a sub-group of 1100 diabetics. For statistical evaluation of the significance of differences in the incidence of the investigated parameters Fisher's exact test was used. The image of "light liver" was significantly more frequent in diabetics type 1 and 2, as compared with non-diabetics (p < 0.001). The sonographic picture, consistent with the diagnosis of cirrhosis of the liver, was at the same level of significance more frequent in non-diabetics, similarly as the incidence of haemangioma. The finding of cholecystolithiasis and the number of patients with a history of CHCE on account of cholecysolithiasis was significantly higher (p < 0.05) only in type 1 diabetics as compared with non-diabetics. The incidence of sonographic changes consistent with acalculous cholecystitis was statistically higher in both groups of diabetics (p < 0.001), as compared with non-diabetics. On examination of the pancreas only the incidence of changes consistent with acute or chronic pancreatitis was significantly higher (p < 0.05) in the group of type 2 diabetics as compared with non-diabetics. Evaluation of sonographic findings of the kidneys revealed statistically significant differences only in the higher incidence of cysts in the group of type 2 diabetics as compared with type 1 diabetics and as compared with non-diabetics (p < 0.01). The impact of the presented findings and their comparison with data reported in the literature is discussed.


The thienopyridines.
Platelet adhesion, activation, and aggregation are key processes in the pathogenesis of coronary disease. Inhibition of these processes forms the cornerstone of therapy for coronary artery disease and particularly of acute coronary syndromes (ACS). Aspirin was the only available antiplatelet therapy for over 100 years, and it improves clinical outcome in a wide range of clinical situations. However, aspirin only inhibits platelet activation mediated by thromboxane A2, allowing platelet activation to occur through innumerable other pathways. As a result, adverse ischemic events are common when aspirin alone is used for the treatment of coronary disease, including ACS, during coronary interventions (particularly during stent implantation), and following coronary vascular brachytherapy (VBT). In these clinical situations, the presence of either thrombus, deep injury to the vessel wall, or delayed vascular reendothelialization leads to intense and often prolonged platelet activation, overwhelming the relatively weak effects of aspirin. The development of the thienopyridines, a class of antiplatelet drugs that reduce adenosine diphosphate-(ADP) mediated platelet activation, has significantly improved clinical outcomes in many coronary conditions. Widespread use of ticlopidine, the first available thienopyridine, was limited by frequent side-effects, including life-threatening neutropenia and thrombotic thrombocytopenic purpura. Following the introduction of clopidogrel, a thienopyridine with an excellent safety profile, dual antiplatelet therapy with aspirin and clopidogrel has become standard therapy following coronary stent implantation and coronary VBT. In patients presenting with ACS, the addition of clopidogrel to aspirin has now been proven to reduce ischemic events. The most important limitation of dual antiplatelet therapy is the increased bleeding risk as compared with aspirin alone, particularly in patients undergoing coronary artery bypass grafting during the index hospitalization. However, for many patients with ACS, combination therapy is appropriate.


Is diabetic cardiomyopathy a specific entity?
Diabetes mellitus (DM) is characterised by hyperglycemia, insulin resistance and metabolic dysregulation leading to diastolic and systolic dysfunction in diabetes. In this review, the pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes are discussed. Changes in metabolic signalling pathways, mediators and effectors contribute to the pathogenesis of cardiac dysfunction in DM called diabetic cardiomyopathy (DC). Echocardiographic studies report on the association between DM and the presence of cardiac hypertrophy and myocardial stiffness that lead to diastolic dysfunction. More recently reported echocardiographic studies with more sensitive techniques, such as strain analysis, also observed systolic dysfunction as an early marker of DC. Depression of systolic and diastolic function is continuum and the line of separation is artificial. To conclude, according to current knowledge, DC is expected to be a common single phenotype that is caused by different pathogenetic and pathomorphological changes leading to diastolic and systolic dysfunction in diabetes.


TOM1 genes map to human chromosome 22q13.1 and mouse chromosome 8C1 and encode proteins similar to the endosomal proteins HGS and STAM.
The avian tom1 (target of myb 1) gene has been previously characterized from v-myb-transformed cells. We report here cloning of the human and mouse tom1 orthologs. Both genes are expressed ubiquitously, with the highest levels in skeletal muscle, brain, and intestines, as assessed by Northern blot and mRNA in situ hybridization. The N-terminal domain of the TOM1 protein shares similarity with HGS (hepatocyte growth factor-regulated tyrosine kinase substrate) and STAM (signal-transducing adaptor molecule), which are associated with vesicular trafficking at the endosome. A putative coiled-coil domain was also detected in the central part of the TOM1 protein. This domain structure suggests that TOM1 is another member of a family of genes implicated in the trafficking regulation of growth-factor-receptor complexes that are destined for degradation in the lysosome. We also show that a human paralog of TOM1 (TOM1-like gene 1) exists. Furthermore, we provide a transcription map over a 190-kb contig of the TOM1 region. This map includes its distal neighbors HMOX1 and MCM5 and two proximal novel genes, one of which is a HMG-box-containing gene (HMG2L1), and the other of unknown function. Using a genomic PAC clone, we demonstrate that the mouse Tom1 and Hmox1 genes are part of an as yet undescribed syntenic group between mouse chromosome 8C1 and human chromosome 22q13.1.


Association of expression of inflammatory response genes and DNA repair genes in colorectal carcinoma.
Inflammation is an important etiological factor of colorectal carcinoma and may be related to colorectal carcinoma growth and proliferation. This study aimed to verify whether the presence of chronic inflammation represented by tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 gene expression is related to hMLH1, hMSH2, hMSH6, and PMS2 gene expression and the corresponding protein levels of these genes from the DNA repair system. A total of 83 patients were operated on for curative or palliative colorectal carcinoma. Expression of the inflammatory response genes tumor necrosis factor-α, interleukin-2, interleukin-6, and interleukin-10 as well as expression of the hMLH1, hMSH2, hMSH6, and PMS2 genes of the DNA repair system (mismatch repair) and the expression levels of the corresponding mismatch repair proteins were measured in neoplastic tissue by reverse transcription polymerase chain reaction and immunohistochemistry, respectively. Associations were observed between hMSH6 mRNA expression and interleukin-2 mRNA expression (p = 0.026) as well as between hMLH1 and hMSH2 gene expression and tumor necrosis factor-α gene expression (p = 0.042). Higher tissue levels of interleukin-2 and tumor necrosis factor-α gene expression were associated with lower hMSH6, hMLH1, and hMSH2 gene expression.


[Multiple sclerosis and anti-phospholipid syndrome--one or two diseases?].
Multiple sclerosis is an autoimmune central nervous system disease that affects young adults and causes inflammation, demyelination and axonal loss. Within the common relapsing-remitting course of the disease patients develop various neurological symptoms that lead to significant disability overtime. The anti-phospholipid syndrome, similarly to multiple sclerosis, appears in young adults and is characterized by thromboembolic events and pregnancy complications. The overlay between these two diseases and the ability to correctly diagnose or differentiate between them is sometimes difficult. The current review approaches this problem and discusses whether multiple sclerosis and anti-phospholipid syndrome are actually one or two diseases.


Effect of Manual versus Robotic-Assisted Total Knee Arthroplasty on Cervical Spine Static and Dynamic Postures.
This study compared surgeon cervical (C) spine postures and repetitive motions when performing traditional manual total knee arthroplasty (MTKA) versus robotic-assisted TKA (RATKA). Surgeons wore motion trackers on T3 vertebra and the occiput anatomical landmarks to obtain postural and repetitive motion data during MTKA and RATKA performed on cadavers. We assessed (1) flexion-extension at T3 and the occiput anatomical landmarks, (2) range of motion (ROM) as the percentage of time in the flexion-extension angle, (3) repetition rate, defined as the number of the times T3 and the occiput flexion-extension angle exceeded ±10°; and (4) static posture, where T3 or occiput postures exceed 10° for more than 30 seconds. The average T3 flexion-extension angle for MTKA cases was 5-degree larger than for RATKA cases (19 ± 8 vs. 14 ± 8 degrees). The surgeons who performed MTKA cases spent 15% more time in nonneutral C-spine ROM than those who performed RATKA cases (78 ± 25 vs. 63 ± 36%, p < 0.01). The repetition rate at T3 was 4% greater for MTKA than RATKA (14 ± 5 vs. 10 ± 6 reps/min). The percentage of time spent in static T3 posture was 5% greater for overall MTKA cases than for RATKA cases (15 ± 3 vs. 10 ± 3%). In this cadaveric study, we found differences in cervical and thoracic ergonomics between manual and robotic-assisted TKA. Specifically, we found that RATKA may reduce a surgeon's ergonomic strain at both the T3 and occiput locations by reducing the time the surgeon spends in a nonneutral position.


3 Tesla MR imaging of the large endolymphatic duct and sac anomaly with audiological correlation.
Large endolymphatic duct and sac (LEDS) is one of the most common imaging abnormalities in congenital sensorineural hearing loss and is frequently seen with coexistent cochlear anomalies, especially incomplete partition type II. However, MRI findings of accompanying cochlear and especially modiolar dysplasias may be subtle. The purpose of this study is to evaluate the imaging findings of LEDS with high-resolution imaging at 3 T and correlate with the audiological data. 3 T temporal bone MRIs of 54 ears in 30 LEDS patients were retrospectively evaluated. The cochlear dysmorphism and modiolar deficiency were assessed qualitatively and quantitatively. The severity of LEDS anomaly, the signal changes within the LEDS and cochlea were also noted. The imaging findings were correlated to the audiological data. The cochlea was abnormal in 77.8% of the ears with an isolated modiolar deficiency in 11.1%. Cochlea and modiolus were completely normal in 11.1% of the ears. In 63% of the ears X-distance was increased. T2 hypointensity within LEDS and cochlea were detected in 42.6%, and 7.4% of the ears, respectively. The median diameters of LEDS were higher in ears with severe to profound HL than ears with normal to moderate HL (p < 0.05). The X-distance, presence of T2 hypointensity within LEDS, and diameters of modiolus did not show statistical correlation with the audiographic data. High-resolution 3 T imaging of patients with LEDS anomaly revealed a spectrum of cochlear anomalies, but up to 11.1% of the ears had no underlying anomaly despite severe (endolymphatic duct/sac) dilatation and/or profound HL.


