Helper-dependent adenoviral vector-mediated long-term expression of human apolipoprotein A-I reduces atherosclerosis in apo E-deficient mice.
Apolipoprotein A-I (APOA-I) is the major protein component of high-density lipoproteins (HDL). It has been shown that over-expression of human APOA-I increases HDL cholesterol and decreases atherosclerosis. We constructed a helper-dependent adenoviral (HD-Ad) vector that contains the entire human APOA-I gene (hgAI). Intravenous delivery of 1x10(13) viral particles/kg of this vector was followed by high levels of human APOA-I expression (up to 200 mg/dl) in the absence of detectable hepatic toxicity. We treated apo E-deficient mice with the hgAI vector and fed them either with a high-fat diet or with regular chow. As a control, two groups of mice were treated with PBS. The apo E-deficient mice treated with the hgAI vector showed supraphysiological levels of expression of human APOA-I at week 4 and high levels of HDL cholesterol compared to the control groups. Analysis of aortic atherosclerotic lesions 20 weeks after treatment, showed a significant reduction of lesion size in the treated mice with both diets. In conclusion, liver-directed gene transfer of human APOA-I using a HD-Ad vector resulted in a reduction of the development of atherosclerosis with the absence of significant toxicity.


The optimal control chart selection for monitoring COVID-19 phases: a case study of daily deaths in the USA.
Epidemiologists frequently adopt statistical process control tools, like control charts, to detect changes in the incidence or prevalence of a specific disease in real time, thereby protecting against outbreaks and emergent health concerns. Control charts have proven essential in instantly identifying fluctuations in infection rates, spotting emerging patterns, and enabling timely reaction measures in the context of COVID-19 monitoring. This study aims to review and select an optimal control chart in epidemiology to monitor variations in COVID-19 deaths and understand pandemic mortality patterns. An essential aspect of the present study is selecting an appropriate monitoring technique for distinct deaths in the USA in seven phases, including pre-growth, growth, and post-growth phases. Stage-1 evaluated control chart applications in epidemiology departments of 12 countries between 2000 and 2022. The study assessed various control charts and identified the optimal one based on maximum shift detection using sample data. This study considered at Shewhart ($\bar X$, $R$, $C$) control charts and exponentially weighted moving average (EWMA) control chart with smoothing parameters λ = 0.25, 0.5, 0.75, and 1 were all investigated in this study. In Stage-2, we applied the EWMA control chart for monitoring because of its outstanding shift detection capabilities and compatibility with the present data. Daily deaths have been monitored from March 2020 to February 2023. Control charts in epidemiology show growing use, with the USA leading at 42% applications among top countries. During the application on COVID-19 deaths, the EWMA chart accurately depicted mortality dynamics from March 2020 to February 2022, indicating six distinct stages of death. The third and fifth waves were extremely catastrophic, resulting in a considerable loss of life. Significantly, a persistent sixth wave appeared from March 2022 to February 2023. The EWMA map effectively determined the peaks associated with each wave by thoroughly examining the time and amount of deaths, providing vital insights into the pandemic's progression. The severity of each wave was measured by the average number of deaths $W5(1899)\,\gt\,W3(1881)\,\gt\,W4(1393)\,\gt\,W1(1036)\,\gt\,W2(853)\,\gt\,(W6(473)$. The USA entered a seventh phase (6th wave) from March 2022 to February 2023, marked by fewer deaths. While reassuring, it remains crucial to maintain vaccinations and pandemic control measures. Control charts enable early detection of daily COVID-19 deaths, providing a systematic strategy for government and medical staff. Incorporating the EWMA chart for monitoring immunizations, cases, and deaths is recommended.