Simultaneous quantification of berberine and lysergol by HPLC-UV: evidence that lysergol enhances the oral bioavailability of berberine in rats.
A sensitive and simple HPLC method was developed for the simultaneous quantification of berberine and lysergol in rat plasma. The chromatographic separation was achieved on a C(18) column using isocratic elution with methanol-acetonitrile-0.1% ortho-phosphoric acid (25:20:55, v/v/v), pH adjusted to 6.5 with triethylamine and detected at a UV wavelength of 230 nm. The extraction of the berberine and lysergol from the rat plasma with methylene chloride resulted in their high recoveries (82.62 and 90.17%). HPLC calibration curves for both berberine and lysergol based on the extracts from the rat plasma were linear over a broad concentration range of 50-1000 ng/mL. The limit of quantification was 50 ng/mL. Intra- and inter-day precisions were <15% and accuracy was 87.12-92.55% for berberine and 87.01-92.26% for lysergol. Stability studies showed that berberine and lysergol were stable in rat plasma for short- and long-term period for sample preparation and analysis. The described method was successfully applied to study the pharmacokinetics of berberine as well as lysergol following oral administration in Sprague-Dawley rats. The results of the study inferred that lysergol improved the oral bioavailability of berberine.


Design, synthesis, and biological evaluation of pyridoquinazoline derivatives as potent epidermal growth factor receptor inhibitors.
Pyridoquinazolines have been synthesized, characterized, and tested for their in vitro epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory activity. The compounds were prepared from alkylideno/arylideno-bis-ureas. Their structures were elucidated on the basis of elemental analyses and spectral studies (infrared, nuclear magnetic resonance [1H NMR], fourier transform infrared spectroscopy [FTIR], and electron ionization mass spectrometry [EI-MS]). Three of the new compounds had IC50 values in the range of 4.5-11.0 nM. The cellular EGFR internalization response of selected compounds was evaluated using HeLa cells. Three halogenated derivatives had a pronounced effect in inhibiting EGFR internalization.


Can a machine be used to replicate the biomechanics of human stabbing performance?
A human performance trial was conducted where the stabbing actions of 40 participants were investigated. A range of factors were assessed such as the action used when the blade shape and familiarity of the knife changed. A qualitative evaluation of these factors was presented in an earlier paper to precede the analysis of quantitative kinematic data in this paper. The data from participants was then compared to that obtained from a stabbing machine. A motion analysis system was used to measure parameters such as the joint angular displacement and absolute linear velocity at impact. Motion data was collected using a 12-camera Vicon MX motion analysis system. Results indicated that the mean absolute linear velocity of overarm stabbing actions was consistently higher than the underarm actions. Forensic textile damage examinations often involve testing of edged weapons by manually performing stabbing actions. An underlying fundamental limitation of manual simulation experiments is the natural variation inherent in human performance. Sufficient control measures can be implemented to successfully use manual simulation experiments in forensic testing and therefore this is the accepted practice. However, performance can be improved using a stabbing machine. A custom-built instrumental stabbing device has been shown to operate within the same parameters of the human participants and is therefore suitable for use in casework.


Might wasp venom desensitization induced Th2 to Th1 shift cause pregnancy failure?
The case of a 28-year-old woman under wasp venom desensitization having a premature birth in her 24th week of pregnancy 16 days after the last injection is described. To test the hypothesis that a special profile of immune cells in the decidua may trigger abortions, placental and decidual tissue sections were stained with antibodies against T cells (CD3), cytotoxic cells (CD8), natural killer cells (CD56), and mast cells, and an in-situ-hybridization was performed for tumor necrosis factor-alpha (TNF-alpha). CD56+ Natural killer cells were the dominating population. In earlier analyses of healthy first trimester decidua the percentage of NK cells and T cells was in a similar range, but the CD8:CD3 ratio was only 2.2% in contrast to 27% in the present case. Mast cells, which are known to be able to secrete abortogenic TNF-alpha, were only detectable in the decidua (10 cells/mm2) and decidua sections were TNF-alpha positive. Since SIT induces a shift of the interleukin and functional profile from a Th2 type towards a Th1 type, and pregnancy is dependent on a Th2 pronounced profile, SIT may trigger abortions or immature births. This is supported by the present results and might have happened in this case.


CbRCI35, a Cold Responsive Peroxidase from Capsella bursa-pastoris Regulates Reactive Oxygen Species Homeostasis and Enhances Cold Tolerance in Tobacco.
Low temperature affects gene regulatory networks and alters cellular metabolism to inhibit plant growth. Peroxidases are widely distributed in plants and play a large role in adjusting and controlling reactive oxygen species (ROS) homeostasis in response to abiotic stresses such as low temperature. The Rare Cold-Inducible 35 gene from Capsella bursa-pastoris (CbRCI35) belongs to the type III peroxidase family and has been reported to be a cold responsive gene in plants. Here we performed an expressional characterization of CbRCI35 under cold and ionic liquid treatments. The promoter of CbRCI35 was also cloned and its activity was examined using the GUS reporter system. CbRCI35 protein was localized in the cytoplasm according to sequence prediction and GFP fusion assay. Heterologous expression tests revealed that CbRCI35 conferred enhanced resistance to low temperature and activated endogenous cold responsive signaling in tobacco. Furthermore, in the normal condition the ROS accumulation was moderately enhanced while after chilling exposure superoxide dismutase activity was increased in CbRCI53 transgenic plants. The ROS metabolism related genes expression was altered accordingly. We conclude that CbRCI35 modulates ROS homeostasis and contributes to cold tolerance in plants.


Methodological quality evaluation of systematic reviews or meta-analysis of trastuzumab-based therapy for breast cancer: A systematic review.
To evaluate the methodological quality of systematic reviews (SRs) or meta-analysis of trastuzumab-based therapy for breast cancer. We searched the PubMed, EMBASE, Web of science, Cochrane library, international prospective register of systematic reviews, Chinese BioMedical Literature Database, Wan Fang, China National Knowledge Infrastructure and VIP database for SRs or meta-analysis. The methodological quality of included literatures was appraised by risk of bias in systematic review (ROBIS) tool. Twenty three eligible systematic reviews or meta-analysis were included. Only 2 systematic reviews provided protocol. The most frequently searched databases were PubMed, MEDLINE, EMBASE, and the Cochrane. The two-reviewers model described in the screening for eligible original articles, data extraction, and methodological quality evaluation had 30%, 61%, and 26%, respectively. In methodological quality assessment, 52% SRs or meta-analysis used the Jadad scoring or Cochrane reviewer' handbook. Research question were well matched to all SRs or meta-analysis in phase 1 and 35% of them evaluated "high" risk bias in study eligibility criteria. The "high" risk of bias in all non-Cochrane SRs or meta-analyses, which involve methods used to identify and/or select studies. And more than half SRs or meta-analysis had a high risk of bias in data collection and study appraisal. More than two-third of SRs or meta-analysis were accomplished with high risk of bias in the synthesis and findings. The study indicated poor methodological and reporting quality of SRs/meta-analysis assessing trastuzumab-based therapy for breast cancer. Registration or publishing the protocol and the reporting followed the PRISMA checklist are recommended in future research.


Influence of combined C-peptide and insulin administration on renal function and metabolic control in diabetes type 1.
The possible influence of C-peptide on renal function and metabolic control in patients with type 1 diabetes was examined in a double blind, randomized study. Nine patients received insulin and equimolar amounts of biosynthetic human C-peptide for 1 month (group 1), and nine were given insulin only (group 2). C-Peptide levels in plasma ranged from 0.3-2.6 nmol/L in group 1 during the study, whereas group 2 had undetectable levels. The urinary excretion of albumin in group 1 was 21 +/- 6 micrograms/min before the study and decreased by 40% and 55% after 2 and 4 weeks, respectively (P < 0.05). No change was seen in group 2. The glomerular filtration rate fell by 6% after 2 and 4 weeks (P < 0.05) in group 1, whereas no change was observed in group 2. Fluorescein leakage across the blood-retinal barrier decreased by 30% in group 1 (P < 0.05) and was unaltered in group 2. Hemoglobin-A1c and fructosamine values decreased by 9-16% in group 1 (P < 0.05), but not in group 2. The findings suggest that administration of C-peptide plus insulin, compared to insulin alone, to type 1 diabetic patients may reduce glomerular permeability and improve metabolic control.


Imaging selection in ischemic stroke: feasibility of automated CT-perfusion analysis.
Advanced imaging may refine patient selection for ischemic stroke treatment but delays to acquire and process the imaging have limited implementation. We examined the feasibility of imaging selection in clinical practice using fully automated software in the EXTEND trial program. CTP and perfusion-diffusion MRI data were processed using fully-automated software to generate a yes/no 'mismatch' classification that determined eligibility for trial therapies. The technical failure/mismatch classification error rate and time to image and treat with CT vs. MR-based selection were examined. In a consecutive series of 776 patients from five sites over six-months the technical failure rate of CTP acquisition/processing (uninterpretable maps) was 3·4% (26/776, 95%CI 2·2-4·9%). Mismatch classification was overruled by expert review in an additional 9·0% (70/776, 95%CI 7·1-11·3%) due to artifactual 'perfusion lesion'. In 154 consecutive patients at one site, median additional time to acquire CTP after non-contrast CT was 6·5 min. Subsequent RAPID processing time varied from 3-10 min across 20 trial centers (median 5 min 20 s). In the EXTEND trial, door-to-needle times in patients randomized on the basis of CTP (n = 47) were median 78 min shorter than MRI-selected (n = 16) patients (P < 0·001). Automated CTP-based mismatch selection is rapid, robust in clinical practice, and associated with faster treatment decisions than MRI. This technological advance has the potential to improve the standardization and reproducibility of interpretation of advanced imaging and extend use to practice settings beyond highly specialized academic centers.