Oenological characteristics, amino acids and volatile profiles of Hongqu rice wines during pottery storage: Effects of high hydrostatic pressure processing.
Hongqu rice wines were subjected to high hydrostatic pressure (HHP) treatments of 200 MPa and 550 MPa at 25 °C for 30 min and effects on wine quality during pottery storage were examined. HHP treatment can significantly (p<0.05) decrease the content of fusel-like alcohols and maintain the concentration of lactones in these wines. After 18 months of storage, the HHP-treated wines exhibited a more rapid decrease in total sugars (9.3-15.3%), lower free amino acid content (e.g. lysine content decreased by 45.0-84.5%), and higher ketone content (e.g. 6- and 14-fold increase for 2-nonanone). These changes could be attributed to the occurrence of Maillard and oxidation reactions. The wines treated at 550 MPa for 30 min developed about twice as rapidly during pottery storage than untreated wines based on principal component analysis. After only 6 months, treated wines had a volatile composition and an organoleptic quality similar to that of untreated wines stored in pottery for 18 months.


Preliminary pilot fMRI study of neuropostural optimization with a noninvasive asymmetric radioelectric brain stimulation protocol in functional dysmetria.
This study assessed changes in functional dysmetria (FD) and in brain activation observable by functional magnetic resonance imaging (fMRI) during a leg flexion-extension motor task following brain stimulation with a single radioelectric asymmetric conveyer (REAC) pulse, according to the precisely defined neuropostural optimization (NPO) protocol. Ten healthy volunteers were assessed using fMRI conducted during a simple motor task before and immediately after delivery of a single REAC-NPO pulse. The motor task consisted of a flexion-extension movement of the legs with the knees bent. FD signs and brain activation patterns were compared before and after REAC-NPO. A single 250-millisecond REAC-NPO treatment alleviated FD, as evidenced by patellar asymmetry during a sit-up motion, and modulated activity patterns in the brain, particularly in the cerebellum, during the performance of the motor task. Activity in brain areas involved in motor control and coordination, including the cerebellum, is altered by administration of a REAC-NPO treatment and this effect is accompanied by an alleviation of FD.


Liver metastasis as an initial recurrence has no impact on the survival of patients with resectable pancreatic adenocarcinoma.
Prognosis of the patients with pancreatic adenocarcinoma is still poor due to a recurrence, and liver metastasis is a distant metastasis that is foreboded the short survival period. Between 1999 and 2005, 68 patients for pancreatic adenocarcinoma underwent a pancreaticoduodenectomy (n = 17), a pylorus-preserving pancreaticoduodenectomy (n = 27), distal pancreatectomy (n = 22), or total pancreatectomy (n = 2) with an extensive lymph node dissection. A tumor recurrence occurred to 55 patients (13 of the liver, 21 of the local recurrence, 16 of peritoneal dissemination, three of the lymph node, and two of lung). The low tumor grade and female demonstrated a risk factor for a liver metastasis (P = 0.043, P = 0.031). A logistic regression analysis demonstrated female (P = 0.02) and low tumor grade (P = 0.04) as independent risk factors for recurrence with liver metastasis. The median survival time (MST) was 13.6 months, and MST of patients with a liver metastasis as an initial recurrent site was 13.7 months; the liver metastasis as an initial recurrent site has no impact on the MST after pancreatic resection. We concluded potentially supporting the hypothesis that even patients thought to be at higher risk of liver metastasis may still be given the chance of resection, considering the satisfying survival.


Clinical experience in nonstressed antepartum cardiotocography.
The condition of the fetus during pregnancy was assessed by 1,763 antepartum cardiotocograms made in 386 patients with the use of fetal movements and physiologic uterine contractions. There appeared to be a significant correlation between the cardiotocograms and the obstetric outcome.


Pulmonary vein isolation plus adjunctive therapy for the treatment of atrial fibrillation: a systematic review and meta-analysis.
Pulmonary vein isolation (PVI) is the primary technique for ablation of atrial fibrillation (AF). It is unclear whether adjunctive therapies in addition to PVI can reduce atrial arrhythmia recurrence (AAR) compared to PVI alone in patients with AF. A meta-analysis of randomized controlled trials comparing PVI plus an adjunctive therapy (autonomic modulation, linear ablation, non-pulmonary vein trigger ablation, epicardial PVI [hybrid ablation], or left atrial substrate modification) to PVI alone was conducted. The primary outcome was AAR. Cumulative odd's ratios (OR) and 95% confidence intervals (CI) were calculated for each treatment type. Forty-six trials were identified that included 8,500 participants. The mean age (± standard deviation) was 60.2 (±4.1) years, and 27.2% of all patients were female. The mean follow-up time was 14.6 months. PVI plus autonomic modulation and PVI plus hybrid ablation were associated with a relative 53.1% (OR 0.47; 95% CI 0.32 to 0.69; p < 0.001) and 59.1% (OR 0.41; 95% CI 0.23 to 0.75; p = 0.003) reduction in AAR, respectively, compared to PVI alone. All categories had at least moderate interstudy heterogeneity except for hybrid ablation. Adjunctive autonomic modulation and epicardial PVI may improve the effectiveness of PVI. Larger, multi-center randomized controlled trials are needed to evaluate the efficacy of these therapies.