Providers' mediating role for medication adherence among cancer survivors.
We conducted a mediation analysis of the provider team's role in changes to chronic condition medication adherence among cancer survivors. We used a retrospective, longitudinal cohort design following Medicare beneficiaries from 18-months before through 24-months following cancer diagnosis. We included beneficiaries aged ≥66 years newly diagnosed with breast, colorectal, lung or prostate cancer and using medication for non-insulin anti-diabetics, statins, and/or anti-hypertensives and similar individuals without cancer from Surveillance, Epidemiology, and End Results-Medicare data, 2008-2014. Chronic condition medication adherence was defined as a proportion of days covered ≥ 80%. Provider team structure was measured using two factors capturing the number of providers seen and the historical amount of patient sharing among providers. Linear regressions relying on within-survivor variation were run separately for each cancer site, chronic condition, and follow-up period. The number of providers and patient sharing among providers increased after cancer diagnosis relative to the non-cancer control group. Changes in provider team complexity explained only small changes in medication adherence. Provider team effects were statistically insignificant in 13 of 17 analytic samples with significant changes in adherence. Statistically significant provider team effects were small in magnitude (<0.5 percentage points). Increased complexity in the provider team associated with cancer diagnosis did not lead to meaningful reductions in medication adherence. Interventions aimed at improving chronic condition medication adherence should be targeted based on the type of cancer and chronic condition and focus on other provider, systemic, or patient factors.


Resveratrol enhances chemosensitivity of doxorubicin in multidrug-resistant human breast cancer cells via increased cellular influx of doxorubicin.
Multidrug resistance is a major problem in the treatment of breast cancer, and a number of studies have attempted to find an efficient strategy with which to overcome it. In this study, we investigate the synergistic anticancer effects of resveratrol (RSV) and doxorubicin (Dox) against human breast cancer cell lines. The synergistic effects of RSV on chemosensitivity were examined in Dox-resistant breast cancer (MCF-7/adr) and MDA-MB-231 cells. In vivo experiments were performed using a nude mouse xenograft model to investigate the combined sensitization effect of RSV and Dox. RSV markedly enhanced Dox-induced cytotoxicity in MCF-7/adr and MDA-MB-231 cells. Treatment with a combination of RSV and Dox significantly increased the cellular accumulation of Dox by down-regulating the expression levels of ATP-binding cassette (ABC) transporter genes, MDR1, and MRP1. Further in vivo experiments in the xenograft model revealed that treatment with a combination of RSV and Dox significantly inhibited tumor volume by 60%, relative to the control group. These results suggest that treatment with a combination of RSV and Dox would be a helpful strategy for increasing the efficacy of Dox by promoting an intracellular accumulation of Dox and decreasing multi-drug resistance in human breast cancer cells.


Cognitive-behavioral therapy: what benefits can it offer people with multiple sclerosis?
Cognitive-behavioral therapy (CBT) originated as a treatment for emotional disorders. However, it is increasingly used to help people with chronic illnesses manage symptoms and improve psychosocial outcomes, such as depression and quality of life. In this article, we focus on uses of CBT in patients with multiple sclerosis, an incurable neurological disease that causes potentially debilitating symptoms and poses numerous challenges to psychological well-being. We examine the rationale for using CBT to deal with distress, symptoms, impairment and disease exacerbation and progression, and discuss examples of existing research on the efficacy and acceptability of these interventions. Finally, we consider areas where CBT could potentially benefit people with multiple sclerosis in the future. Ongoing challenges in this field are discussed.


Acute graft rejection in a high-risk corneal transplant following COVID-19 vaccination: A case report.
As COVID-19 vaccination is being undertaken all over the world, its side effects are materializing slowly. One such emerging side effect is acute graft rejection in corneal transplant (CT) cases post COVID-19 vaccination. We report a case of left eye (LE) repeat penetrating keratoplasty presenting with diminished vision in LE within 2 days of COVID-19 vaccination (ChAdOx1 nCoV-19 Corona Virus Vaccine Recombinant, COVISHIELD™). The patient was diagnosed with acute graft rejection post vaccination and was treated with topical and systemic immunosuppression therapy with successful outcome in terms improvement of visual acuity and corneal graft clarity. Timely presentation, diagnosis, and management may help to survive acute rejection episodes post vaccination.


Differentiation of adenocarcinoma of the lung from mesothelioma. Periodic acid-Schiff, monoclonal antibodies B72.3, and Leu M1.
The immunohistochemical reactivity of 38 mesotheliomas and 44 adeno-carcinomas or large cell carcinomas of the lung with monoclonal antibodies (MAb) B72.3 and Leu M1 was compared with their reactivity with the routine histochemic stains periodic acid-Schiff with diastase digestion (PAS-D) and alcian blue +/- hyaluronidase. Both MAbs reacted selectively with carcinomas when a positive test was set at greater than or equal to 10% reactive tumor cells. However, MAb B72.3 reacted with significantly more of the carcinomas (86%, chi-square test, P less than 0.01) and bound to a greater percentage of tumor cells (47 +/- 28%; mean +/- SD, t-test, P less than 0.001) than Leu M1 (57% and 25 +/- 28%, respectively). The similar reactivities of surgically resected tumor specimens and post mortem tissues with both antibodies confirmed antigen stability and suggested broad clinical utility. PAS-D stained 61% of the carcinomas. Using the markers for carcinomas (PAS-D, B72.3, and Leu M1), the tumors were classified into the correct group in 80 of 82 (98%) cases (95% confidence level: greater than 92% accuracy). The alcian blue stain was useful to confirm a diagnosis of dimorphic or epithelial mesothelioma (48% were positive).


Improving the Fluorescent Probe Acridonylalanine Through a Combination of Theory and Experiment.
Acridonylalanine (Acd) is a useful fluorophore for studying proteins by fluorescence spectroscopy, but it can potentially be improved by being made longer wavelength or brighter. Here, we report the synthesis of Acd core derivatives and their photophysical characterization. We also performed ab initio calculations of the absorption and emission spectra of Acd derivatives, which agree well with experimental measurements. The amino acid aminoacridonylalanine (Aad) was synthesized in forms appropriate for genetic incorporation and peptide synthesis. We show that Aad is a superior FRET acceptor to Acd in a peptide cleavage assay, and that Aad can be activated by an aminoacyl tRNA synthetase for genetic incorporation. Together, these results show that we can use computation to design enhanced Acd derivatives which can be used in peptides and proteins.


Posturography stability score generation for stroke patient using Kinect: Fuzzy based approach.
Aim of this paper is to formulate a posturography stability score for stroke patients using fuzzy logic. Postural instability is one of the prominent symptoms of stroke, dementia, parkinsons disease, myopathy, etc. and is the major precursor of fall. Conventional scoring techniques used to assess postural stability require manual intervention and are dependent on live interaction with physiotherapist. We propose a novel scoring technique to calculate static stability of a person using posturography features acquired by Kinect sensor, which do not require any manual intervention or expert guidance, is cost effective and hence are ideal for tele rehabilitation purpose. Stability analysis is done during Single Limb Stance (SLS) exercise. Kinect sensor is used to calculate three features, naming SLS duration, vibration index, calculated from mean vibration of twenty joints and sway area of Centre of Mass (CoM). Based on the variation of these features, a fuzzy rule base is generated which calculates a static stability score. One way analysis of variance (Anova) between a group of stroke population and healthy individuals under study validates the reliability of the proposed scorer. Generated fuzzy score are comparable with standard stability scorer like Berg Balance scale and fall risk assessment tool like Johns Hopkins scale. Stability score, besides providing an index of overall stability can also be used as a fall predictability index.


Domino Prins/pinacol reaction for the stereoselective synthesis of spiro[pyran-4,4'-quinoline]-2',3'-dione derivatives.
A wide array of aldehydes undergo smooth cross-coupling with 3-hydroxy-3-(4-hydroxybut-1-en-2-yl)-1-methylindolin-2-one in the presence of 10 mol% BF3·OEt2 at 0 °C in dichloromethane to afford the corresponding 2,3,5,6-tetrahydro-1'H-spiro[pyran-4,4'-quinoline]-2',3'-dione derivatives in good yields with excellent diastereoselectivity. This is the first report on the synthesis of tetrahydro-1'H-spiro[pyran-4,4'-quinoline]-2',3'-dione scaffolds through a cascade of Prins/pinacol reactions.


Topology-Aware Non-Rigid Point Cloud Registration.
In this paper, we introduce a non-rigid registration pipeline for pairs of unorganized point clouds that may be topologically different. Standard warp field estimation algorithms, even under robust, discontinuity-preserving regularization, tend to produce erratic motion estimates on boundaries associated with 'close-to-open' topology changes. We overcome this limitation by exploiting backward motion: in the opposite motion direction, a 'close-to-open' event becomes 'open-to-close', which is by default handled correctly. At the core of our approach lies a general, topology-agnostic warp field estimation algorithm, similar to those employed in recently introduced dynamic reconstruction systems from RGB-D input. We improve motion estimation on boundaries associated with topology changes in an efficient post-processing phase. Based on both forward and (inverted) backward warp hypotheses, we explicitly detect regions of the deformed geometry that undergo topological changes by means of local deformation criteria and broadly classify them as 'contacts' or 'separations'. Subsequently, the two motion hypotheses are seamlessly blended on a local basis, according to the type and proximity of detected events. Our method achieves state-of-the-art motion estimation accuracy on the MPI Sintel dataset. Experiments on a custom dataset with topological event annotations demonstrate the effectiveness of our pipeline in estimating motion on event boundaries, as well as promising performance in explicit topological event detection.


Simulating the electrostatic guidance of the vectorial translocations in hexameric helicases and translocases.
The molecular origin of the action of helicases is explored, starting with a model built based on the different X-ray structures of the large tumor antigen (LTag) hexameric helicase and a simplified model containing the ionized phosphate backbones of a single-strand DNA. The coupling between the protein structural changes and the translocation process is quantified using an effective electrostatic free-energy surface for the protein/DNA complex. This surface is then used in Langevin dynamics simulations of the time dependence of the translocation process. Remarkably, the simulated motion along the free-energy surface results in a vectorial translocation of the DNA, consistent with the biological process. The electrostatic energy of the system appears to reproduce the directionality of this process. Thus, we are able to provide a consistent structure-based molecular description of the energetic and dynamics of the translocation process. This analysis may have general implications for relating structural models to translocation directionality in helicases and other DNA translocases.


Four Cases of Maturity Onset Diabetes of the Young (MODY) Type 5 Associated with Mutations in the Hepatocyte Nuclear Factor 1 Beta (HNF1B) Gene Presenting in a 13-Year-Old Boy and in Adult Men Aged 33, 34, and 35 Years in Poland.
BACKGROUND Maturity onset diabetes of the young (MODY) usually presents in patients under the age of 25 years and is an autosomal dominant condition associated with mutations in the hepatocyte nuclear factor 1 alpha gene, glucokinase gene, or hepatocyte nuclear factor 4 alpha gene. This report is of a series of 4 cases from Poland of MODY type 5 associated with mutations in the hepatocyte nuclear factor 1 beta (HNF1B) gene, including a 13-year-old boy and adult men aged 33, 34, and 35 years. CASE REPORT Three cases were diagnosed late, in patients in their mid-thirties. In two patients, the initial presentation was symptomatic diabetes complicated by ketoacidosis and hyperglycemic hyperosmolar state. Renal cysts were found in all patients, and pancreatic hypoplasia in 3 patients. All patients except 1 were negative for autoantibodies; 1 presented with hypomagnesemia. Insulin therapy was instituted in all cases. The combination of family history, imaging study results, and biochemical characteristics led to the decision to perform genetic analysis, which was conducted in 2 cases at diagnosis, and in the 2 remaining patients at 1 month and 2 years after diagnosis, respectively. Follow-up data revealed hypomagnesemia and/or hypermagnesuria in all patients. CONCLUSIONS We present 3 young men over 25 years and 1 boy with HNF1B-MODY. Although rare, autosomal dominant gene associations should be considered in young patients with diabetes who present with renal/pancreatic anomalies and low serum magnesium. Unusual presentation and the presence of autoantibodies should not eliminate the possibility of a HNF1B defect.


Liposome-Mediated Inhibition of Inflammation by Hydroxycitrate.
Hydroxycitrate (HCA), a main organic acid component of the fruit rind of Garcinia cambogia, is a natural citrate analog that can inhibit the ATP citrate lyase (ACLY) enzyme with a consequent reduction of inflammatory mediators (i.e., nitric oxide (NO), reactive oxygen species (ROS), and prostaglandin E2 (PGE2)) levels. Therefore, HCA has been proposed as a novel means to prevent, treat, and ameliorate conditions involving inflammation. However, HCA presents a low membrane permeability, and a large quantity is required to have a biological effect. To overcome this problem, HCA was formulated in liposomes in this work, and the enhancement of HCA cell availability along with the reduction in the amount required to downregulate NO, ROS, and PGE2 in macrophages were assessed. The liposomes were small in size (~60 nm), monodispersed, negatively charged (-50 mV), and stable on storage. The in vitro results showed that the liposomal encapsulation increased by approximately 4 times the intracellular accumulation of HCA in macrophages, and reduced by 10 times the amount of HCA required to abolish LPS-induced NO, ROS, and PGE2 increase. This suggests that liposomal HCA can be exploited to target the citrate pathway involved in inflammatory processes.


Neurosurgeon as innovator: William V. Cone (1897-1959).
Neurosurgeons are well known for being productive researchers and innovators. Few, however, have possessed the prolific ingenuity of William Cone. In 1934, he and William Penfield were cofounders of the Montreal Neurological Institute where, until 1959, he filled the twin roles of neurosurgeon-in-chief and neuropathologist. Because he did not find writing easy, many of his technical inventions and refinements remained unpublished. His numerous innovations included the extensive use of twist-drill technique for biopsy, drainage for subdural hematoma and cerebral abscess, and ventriculography. In the mid-1940's, he developed power tools driven by nitrogen that led to the modern, universally used air-driven tool systems. He had a special interest in the treatment of spinal dysfunction, for which he invented the Cone-Barton skull-traction tongs along with the Cone spinal operating table. He also devised operative procedures for vertebral fracture-dislocation and craniospinal anomalies. For the maintenance of muscle tone in the paralyzed bladder, he constructed a tidal drainage system. He introduced and popularized ventriculoperitoneal shunting techniques and carried out some of the earliest experimental trails to treat brain infections with sulphonamide and antibiotic drugs. He designed his own set of surgical suction devices, bone rongeurs, and a personal suction "air-conditioning" system for each surgeon. He had a keen early interest in intracranial tumors, and also demonstrated on monkeys how subdural mass lesions caused pupillary dilation and mesial temporal lobe damage due to cerebral compression. His work for the military during World War II on effects of altitude on brain pressure remained classified for many years. The first clipping and excision of an intracranial aneurysm is attributed to Cone. Although Penfield was known as "the Chief," Cone was referred to as "the Boss." His fervent dedication to provide total care to his patients was expressed in round-the-clock vigils; he did not separate "nursing" from "surgical" care. Ultimately, Cone's driving passion for perfection led in part to his tragic death. His accomplishments, inventions, and his example as teacher and physician have become part of neurosurgery's collective legacy.


Lorentz force optical coherence elastography.
Quantifying tissue biomechanical properties can assist in detection of abnormalities and monitoring disease progression and/or response to a therapy. Optical coherence elastography (OCE) has emerged as a promising technique for noninvasively characterizing tissue biomechanical properties. Several mechanical loading techniques have been proposed to induce static or transient deformations in tissues, but each has its own areas of applications and limitations. This study demonstrates the combination of Lorentz force excitation and phase-sensitive OCE at ?1.5??million A-lines per second to quantify the elasticity of tissue by directly imaging Lorentz force-induced elastic waves. This method of tissue excitation opens the possibility of a wide range of investigations using tissue biocurrents and conductivity for biomechanical analysis.


Synergistic effect of growth hormone and gonadotropins in achieving conception in "clonidine-negative" patients with unexplained infertility.
Based on preliminary reports by others and by us of a potentiating effect of growth hormone (GH) on human menopausal gonadotropin (hMG)-induced ovulation, a study using a randomized, prospective, cross-over protocol between GH + hMG/human chorionic gonadotropin (hCG) and hMG/hCG was undertaken. The study included patients with long-standing (2-11 years) unexplained infertility with a negative or reduced GH response to clonidine (up to 150 micrograms of clonidine orally). The first cycle was randomly assigned between GH/hMG/hCG (study cycle) and hMG/hCG alone (control cycle), and after an interval cycle the patient's treatment was crossed over. All patients who completed the study had previously undergone 1-20 attempts at ovulation induction for in vitro fertilization (IVF) and 5-40 cycles of ovulation induction for in vivo fertilization at three different medical centers. Three patients conceived on the combined GH/hMG cycle, with diminution in the hMG consumption needed for ovulation induction in the study cycles. Another patient with long-standing mechanical infertility underwent 11 abortive attempts at ovulation induction with hMG for IVF but has never achieved egg retrieval. On the GH/hMG/hCG ovulation induction cycle, three mature ova were retrieved as opposed to no response and cancellation of the "hMG only" cycle. Another patient with 11 years of primary infertility who had undergone 21 previous attempts at ovulation induction and had reached follicular aspiration in only three of those cycles conceived spontaneously on the first cycle after the GH/hMG/hCG IVF/ET cycle. All four pregnancies that have been achieved by now in seven GH/hMG-treated patients ended in cesarean deliveries of four normal male neonates. No correlation was found between the follicular fluid levels of insulin-like growth factor I (IGF-I) and the fertilization rate in vitro. The peripheral IGF-I levels were significantly higher during the follicular phase of the study cycles than during the respective stage of the control cycles or the luteal phase of either cycle. A study of serum GH-binding protein (GH-BP) levels revealed gradual increases in the late follicular phase, in the luteal phase, and in early pregnancy. On the basis of this study and in keeping with earlier reports, we conclude that the addition of GH to hMG/hCG may serve as a contributory adjunct in selected patients. However, in contrast to others who could not find a correlation between the response to acute tests for GH release and the ovarian response to combined treatment, we conclude that the clonidine test can play a discriminatory role in identifying patients who may benefit from this innovative combination.


Genomewide screen for negative regulators of sirtuin activity in Saccharomyces cerevisiae reveals 40 loci and links to metabolism.
Sirtuins are conserved proteins implicated in myriad key processes including gene control, aging, cell survival, metabolism, and DNA repair. In Saccharomyces cerevisiae, the sirtuin Silent information regulator 2 (Sir2) promotes silent chromatin formation, suppresses recombination between repeats, and inhibits senescence. We performed a genomewide screen for factors that negatively regulate Sir activity at a reporter gene placed immediately outside a silenced region. After linkage analysis, assessment of Sir dependency, and knockout tag verification, 40 loci were identified, including 20 that have not been previously described to regulate Sir. In addition to chromatin-associated factors known to prevent ectopic silencing (Bdf1, SAS-I complex, Rpd3L complex, Ku), we identified the Rtt109 DNA repair-associated histone H3 lysine 56 acetyltransferase as an anti-silencing factor. Our findings indicate that Rtt109 functions independently of its proposed effectors, the Rtt101 cullin, Mms1, and Mms22, and demonstrate unexpected interplay between H3K56 and H4K16 acetylation. The screen also identified subunits of mediator (Soh1, Srb2, and Srb5) and mRNA metabolism factors (Kem1, Ssd1), thus raising the possibility that weak silencing affects some aspect of mRNA structure. Finally, several factors connected to metabolism were identified. These include the PAS-domain metabolic sensor kinase Psk2, the mitochondrial homocysteine detoxification enzyme Lap3, and the Fe-S cluster protein maturase Isa2. We speculate that PAS kinase may integrate metabolic signals to control sirtuin activity.