Sequence-Dependent Stereodivergent Allylic Alkylation/Fluorination of Acyclic Ketones.
The stereodivergent iridium-catalyzed allylic alkylation and fluorination of acyclic ketones is described. α-Pyridyl-α-fluoroketones with vicinal tertiary and quaternary stereocenters were obtained in moderate to excellent yields and stereoselectivities. Distinct from known stereodivergent synthesis, for which two different chiral catalysts are required in general, herein we report a sequence-dependent stereodivergent synthesis. With only a single chiral Ir catalyst, all four possible stereoisomers of the products were prepared from the same starting materials by simply adjusting the sequence of asymmetric allylic alkylation and fluorination and varying the absolute configuration of the Ir catalyst.


Potential application of high pressure carbon dioxide in treated wastewater and water disinfection: Recent overview and further trends.
Recently emerging disadvantages in conventional disinfection have heightened the need for finding a new solution. Developments in the use of high pressure carbon dioxide for food preservation and sterilization have led to a renewed interest in its applicability in wastewater treatment and water disinfection. Pressurized CO2 is one of the most investigated methods of antibacterial treatment and has been used extensively for decades to inhibit pathogens in dried food and liquid products. This study reviews the literature concerning the utility of CO2 as a disinfecting agent, and the pathogen inactivation mechanism of CO2 treatment is evaluated based on all available research. In this paper, it will be argued that the successful application and high effectiveness of CO2 treatment in liquid foods open a potential opportunity for its use in wastewater treatment and water disinfection. The findings from models with different operating conditions (pressure, temperature, microorganism, water content, media …) suggest that most microorganisms are successfully inhibited under CO2 treatment. It will also be shown that the bacterial deaths under CO2 treatment can be explained by many different mechanisms. Moreover, the findings in this study can help to address the recently emerging problems in water disinfection, such as disinfection by-products (resulting from chlorination or ozone treatment).


Association between epidermal growth factor gene +61A/G polymorphism and the risk of hepatocellular carcinoma: a meta-analysis based on 16 studies.
The association between epidermal growth factor (EGF) gene +61A/G polymorphism (rs4444903) and hepatocellular carcinoma (HCC) susceptibility has been widely reported, but the results were inconsistent. To clarify the effect of this polymorphism on HCC risk, a meta-analysis was performed. The PubMed, Embase, Cochrane Library, Web of Science, Chinese BioMedical Literature (CBM), Wanfang and Chinese National Knowledge Infrastructure (CNKI) databases were systematically searched to identify relevant studies published up to December 2013. Data were extracted independently by two authors. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to assess the strength of association. A total of 16 studies including 2475 HCC cases and 5381 controls were included in this meta-analysis. Overall, a significantly increased HCC risk was observed under all genetic models (G vs. A: OR = 1.383, P < 0.001, 95% CI: 1.174-1.629; GG vs. GA + AA: OR = 1.484, P < 0.001, 95% CI: 1.198-1.838; GG + GA vs. AA: OR = 1.530, P < 0.001, 95% CI: 1.217-1.924; GG vs. AA: OR = 1.958, P < 0.001, 95% CI: 1.433-2.675; GA vs. AA: OR = 1.215, P = 0.013, 95% CI: 1.041-1.418). In the subgroup analyses by ethnicity, a significant association with HCC risk was found in Asian populations (G vs. A: OR = 1.151, P = 0.001, 95% CI: 1.056-1.255), European populations (G vs. A: OR = 1.594, P = 0.027, 95% CI: 1.053-2.413, and African populations (G vs. A: OR = 3.599, P < 0.001, 95% CI: 2.550-5.080), respectively. Our study shows that EGF +61A/G polymorphism is significantly associated with the increased HCC risk, especially in Asian populations. Further large-scale and well-designed studies are required to confirm this conclusion.