Identifying pre- and postoperative predictors of cost and length of stay for coronary artery bypass surgery.
Prior studies of resource use for coronary artery bypass graft (CABG) surgery have either focused on a limited number of hospitals or have used charges instead of costs. We used a large statewide database (n = 6791) to study predictors of cost and length of stay (LOS) for CABG surgery. We used linear regression to sequentially model (a) specific procedures performed, (b) preoperative patient characteristics, and (c) postoperative events to determine the relative impact of these 3 factors on resource use. We then used the resulting models to calculate adjusted mean hospital costs and LOS. These 3 factors were all significantly associated with resource use. Postoperative events were the greatest determinant of costs, while preoperative characteristics were the greatest determinant of LOS. Despite risk adjustment for these factors, resource use differed significantly across 12 hospitals (mean cost range, $22,200 to $41,900; mean LOS range, 11 to 18 days), suggesting that some institutions may need to reduce their resource use.


[Infection of sternal wound in heart surgery: analysis of 1000 operations].
Sternal wound infection (SWI) is the most important complication in cardiac surgery. The aim of this study was to describe the frequency and clinical and microbiological features of this complication. All the cases of SWI which were observed in the authors' hospital in the first 1,000 cardiac surgery operations performed with extracorporeal circulation were retrospectively reviewed. The cases were identified through the Infectious Diseases and Cardiac Surgery Department files and were classified according to the depth of the infection. During the study period neither the prophylaxis against infection nor the surgical techniques were modified. Forty-three patients (4.3%) presented SWI. Fourteen were superficial infections and 29 were deep infections of which 9 were classified as osteomyelitis and 20 as mediastinitis. A progressive decrease was observed in the proportion of SWI over time parallel to an increase in the number of operations performed. Staphylococcus aureus was the agent most frequently isolated (60.4%). Gram-positive aerobic cocci were found in 66.7% of the total number of isolations, being most frequent in the deep infections (83.3% of the isolations). The gram-negative aerobic bacilli were isolated more frequently in the superficial infections than in the deep infections (57.8% v.s. 16.7% of the isolations, respectively p < 0.01). In patients with SWI the predictive value of the positive blood cultures for the diagnosis of mediastinitis was 83.3%, with a sensitivity of 50% and specificity of 91.3%. Three patients with deep infection developed chronic complications and another three died (mortality by mediastinitis 15.0%). The mean postoperative stay was 52 days for the patients with deep infection and 39 days for those with superficial infection (p = NS). The percentage of surgical wound infection during the study period showed a trend to a decrease parallel with an increase in the number of operations. The gram-positive bacteria were responsible for most of the SWI. Although the depth of SWI is difficult to clinically predict, the presence of bacteremia suggests the existence of mediastinitis. Despite their lesser clinical importance, the superficial infections carry a long postoperative stay.


Physiological stress reactivity and recovery: Some laboratory results transfer to daily life.
Stress is a prevalent theme in our daily lives and is related to numerous negative health outcomes. Laboratory research has studied the physiological stress response extensively with objective measures such as vagally-mediated heart rate variability (vmHRV). Recently, the vagal tank theory emerged as a promising approach to predicting adaptive vmHRV levels around stressful events. This study aimed to investigate whether the predictions of the vagal tank theory about vmHRV during stress reactivity and recovery translate into naturalistic stressful events in daily life. Sixty-seven students wore an EcgMove 4 sensor for 4 days to measure vmHRV. Through a combination of device-based and self-report assessment, vmHRV data were segmented into before, during, and after stressful events. VmHRV segments were analyzed with multilevel modeling, accounting for physiological and psychological covariates. VmHRV before stressful events predicted more adaptive vmHRV during the event but not vmHRV recovery afterwards. The results therefore partially support the vagal tank theory's predictions with data from daily life and allow recommendations for future studies of real-world stress reactivity and recovery. The value of intraindividual variations in vmHRV as predictors of adaptive stress response is underscored by these findings and could inform future interventions that seek to increase momentary vmHRV.


Efficient silver-catalyzed direct sulfenylation and selenylation of rich arenes.
An efficient protocol for silver/copper-cocatalyzed direct sulfenylation and selenylation of arenes with aryl disulfides and diselenides has been developed. This strategy exhibits excellent functional group tolerance and high regioselectivity. Mono sulfenylation and selenylation products can be exclusively achieved. This reaction provides a simple and practical route to the preparation of aryl sulfides and selenides.


Genetic analysis of disease resilience of wean-to-finish pigs under a natural disease challenge model using reaction norms.
Disease resilience is the ability to maintain performance across environments with different disease challenge loads (CL). A reaction norm describes the phenotypes that a genotype can produce across a range of environments and can be implemented using random regression models. The objectives of this study were to: (1) develop measures of CL using growth rate and clinical disease data recorded under a natural polymicrobial disease challenge model; and (2) quantify genetic variation in disease resilience using reaction norm models. Different CL were derived from contemporary group effect estimates for average daily gain (ADG) and clinical disease phenotypes, including medical treatment rate (TRT), mortality rate, and subjective health scores. Resulting CL were then used as environmental covariates in reaction norm analyses of ADG and TRT in the challenge nursery and finisher, and compared using model loglikelihoods and estimates of genetic variance associated with CL. Linear and cubic spline reaction norm models were compared based on goodness-of-fit and with multi-variate analyses, for which phenotypes were separated into three traits based on low, medium, or high CL. Based on model likelihoods and estimates of genetic variance explained by the reaction norm, the best CL for ADG in the nursery was based on early ADG in the finisher, while the CL derived from clinical disease traits across the nursery and finisher was best for ADG in the finisher and for TRT in the nursery and across the nursery and finisher. With increasing CL, estimates of heritability for nursery and finisher ADG initially decreased, then increased, while estimates for TRT generally increased with CL. Genetic correlations for ADG and TRT were low between high versus low CL, but high for close CL. Linear reaction norm models fitted the data significantly better than the standard genetic model without genetic slopes, while the cubic spline model fitted the data significantly better than the linear reaction norm model for most traits. Reaction norm models also fitted the data better than multi-variate models. Reaction norm models identified genotype-by-environment interactions related to disease CL. Results can be used to select more resilient animals across different levels of CL, high-performance animals at a given CL, or a combination of these.


A high-performance and simplified quasi-elastic laser scattering method using homodyne detection in beam divergence.
We devise the new principle of the quasi-elastic laser scattering (QELS) method using a homodyne detection technique in a beam divergence and successfully facilitate the equipment The QELS method is a unique technique for the noncontact and time-resolved study of surface tension at liquid surfaces and liquid/liquid interfaces. The conventional QELS method requires a precise optical alignment using a local oscillator such as a diffraction grating, and the determination of the surface tension accompanies much difficulty because of the low S/N ratio of the power spectra. Our new principle allows high-performance QELS measurements by only a simple alignment of a downsized experimental setup. The power spectra are obtained with 50-100 times higher S/N ratios than the conventional ones. The power spectra are analyzed by a new theory, and the calculated surface tensions agree with the literature values. The accuracy of the surface tension measurements using the QELS method is substantially improved.


Formal determinants of informal arrangements: housing and undocumented immigrants in Rotterdam.
"Using data on undocumented immigrants in the city of Rotterdam, it is argued that peculiarities of the Dutch housing market, especially the large degree of decommodification of the housing stock, lead to a specific housing situation and housing career of illegal immigrants.... The housing situation of undocumented immigrants in Rotterdam clearly shows how formal arrangements create conditions for informal practices.... A comparison between Dutch and U.S. data shows that differences in formal arrangements have substantial effects on the potential of ethnic solidarity within immigrant communities."


A Highly Stretchable Liquid Metal Polymer as Reversible Transitional Insulator and Conductor.
Materials with a temperature-controlled reversible electrical transition between insulator and conductor are attracting huge attention due to their promising applications in many fields. However, most of them are intrinsically rigid and require complicated fabrication processes. Here, a highly stretchable (680% strain) liquid metal polymer composite as a reversible transitional insulator and conductor (TIC), which is accompanied with huge resistivity changes (more than 4 × 109 times) reversibly through a tuning temperature in a few seconds is introduced. When frozen, the insulated TIC becomes conductive and recovers after warming. Both the phase change of the liquid metal droplets and the rigidity change of the polymer contribute directly to transition between insulator and conductor. A simplified model is established to predict the expansion and connection of liquid metal droplets. Along with high stretchability, straightforward fabrication methods, rapid triggering time, large switching ratio, good repeatability, the TIC offers tremendous possibilities for numerous applications, like stretchable switches, semiconductors, temperature sensors, and resistive random-access memory. Accordingly, a system that can display numbers and letters via converting alternative TIC temperature to a binary signal on a computer is conceived and demonstrated. The present discovery suggests a general strategy for fabricating and stimulating a stretchable transitional insulator and conductor based on liquid metal and allied polymers.


Paradoxical embolus to the brain from embolization of a carotid body tumor.
A patent foramen ovale (PFO) is a common heart defect in the general population. Paradoxical embolization of material through a PFO has been an identified cause of stroke. Taking measures to recognize a PFO in a patient undergoing intra-arterial particulate embolization is necessary in order to reduce the risk of stroke secondary to paradoxical embolism. We present a case of paradoxical stroke in a patient with a highly vascular head and neck tumor and an asymptomatic PFO.