Docking and scoring for nucleic acid-ligand interactions: Principles and current status.
Nucleic acid (NA)-ligand interactions have crucial roles in many cellular processes and, thus, are increasingly attracting therapeutic interest in drug discovery. Molecular docking is a valuable tool for studying molecular interactions. However, because NAs differ significantly from proteins in both their physical and chemical properties, traditional docking algorithms and scoring functions for protein-ligand interactions might not be applicable to NA-ligand docking. Therefore, various sampling strategies and scoring functions for NA-ligand interactions have been developed. Here, we review the basic principles and current status of docking algorithms and scoring functions for DNA/RNA-ligand interactions. We also discuss challenges and limitations of current docking and scoring approaches.


BEAR reveals that increased fidelity variants can successfully reduce the mismatch tolerance of adenine but not cytosine base editors.
Adenine and cytosine base editors (ABE, CBE) allow for precision genome engineering. Here, Base Editor Activity Reporter (BEAR), a plasmid-based fluorescent tool is introduced, which can be applied to report on ABE and CBE editing in a virtually unrestricted sequence context or to label base edited cells for enrichment. Using BEAR-enrichment, we increase the yield of base editing performed by nuclease inactive base editors to the level of the nickase versions while maintaining significantly lower indel background. Furthermore, by exploiting the semi-high-throughput potential of BEAR, we examine whether increased fidelity SpCas9 variants can be used to decrease SpCas9-dependent off-target effects of ABE and CBE. Comparing them on the same target sets reveals that CBE remains active on sequences, where increased fidelity mutations and/or mismatches decrease the activity of ABE. Our results suggest that the deaminase domain of ABE is less effective to act on rather transiently separated target DNA strands, than that of CBE explaining its lower mismatch tolerance.


Cold Atmospheric Pressure Plasma Device Exhibits Etching Effects on Bacterial Biofilms.
Cold atmospheric pressure plasma (CAP) treatment has been shown to kill bacteria and remove bacterial biofilms from surfaces. Here we report the etch capacity of a linear discharge CAP device on Pseudomonas fluorescens biofilms. A 21 kHz, 1.4 kV RMS AC voltage applied to the CAP electrodes generated a hydrated Ar plasma between the plates, with the gas flow directing the plasma species toward the biological sample, causing both bacterial killing and etching of the biofilm. Typical discharge currents for a 2.4 cm long, 0.6 mm wide linear discharge device were 1-4.4 mA. Hydrated Ar flow gas was critical for removal of biofilm from a stainless steel substrate, while both hydrated and dry Ar + O2, Ar + air, O2 only, and air only flow gas mixtures did not cause etching at equivalent or greater discharge current intensities. A biofilm etch rate of > 2 μm/min was achieved, provided the plasma discharge was within 1-2 mm of the substrate surface and used a hydrated Ar gas flow of at least 5 LPM.


Neurofunctional assessment of early phases of Alzheimer's disease: a preliminary note on hemispheric EEG characteristics during cognitive tasks.
EEG characteristics, in terms of power distribution in 1-4, 4-6, 6-8, 8-10, 10-13, 13-18, 18-30 Hz frequency bands were evaluated in six putative non-medicated male Alzheimer patients. The latter were compared with six age and sex-matched normal controls during both resting conditions and tactile identification tasks specific for the left and right hemispheres. The result indicate a significant difference in the power of the 8-10 frequency band between the two groups and a significant hypovariability in the 6-8 and 8-10 bands during tactile tasks: Alzheimer patients showed reduced power and, also, where less reactive, no differences between the left and right hemispheres having appeared. These findings seem to confirm the specificity of EEG modifications in Alzheimer's disease, even in the very early phases of the pathological process. Possible implications are discussed in the light of some biochemical hypotheses.