Antimuscarinic activities of hycanthone analogs: possible relationship with animal toxicity.
The antimuscarinic activity of hycanthone and five antischistosomal analogs was determined in three biological assays of cholinergic systems. A linear relationship was established between the LD50 values of hycanthone analogs in mice and 1) the Ki values obtained from the inhibition of [3H]quinuclidinyl benzilate binding to the muscarinic receptors of N4TG1 neuroblastoma cells; 2) the I50 values obtained from the inhibition of alpha-amylase secretion induced by carbachol in pancreatic acini cells; and 3) the KB values obtained from the inhibition of guinea-pig ileum contraction induced by acetylcholine. The linear relationship established between antimuscarinic potency and toxicity in mice suggests that a possible relationship exists between the toxicity of the hycanthone analogs and their antimuscarinic activities. On the other hand, no correlation was established between antischistosomal efficacy and antimuscarinic potency. The Ki and I50 values ranged from 10(-7) to 10(-5) M for the inhibition of the binding of [3H]quinuclidinyl benzilate to the muscarinic receptors and for the inhibition of alpha-amylase secretion. The KB values determined by the guinea-pig ileum assays were approximately 10(-5) to 10(-6) M. The ranking of antimuscarinic potency of the compounds in the three different assays were in good agreement.


Current and future therapies for age-related macular degeneration.
Age-related macular degeneration is the leading cause of blindness, with an increasing incidence as the elderly population expands. In this article we review current therapeutic strategies and discuss possible future targets. A review of the literature and ongoing clinical trials was undertaken. Currently, established therapies for neovascular AMD-like photodynamic therapy and anti-VEGF therapies allow stabilization or even improvement of vision. Potential future drugs under development for advanced AMD or its prevention target the signal transduction cascade of different angiogenic molecules. These drugs intervene at different levels of the involved processes including the RNA production and specific protein expression as well as inflammatory, apoptotic, or metabolic processes. Combining different strategies targeting angiogenesis, inflammation and apoptosis, or interfering early in--or even prior to--the formation of choroidal neovascularization, may improve the future management of age-related macular degeneration.


Thermodynamic investigation of n-hexane thin films adsorbed on magnesium oxide.
The thermodynamic properties of n-hexane adsorption on MgO(100) were determined using high-resolution volumetric adsorption isotherms in the temperature range 195-255 K. Two distinct layering transitions are observed in the isotherms. The isotherms are used to calculate the two-dimensional compressibility, the differential enthalpy and entropy, the heat of adsorption, and the isosteric heat of adsorption. Neutron Diffraction is used to identify where melting of the n-hexane monolayer takes place.


Resolving a double standard for risk management of thalidomide: an evaluation of two different risk management programmes in Japan.
Thalidomide, once withdrawn because of its teratogenicity, has now been re-launched worldwide. In Japan, thalidomide has been imported by individual doctors since around the year 2000. In October 2008, it was approved for the treatment of multiple myeloma (MM) by the Ministry of Health, Labour and Welfare (MHLW) on the condition that the manufacturer implemented a risk management programme termed the Thalidomide Education and Risk Management System (TERMS). It is likely that the imports of thalidomide will be used off-label to treat diseases other than MM. Thus, the MHLW is also planning to introduce a web-based registration system, referred to as the Safety Management System for Unapproved Drugs (SMUD), for thalidomide imported by individual doctors. To evaluate the difference between TERMS and SMUD and establish a way to resolve the 'double standard' for risk management of thalidomide treatment in Japan. The fraction of patients with disorders other than MM was estimated by the volume of annual imports obtained from the MHLW and records of the imports for patients with MM, other oncological diseases (ODs) and non-ODs in 2007 through a major supplier covering 63% of the total imported thalidomide. The information for TERMS was obtained from web pages of the manufacturer and the MHLW. The components of TERMS were compared with those in SMUD. Provided that the distribution of the indication for thalidomide (MM) in 2007, estimated from the records of imports through the major supplier, is representative of the entire nation, it is estimated that on average 866 patients, including 851 (98.3%) with MM, are using thalidomide on any one day. However, if the major supplier's imports, which account for 63% of the total imports, are not representative of the nation as a whole, possibly only half of the patients treated with thalidomide in Japan have MM. This would be the case in a scenario where the remaining 37% of imports are exclusively used to treat disorders other than MM. TERMS consists of tools for education and registration of patients, and has the potential for real-time intervention. SMUD is a system for registration of patients and exchange of safety information between health professionals, but has some mandatory components that encourage patient registration. TERMS and SMUD are different in nature, and they impose different criteria that doctors and patients should satisfy in order to use thalidomide. To eliminate this double standard, implementation of a single system would be desirable. However, improvement of SMUD may be the second best option by developing tools for patient education, enhancing the potential for real-time intervention and monitoring thalidomide usage by each patient. On average, a total of about 1000 patients are estimated to be using thalidomide on any one day in Japan. It is likely that those patients are placed under one of two different risk management programmes. SMUD should be improved so that all patients are monitored in a way that results in a similar level of risk management.


Tetraspanin 1 (TSPAN1) promotes growth and transferation of breast cancer cells via mediating PI3K/Akt pathway.
The incidence and mortality of breast cancer rank first among all types of female tumors. To improve patients' prognosis with advanced breast cancer, new and more effective targets still need to be explored and identified. Tetraspanin 1 (TSPAN1) is highly expressed in several cancers and affects the progression of these tumors. However, there are few studies focused on its role in breast cancer. Previous study showed that TSPAN1 promoted epithelial-mesenchymal transition (EMT) and metastasis, and whether TSPAN1 could promote breast cancer via regulating EMT needs further study. In this study, we found high TSPAN1 expression in breast cancer tumor samples and cell lines which was confirmed by bioinformation analysis. The ablation of TSPAN1 suppressed the growth, and motility of breast cancer cells. We further found that TSPAN1 affected the EMT and mediated the PI3K/Akt pathway in breast cancer cells. In addition, TSPAN1 depletion suppressed tumor growth of breast cancer in mice. In summary, we thought TSPAN1 suppressed growth and motility of breast cancer via mediating EMT and PI3K/AKT pathway, and could serve as a potential target for treatment of breast cancer.


Effect of Mesenchymal Stem Cell-Derived Exosomes on Retinal Injury: A Review of Current Findings.
In recent years, various studies have followed in the literature on the therapeutic effects of mesenchymal stem cells (MSC) on damage in retinal cells. The evidence that MSCs exert their regenerative and damage reduction effect in a paracrine way, through the release of soluble factors and exosomes, is now consolidated. Exosomes are microvesicles formed by a double layer of phospholipid membrane and carry proteins and RNA, through which they play a therapeutic role on target cells. Scientific research has recently focused on the use of exosomes derived from MSC in various models of retinal damage in vitro and in vivo as they, compared to MSCs, have similar functions and at the same time have different advantages such as greater stability and handling, a lower chance of immunological rejection and no risk of malignant transformation. The purpose of this review is to summarize current knowledge on the therapeutic use of exosomes derived from MSCs in retinal damage and to stimulate new clinical perspectives regarding their use.


Decree No. 2.050, Regulations of the Consultative Council for the Twelfth General Census of Population and Housing, 29 March 1988.
This Decree provides that the Consultative Council has the duty of advising the Central Office of Statistics and Information on the technical aspects of the preparation and execution of the Twelfth General Census of Population and Housing in Venezuela. It is to examine and discuss ideas on the Census and to establish priorities in classifying national needs with respect to census information. Further provisions of the Decree deal with the composition and meetings of the Council, the duties of the Council President, and working groups.


Intestinal migrating myoelectric complexes in rats with acute pancreatitis and bile duct ligation.
Intestinal migrating myoelectric complexes (MMC) were studied in rats subjected to common bile duct ligation. Four pairs of bipolar electrodes were implanted on the jejunum and the ileum of 21 rats. Animals were allowed to recover 7 days before electrical recordings were made. Bile duct ligation at the entrance to the duodenum (low) or above the pancreas (high) or sham operation was performed. MMCs were recorded before and 48 and 72 hr after the operation in each animal. MMC intervals were unchanged following high ligation or sham operation. However, 48 hr after low bile duct ligation, the MMC interval (20.6 +/- 2.5 min) was significantly prolonged compared with that before ligation (14.0 +/- 1.2 min). Further prolonged intervals (28.4 +/- 4.2 min) were observed 72 hr after the ligation. There were no significant differences among the slow wave frequencies in any group of animals, being in the range of 34.1 +/- 1.1 to 36.3 +/- 1.0 cycles/min. Thus, the MMC pattern in this rat model may be affected by the development of acute pancreatitis. The mechanism(s) responsible for altering the MMC pattern are not known; however, hepatic biliary secretion alone does not appear to play a primary role.


Gain in Alzheimer care INstrument--a new scale to measure caregiving gains in dementia.
To describe and validate a new scale, Gain in Alzheimer care Instrument (GAIN), and to measure gains in dementia caregiving. Items in GAIN were derived through a qualitative study of family carers of persons with dementia (PWD). Content validity of GAIN was established by a team of dementia care experts (geriatrician, nurse, and social worker) and through focus group discussion with 15 family carers. Consecutive carers of PWD were administered a questionnaire containing GAIN and other measures. Ambulatory dementia clinic of a tertiary hospital and the local Alzheimer's Association. Family carers of PWD. The psychometric properties of GAIN were examined, in particular, exploratory factor analysis and construct validity through correlation with extant measures; Positive Aspects of Caregiving (PAC), Dementia Management Strategies Scale (DMSS), and Zarit Burden Interview (ZBI). Two hundred thirty-eight English-speaking carers completed the survey. Mean age of carers was 50.1 year (standard deviation [SD] 10.1) and females (68.1%) and child carers (81.3%) comprised the majority. Mean GAIN score was 30.5 (SD 6.5). Internal consistency of GAIN by Cronbach's alpha was 0.89 and test-retest reliability (2 weeks) by Intraclass Correlation Coefficient was 0.70. GAIN correlated strongly with PAC (r = 0.68, df = 236, p <0.0001), moderately with DMSS (encouragement) (r = 0.35, df = 234, p <0.0001) and DMSS (active management) (r = 0.42, df = 235, p <0.0001), and modestly with DMSS (criticism) (r = -0.14, df = 236, p = 0.03) and ZBI (r = -0.15, df = 236, p = 0.02). Principal component analysis revealed a single component with an Eigen value >1 at 5.28, accounting for 52.8% of the variance. GAIN is a psychometrically reliable and valid instrument for measuring gains in dementia caregiving. It adds an important dimension to carer assessment in dementia.


The subacute neurotoxicity of excess pyridoxine HCl and clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) in beagle dogs. II. Pathology.
The lesions caused by excess oral pyridoxine hydrochloride (150 mg/kg body weight/day) and clioquinol (200 mg/kg body weight/day), given individually and in combination to adult Beagle dogs, were evaluated. The experimental period was 100 to 112 days, except that four dogs in each of the clioquinol and combined-treatment groups were killed early because of severe debilitation or neurologic disease, and one dog given both compounds died on the third day of compound administration. Degenerative neurologic lesions had distribution specific for the compound given. Pyridoxine-treated dogs had lesions limited to tracts and nerves with neuronal bodies of their nerve fibers in the spinal and trigeminal ganglia. Clioquinol-treated dogs had neurologic lesions limited to the central nervous system. The most lesions were in the rostral dorsal funiculus and distal aspects of the optic nerve fibers, but minimal to mild degenerative changes also occurred in distal aspects of the corticospinal and spinocerebellar tracts. Dogs given both pyridoxine hydrochloride and clioquinol had a combination of the lesions in dogs given pyridoxine or clioquinol individually. Several dogs given clioquinol or pyridoxine plus clioquinol had extraneural lesions, including myocardial degeneration and thyroidal alterations.


Calorigenic effects of growth hormone: the role of thyroid hormones.
GH administration increases energy expenditure, independent of changes in lean body mass, in healthy, obese, and GH-deficient subjects. This may be causally linked to the well known GH-induced increase in peripheral T4 to T3 generation, but experimental data are sparse. In this study we have addressed whether 1) the calorigenic effects of GH administration could be reproduced by oral supplementation of T3 in a dose selected to mimic the GH-induced increase in peripheral T3 levels; and 2) combined GH and T3 administration have a synergistic effect on resting energy expenditure (REE). Eight normal male subjects (aged 21-27 yr; body mass index, 21.11-27.17 kg/m2) were randomly studied during four 10-day treatment periods with 1) daily sc placebo injections and placebo tablets, 2) daily sc GH injections (0.1 IU/kg x day) and placebo tablets, 3) daily T3 administration (40 microg on even dates, 20 microg on uneven dates) plus placebo injections, and 4) daily GH injections plus T3 administration. GH administration increased both free T3 (FT3) levels [mean +/- SE, 6.2 +/- 0.3 (control) vs. 7.3 +/- 0.5 (GH) pmol/L; P < 0.05] and REE [mean +/- SE, 1959 +/- 67 (control) vs. 2164 +/- 55 (GH) Cal/24 h; P < 0.01]. T3 administration yielded comparable levels of FT3 (7.7 +/- 0.5 pmol/L; T3 vs. GH, P = 0.37), but did not increase REE (2015 +/- 48 Cal/24 h; T3 vs. control, P = 0.23). Combined GH and T3 administration increased REE to a level higher than that seen with T3 alone (2279 +/- 68 Cal/24 h; T3 vs. GH plus T3, P < 0.01). Significant increments in serum levels of insulin-like growth factor I and insulin were recorded with GH administration, but not with T3 alone. Resting heart rate increased to a similar degree after GH administration and T3 supplementation, respectively. Tympanic temperature remained unaltered in all four studies. The results suggest that the calorigenic effect of GH is not mediated solely through increased conversion of T4 to T3.


A new route to the evolution of cooperation.
The Prisoner's Dilemma (PD) constitutes a widely used metaphor to investigate problems related to the evolution of cooperation. Whenever evolution takes place in well-mixed populations engaged in single rounds of the PD, cooperators cannot resist invasion by defectors, a feature, which is somewhat alleviated whenever populations are spatially distributed. In both cases the populations are characterized by a homogeneous pattern of connectivity, in which every individual is equivalent, sharing the same number of neighbours. Recently, compelling evidence has been accumulated on the strong heterogeneous nature of the network of contacts between individuals in populations. Here we describe the networks of contacts in terms of graphs and show that heterogeneity provides a new mechanism for cooperation to survive. Specifically, we show that cooperators are capable of exploring the heterogeneity of the population structure to become evolutionary competitive. As a result, cooperation becomes the dominating trait in scale-free networks of contacts in which the few highly connected individuals are directly inter-connected, in this way contributing to self-sustain cooperation.


Electroencephalography (EEG) spectral edge frequency for assessing the sedative effect of acupuncture in dogs.
Electroencephalography (EEG) is an effective method for the evaluation of sedation or anesthesia. The purpose of this study was to examine the sedative effect of acupuncture by electroencephalographic spectral edge frequency (SEF) in Miniature Schnauzer dogs (4.2-6.1 kg, 1-2 years old). The acupuncture points "GV20 and Yintang" were applied for 20 min. Sedation level was assessed before, during, and after acupuncture by spectral edge frequency 95 values and the Ramsay sedation score. The spectral edge frequency 95 values were significantly reduced during acupuncture on GV20 or Yintang point and returned to the baseline values after acupuncture releasing. The Ramsay sedation score (RSS) also showed the acceptable sedation level during acupuncture. It was concluded that an acupuncture application at GV20 or Yintang point used in the present study would be a valuable method to induce the sedation in dogs.


Ratchet effect for nanoparticle transport in hair follicles.
The motion of a single rigid nanoparticle inside a hair follicle is investigated by means of Brownian dynamics simulations. The cuticular hair structure is modeled as a periodic asymmetric ratchet-shaped surface. Induced by oscillating radial hair motion we find directed nanoparticle transport into the hair follicle with maximal velocity at a specific optimal frequency and an optimal particle size. We observe flow reversal when switching from radial to axial oscillatory hair motion. We also study the diffusion behavior and find strongly enhanced diffusion for axial motion with a diffusivity significantly larger than for free diffusion.


Type 2 Myocardial Infarction Related to Very Low Carbohydrate Ketogenic Diet.
A 38-year-old male with no history of cardiac disease presented with chest pain typical of acute coronary syndrome. He assumed very-low-carbohydrate ketogenic diet (VLC-KD) 4 weeks prior to admission but no other lifestyle change. Workup showed dynamic ST-T changes on electrocardiogram, significantly elevated troponins, ketonuria, and mild rhabdomyolysis. Transthoracic echocardiogram revealed mild inferior wall hypokinesia and cardiac catheterization showed normal coronaries; hence, the diagnosis of type II myocardial infarction (MI) was established. Although the pathogenesis remains unclear, this temporal association between VLC-KD and type 2 MI raised some concerns about VLC-KD's cardiovascular safety profile.


[A pilot study of intraperitoneal gemcitabine for reduction of peritoneal dissemination in advanced pancreatic cancer].
We schemed intraperitoneal gemcitabine (ipGEM) for reduction of peritoneal dissemination to three patients with unresectable and one patient with recurrent pancreatic cancer, followed by intraperitoneal catheter and subcutaneous port placement. Two locally advanced cases were performed for intra-operative radiotherapy, and one of 2 locally advanced cases was performed for gastrojejunostomy. And another locally advanced case had ileostomy. The recurrent case was resected for metastatic tumor of abdominal wall. In one of locally advanced cases, we couldn't perform ipGEM for progression of disease. In two remaining locally advanced cases, we could keep on doing ipGEM, and the patients did not experience with abdominal discomfort or hematological toxicity.


Drosophila spoonbill encodes a dual-specificity A-kinase anchor protein essential for oogenesis.
spoonbill is a Drosophila female-sterile mutation, which interferes with normal egg patterning during oogenesis. Previous analyzes linked the mutation to a number of seemingly unrelated pathways, including GRK/EGFR and DPP, two major pathways essential for Drosophila and vertebrate development. Further work suggested that spoonbill may also function in actin polymerization and border-cell migration. Here we describe the molecular cloning of the spoonbill gene and characterize new mutant alleles, further demonstrating that spoonbill's function is essential during oogenesis. We found spoonbill to be allelic to CG3249 (also known as yu), which encodes the only known dual-specificity A-kinase anchor protein in Drosophila. Our data indicate that similar to mammalian AKAPs, Spoonbill protein contains a number of potential kinase and phosphatase binding motifs, and is targeted, in the ovary, to mitochondria and Golgi. Finally, we address some of spoonbill's mutant phenotypes from the perspective of the published data on the AKAP protein family.


New dimeric stilbenoids from fungal-challenged peanut ( Arachis hypogaea) seeds.
The peanut plant can resist fungal attacks by producing stilbene-derived phytoalexins. Once understood, such a natural phytoalexin-based mechanism of peanut resistance could be potentially manipulated to obtain fungal-resistant peanut breeding lines. Several simple stilbenoid phytoalexins from peanuts have been reported. However, more complex stilbenoid derivatives such as those that have been reported from other sources and considered important factors in plant defense have not been found in peanuts. The purpose of this research was to isolate and characterize further new oligomeric peanut stilbenoids that may act as phytoalexins. Two new prenylated stilbene dimers named arahypin-6 (3) and arahypin-7 (4) have been isolated from wounded peanut seeds challenged by an Aspergillus caelatus strain. The structures of these new putative phytoalexins were determined by analysis of NMR, MS, and UV spectroscopic data. Together with other known peanut stilbenoids that were also produced in the challenged seeds, these new compounds may play a defensive role against invasive fungi.