Levels of the 90kd heat shock protein and resistance to glucocorticoid-mediated cell killing in a range of human and murine lymphocyte cell lines.
The 90kd heat shock protein is associated with the receptors for glucocorticoids and other steroids. The steroid is believed to function by releasing the receptor from hsp90 allowing the receptor to bind to DNA and activate transcription. The levels of hsp90 have been measured in a variety of lymphoid cell lines and compared with their sensitivity to steroid mediating killing. No correlation of high hsp90 levels with steroid resistance was observed. However, increased levels of hsp90 in response to steroid were observed in a number of cell lines. The significance of these findings is discussed in terms of the modulation of the cells response to steroid treatment and the mechanism of steroid resistance.


Neurotoxicity of the CNS: diagnosis, treatment and prevention.
Treatment-induced CNS toxicity remains a major cause of morbidity in patients with cancer. Real advances in the design of safer radiation procedures have been counterbalanced by a wider use of combined radiotherapy (RT)-chemotherapy regimens, the development of radiosurgery, and the increasing number of long-term survivors. While classic radionecrosis or chemonecrosis have become less common, more subtle changes such as progressive cognitive dysfunction are increasingly reported after RT (radiation-induced leukoencephalopathy) or chemotherapy (administered alone or in combination). The most important and controversial complications of RT, chemotherapy and combined treatments in the CNS are reviewed here, including new diagnostic tools, practical management and prevention that will influence the future management of cancer patients.


To what degree is the governance of Dutch hospitals orientated towards quality in care? Does this really affect performance?
Changing health care systems and market competition requires hospital boards to shift their focus towards a systematic governance of the quality of care. The objective of our study was to describe hospital governance and the quality orientation in the Netherlands. Also we wished to investigate the relationship with hospital performance. The chairs of both the boards of trustees and the management boards from all 97 Dutch hospitals were asked to participate in a cross-sectional study between November 2010 and February 2011. In this period data on their quality orientation were collected using a web-based survey. Data on hospital performance over the year 2010 were obtained in July 2011. A mixture of reforms and national guidelines increased the emphasis on quality governance in Dutch hospitals. Our results show that boards of trustees and management boards had a reasonable quality orientation. Boards were familiar with quality guidelines, received a reasonable amount of information related to quality and used this for monitoring quality and policy-making. However, we found no association between their quality orientation and hospital performance. There was a growing awareness of the quality of care among boards of trustees and management boards; yet some boards still lagged behind. Quality orientation is an important asset because receiving, reviewing and responding to the quality of their performance should provide opportunities to improve quality. However, we were not able to find a relationship between quality orientation and hospital performance. Future research should investigate how boards can develop quality management systems which in turn could enable medical professionals to optimise their delivery of care and thus its quality.


Electrochemically activated pencil lead electrode as a sensitive voltammetric sensor to determine gallic acid.
An electrochemical sensor for the determination of some polyphenolic compounds such as Gallic acid (GA) and Galloyl esters was developed using the activated pencil lead electrode (APLE). At first, a study has been made of the optimum conditions for electrochemical activation of the pencil lead electrode. Potentiodynamic and potentiostatic strategies were investigated for activation of the pencil lead electrode and the results show that the potentiodynamic pretreatment gives better performance toward measurement of the polyphenolic compounds. Electrochemical properties of GA were investigated using chronoamperometry and cyclic voltammetry; and some thermodynamic and kinetic variables such as α, n α, and D were calculated. Sensitive differential pulse voltammetry (DPV) technique was applied for the determination of Gallic acid and Galloyl esters in different samples. Enhanced oxidation peak currents of Gallic acid were observed at APLE when compared with non-activated PLE. The calibration graph has two linear ranges of 0.49-24.3 µM and 0.07-0.83 mM, and the obtained limit of detection for S/N = 3 was 0.25 µM. Adsorptive stripping differential pulse voltammetry (AdSDPV) was also conducted to determine Gallic acid and Galloyl esters in sub-micromolar concentration range. Using the AdSDPV method, the limit of detection was improved and calculated to be 5.2 nM. The proposed method was successfully applied for quantification of the total concentration of Gallic acid and Galloyl esters in a variety of real samples such as black and green tea, and mango juice samples, and desirable recovery values indicated the good accuracy of the developed sensor.