Tempo and mode of climatic niche evolution in Primates.
Climatic niches have increasingly become a nexus in our understanding of a variety of ecological and evolutionary phenomena, from species distributions to latitudinal diversity gradients. Despite the increasing availability of comprehensive datasets on species ranges, phylogenetic histories, and georeferenced environmental conditions, studies on the evolution of climate niches have only begun to understand how niches evolve over evolutionary timescales. Here, using primates as a model system, we integrate recently developed phylogenetic comparative methods, species distribution patterns, and climatic data to explore primate climatic niche evolution, both among clades and over time. In general, we found that simple, constant-rate models provide a poor representation of how climatic niches evolve. For instance, there have been shifts in the rate of climatic niche evolution in several independent clades, particularly in response to the increasingly cooler climates of the past 10 My. Interestingly, rate accelerations greatly outnumbered rate decelerations. These results highlight the importance of considering more realistic evolutionary models that allow for the detection of heterogeneity in the tempo and mode of climatic niche evolution, as well as to infer possible constraining factors for species distributions in geographical space.


Statistical Models and Methods for Network Meta-Analysis.
Meta-analysis, the methodology for analyzing the results from multiple independent studies, has grown tremendously in popularity over the last four decades. Although most meta-analyses involve a single effect size (summary result, such as a treatment difference) from each study, there are often multiple treatments of interest across the network of studies in the analysis. Multi-treatment (or network) meta-analysis can be used for simultaneously analyzing the results from all the treatments. However, the methodology is considerably more complicated than for the analysis of a single effect size, and there have not been adequate explanations of the approach for agricultural investigations. We review the methods and models for conducting a network meta-analysis based on frequentist statistical principles, and demonstrate the procedures using a published multi-treatment plant pathology data set. A major advantage of network meta-analysis is that correlations of estimated treatment effects are automatically taken into account when an appropriate model is used. Moreover, treatment comparisons may be possible in a network meta-analysis that are not possible in a single study because all treatments of interest may not be included in any given study. We review several models that consider the study effect as either fixed or random, and show how to interpret model-fitting output. We further show how to model the effect of moderator variables (study-level characteristics) on treatment effects, and present one approach to test for the consistency of treatment effects across the network. Online supplemental files give explanations on fitting the network meta-analytical models using SAS.


Uptake of liposomes by cultured cardiomyocytes.
Small unilamellar liposomes (SUV) of different phospholipid/polymer composition were labeled with NBD-PC, which served as a bilayersituated fluorescence marker. Neonatal cardiomyocytes were incubated with liposomes and then the cell-associated fluorescence was measured. The factors influencing the liposome uptake by cardiomyocytes such as concentration of lipid, time of incubation, membrane fluidity of liposomes, charge lipid/polymer modification of liposomes and anoxia of cultured cardiomyocytes were investigated. The liposome uptake by cardiomyocytes increased dose-dependently and time-dependently. Liposome uptake was strongly influenced by the electrical charge and modified polymer. After 2 h incubation, the uptake of positively charged liposomes was 1.7-fold higher than that of negatively charged one and both higher than that of the neutral one. The presence of PE-PEG2000 distinctly reduced the liposome uptake and the difference between the uptake of charged and neutral liposome. Anoxia increased the uptake of liposome at the first hour (increased 20%), but after 2 h incubation the liposome uptake by hypoxia cellswas less than that of normoxia cells (decreased 18%). Mechanisms involved are also discussed.


TfNH2 as achiral hydrogen-bond donor additive to enhance the selectivity of a transition metal catalyzed reaction. Highly enantio- and diastereoselective rhodium-catalyzed cyclopropanation of alkenes using alpha-cyano diazoacetamide.
A highly stereoselective (up to 98% ee and 99:1 dr) Rh(II)-catalyzed formation of nitrile-substituted cyclopropanes is described. Alpha-cyano diazoacetamide reagents react with a variety of mono- and disubstituted olefins in good yields and excellent enantio- and diastereocontrol. Less reactive substrates, such as aliphatic olefins, also undergo the reaction. This new methodology features the unprecedented use of an achiral hydrogen-bond donor additive to enhance the selectivity and exploits the powerful trans-directing ability of amides solving the diastereocontrol issue of the formation of substituted 1-cyanocyclopropane-1-carboxy derivatives.


Being-in-tune caregiving.
The practice of providing developmentally supportive caregiving is familiar to nurses but often is not practiced until after the infant's stabilization in the neonatal intensive care unit (NICU). The study reported here explored the constructs that describe the characteristics of physiologically stable extremely low-birthweight infants and the process of caregiving to these infants. A purposive sample of 20 experienced nurses in a level III NICU was selected. Two separate constructs emerged: individually defined stability and being-in-tune caregiving.


Calcium and gadolinium ions stimulate the GTPase activity of purified chicken brain tubulin through a conformational change.
Ca2+ and Gd3+ stimulated the GTPase activity of chicken brain tubulin 13- and 26-fold, respectively. Mg2+, Tb3+, and Na+ had no effect. This GTPase activity showed a saturation behavior with Ca2+ and Gd3+ with a maximal activity of 0.26 +/- 0.026 and 1.15 +/- 0.78 nmol min-1 per mg of tubulin and semisaturation constants, expressed as the concentration of the cation needed for 50% of saturation, of 0.32 +/- 0.18 and 0.011 +/- 0.007 mM, respectively. In the presence of Ca2+, the GTPase activity was proportional to tubulin concentration in the range 0.9-31.8 microM. The semisaturation constants for the inhibition of tubulin polymerization and for the depolymerization of microtubules by Ca2+ were 0.71 +/- 0.1 and 0.049 +/- 0.043 mM, respectively. The similarity of the Ca2+ semisaturation constants for inhibition of tubulin assembly and stimulation of the GTPase activity suggests that these processes are correlated. These results support the hypothesis that the GTPase activity is related to but not directly involved in the mechanism of inhibition of Ca2+ -dependent tubulin assembly. This inhibition could be better explained by the formation of a nonfunctional conformational state of tubulin induced by Ca2+ that is responsible for the GTPase activity. Quenching of the intrinsic fluorescence of tryptophan induced by Ca2+ showed an apparent dissociation constant of 0.14 +/- 0.005 mM, in the range of values determined through tubulin polymerization inhibition or through the induction of GTPase activity by Ca2+. Acrylamide-induced quenching of the intrinsic fluorescence showed values of the Stern-Volmer constants of 5.4 +/- 0.12 and 5.0 +/- 0.15 M-1 in the absence and presence of Ca2+, respectively. These results support the hypothesis that the inhibition of tubulin polymerization and the induction of the GTPase activity by Ca2+ is mediated by a conformational change. Ca2+ failed to induce depolymerization of GDP-AIF4-microtubules; this could be explained by a model in which Ca-tubulin is unable to assemble into microtubules and the rate of dissociation of GDP-Pi-tubulin from the microtubule ends is extremely slow compared with the rate of GDP-subunit dissociation, supporting the concept that the GTP- and GDP-Pi-tubulin cap at the ends of microtubules regulates their dynamic instability.


Identification of CNS-Penetrant Aryl Sulfonamides as Isoform-Selective NaV1.6 Inhibitors with Efficacy in Mouse Models of Epilepsy.
Nonselective antagonists of voltage-gated sodium (NaV) channels have been long used for the treatment of epilepsies. The efficacy of these drugs is thought to be due to the block of sodium channels on excitatory neurons, primarily NaV1.6 and NaV1.2. However, these currently marketed drugs require high drug exposure and suffer from narrow therapeutic indices. Selective inhibition of NaV1.6, while sparing NaV1.1, is anticipated to provide a more effective and better tolerated treatment for epilepsies. In addition, block of NaV1.2 may complement the anticonvulsant activity of NaV1.6 inhibition. We discovered a novel series of aryl sulfonamides as CNS-penetrant, isoform-selective NaV1.6 inhibitors, which also displayed potent block of NaV1.2. Optimization focused on increasing selectivity over NaV1.1, improving metabolic stability, reducing active efflux, and addressing a pregnane X-receptor liability. We obtained compounds 30-32, which produced potent anticonvulsant activity in mouse seizure models, including a direct current maximal electroshock seizure assay.


Molecular, serological, pathological, immunohistochemical and microbiological investigation of Brucella spp. in marine mammals of Brazil reveals new cetacean hosts.
Brucella-exposure and infection is increasingly recognized in marine mammals worldwide. To better understand the epidemiology and health impacts of Brucella spp. in marine mammals of Brazil, molecular (conventional PCR and/or real-time PCR), serological (Rose Bengal Test [RBT], Competitive [c]ELISA, Serum Agglutination Test [SAT]), pathological, immunohistochemical (IHC) and/or microbiological investigations were conducted in samples of 129 stranded or by-caught marine mammals (orders Cetartiodactyla [n = 124], Carnivora [n = 4] and Sirenia [n = 1]). Previous serological tests performed on available sera of 27 of the 129 animals (26 cetaceans and one manatee), indicated 10 seropositive cetaceans. Conventional PCR and/or real-time PCR performed in cases with available organs (n = 119) and/or blood or swabs (n = 10) revealed 4/129 (3.1%) Brucella-infected cetaceans (one of them with positive serology; the remaining three with no available sera). Pathological, IHC and/or microbiological analyses conducted in PCR/real-time PCR and/or seropositive cases (n = 13) revealed Brucella-type lesions, including meningitis/meningoencephalitis, pneumonia, necrotizing hepatitis, pericarditis and osteoarthritis in some of those animals, and positive IHC was found in all of them (excepting two live-stranded animals without available organs). Brucella spp. culture attempts were unsuccessful. Our results demonstrated exposure, asymptomatic, acute and chronic Brucella sp. infection in several cetacean species in the Brazilian coast, highlighting the role of this pathogen in stranding and/or death, particularly in Clymene dolphin (Stenella clymene) and short-finned pilot whale (Globicephala macrorhynchus) off Ceará State. Novel hosts susceptible to Brucella included the franciscana (Pontoporia blainvillei), the Guiana dolphin (Sotalia guianensis) and the spinner dolphin (Stenella longirostris). Additionally, three coinfection cases involving Brucella spp. and cetacean morbillivirus, Edwarsiella tarda and Proteus mirabilis were detected. To the best of our knowledge, this is the first long-term and large-scale survey of Brucella spp. in marine mammals of South America, widening the spectrum of susceptible hosts and geographical distribution range of this agent with zoonotic potential.