Targeting molecular cross-talk between tumor cells and tumor associated macrophage as therapeutic strategy in triple negative breast cancer.
Triple-negative Breast cancer (TNBC) is a subtype of breast cancer (BC) that lacks expression for ER/PR/Her2 receptors and is associated with aggressive disease pathogenesis and the worst prognosis among other subtypes of BC. Accumulating evidence-based studies indicate the high immunogenic ability of TNBC tumors and the applicability of immunotherapeutic strategies to overcome therapy resistance and tumor recurrence in TNBC patients. However, not all TNBC patients respond equally well to current immunotherapies that mainly target the adaptive immune system for tumor rejection. Recent studies are contemplating the efficacy of tumor-associated macrophage (TAM) targeted therapies since these subpopulations of cells comprise one of the major components of tumor-infiltrating immune cells (TIIs) in the TNBC tumor microenvironment (TME) and play an essential role in priming the adaptive immune response mediators towards both antitumorigenic and pro-tumorigenic response facilitated by intercellular cross-talk between tumor cells and TAM populations present within TNBC-TME. The present review discusses these molecular mechanisms and their consequence on the progression of TNBC tumors. Also, the therapeutic strategies targeting candidate genes/pathways involved in molecular cross-talk between TAM-TNBC cells and their impact on the development and progression of TNBC tumors are also discussed.


Genome-wide analyses reveal drivers of penguin diversification.
Penguins are the only extant family of flightless diving birds. They currently comprise at least 18 species, distributed from polar to tropical environments in the Southern Hemisphere. The history of their diversification and adaptation to these diverse environments remains controversial. We used 22 new genomes from 18 penguin species to reconstruct the order, timing, and location of their diversification, to track changes in their thermal niches through time, and to test for associated adaptation across the genome. Our results indicate that the penguin crown-group originated during the Miocene in New Zealand and Australia, not in Antarctica as previously thought, and that Aptenodytes is the sister group to all other extant penguin species. We show that lineage diversification in penguins was largely driven by changing climatic conditions and by the opening of the Drake Passage and associated intensification of the Antarctic Circumpolar Current (ACC). Penguin species have introgressed throughout much of their evolutionary history, following the direction of the ACC, which might have promoted dispersal and admixture. Changes in thermal niches were accompanied by adaptations in genes that govern thermoregulation and oxygen metabolism. Estimates of ancestral effective population sizes (Ne ) confirm that penguins are sensitive to climate shifts, as represented by three different demographic trajectories in deeper time, the most common (in 11 of 18 penguin species) being an increased Ne between 40 and 70 kya, followed by a precipitous decline during the Last Glacial Maximum. The latter effect is most likely a consequence of the overall decline in marine productivity following the last glaciation.


Evidence for a band III analogue in the near-infrared absorption spectra of cytochrome c oxidase.
Ground state near-infrared absorption spectra of fully reduced unliganded and fully reduced CO (a2+ CuA+ a3(2+)-CO CuB+) cytochrome c oxidase were investigated. Flash-photolysis time-resolved absorption difference spectra of the mixed-valence (a3+ CuA2+ a3(2+)-CO CuB+) and the fully reduced CO complexes were also studied. A band near 785 nm (epsilon approximately 50 M-1cm-1) was observed in the fully reduced unliganded enzyme and the CO photoproducts. The time-resolved 785 nm band disappeared on the same timescale (t1/2 approximately 7 ms) as CO recombined with cytochrome a3(2+). This band, which is attributed to the unliganded five coordinate ferrous cytochrome a3(2+), has some characteristics of band III in deoxy-hemoglobin and deoxy-myoglobin. A second band was observed at approximately 710 nm (epsilon approximately 80 M-1cm-1) in the fully reduced unliganded and the fully reduced CO complexes. This band, which we assign to the low spin ferrous cytochrome a, appears to be affected by the ligation state at the cytochrome a3(2+) site.


The relationship of serum vitamin A, cholesterol, and triglycerides to the incidence of ovarian cancer.
Prospective and retrospective studies have suggested that serum vitamin A and total cholesterol levels may be associated with cancer. Our study showed that the mean (+/- SEM) concentrations of serum vitamin A 489 +/- 33.28 (mean +/- SEM micrograms/liter and serum total cholesterol 174.7 +/- 8.96 (mean +/- SEM) mg/dl from ovarian cancer patients in Singapore were significantly lower than the respective values of 668 +/- 25.10 (mean +/- SEM) microgram/liter and 210.7 4.48 (mean +/- SEM) mg/dl from noncancerous control subjects (P less than 0.0001 for both compounds). In addition, ovarian cancer patients did not show significantly lower serum triglyceride levels than the control subjects. Age did not significantly correlate the serum vitamin A and total cholesterol concentrations, but there was correlation with respect to the serum triglyceride levels. There were moderate correlations between vitamin A and cholesterol levels (r = 0.36, P less than 0.0027) and between cholesterol and triglyceride levels (r = 0.37, P less than 0.0024) in the control subjects but not in the cancer patients. Vitamin A levels correlated moderately with triglyceride levels in both the cancer patients (r = 0.42, P less than 0.0258) and the control subjects (r = 0.33, P less than 0.0069). The inverse relationship between the incidence of ovarian cancer and serum vitamin A and serum total cholesterol concentrations may have distinct implications for preventive medicine and public health.


Growth patterns and cardiovascular abnormalities in SGA fetuses: 2. Normal growth and progressive growth restriction.
To characterize growth processes and their associated cardiovascular abnormalities in SGA fetuses with normal growth and progressive growth restriction patterns as defined by Individualized Growth Assessment (IGA). A SGA cohort (EFW and BW < 10th percentile) was derived from the PORTO study that included 47 fetuses with normal growth outcome (SGA Normal) and 34 fetuses with progressive growth restriction (SGA Growth Restricted, Pattern 1). Composite fetal size parameters were used to quantify growth pathology at individual third trimester time points (individual composite Prenatal Growth Assessment Score {icPGAS}) and calculated cumulatively during the third trimester (Fetal Growth Pathology Score 1{FGPS1}). Paired Doppler evaluations of the umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV) and myocardial performance index (MPI) were used to detect cardiovascular anomalies. Outcome variables were birth age and birth weight. Ranking fetuses with respect to the severity of the 3rd trimester growth pathology (-FGPS1) revealed three subgroups in each of these two groups. In SGA Normal, no (51%), minimal (19%) or minor (30%) growth abnormalities were present. Although vascular flow abnormalities occurred without growth abnormalities (UA: 38%; MCA: 35%), they increased with minor growth disturbances (UA: 64%; MCA: 50%). All fetuses delivered at term and in only 7 cases (minor growth abnormalities subgroup) were the neonates abnormally small based on IGA criteria. In SGA Growth Restricted, Pattern 1, the progression of growth restriction was slow (47%), moderate (21%) and rapid (32%). Corresponding median -FGPS1 values were -1.34%, -2.67% and -4.88%, respectively. The median age of onset was 33.6, 29.7 and 29.7 weeks in these three subgroups. UA abnormalities occurred infrequently in the first two subgroups but were found in all cases of rapidly progressing pathology. Similar results were found for the MCA and DV + MPI Doppler parameters (rapid progression: MCA = 50%; DV + MPI = 50%). Premature delivery occurred less frequently with slow progression but was nearly 100% in the moderately and rapidly progressive subgroups. Negative FGPS1 growth restriction patterns can be used to classify SGA fetuses. Subgroups, based on ranked -FGPS1 values in both SGA Normal and SGA Growth Restricted Pattern 1 groups had marked differences in cardiovascular abnormalities and neonatal outcomes. The characteristics of these two groups are consistent with small, normally growing fetuses and fetuses with "early" growth restriction, respectively.


Genome-wide transcriptional changes associated with enhanced activity in the Drosophila nervous system.
Neuronal plasticity is an important feature of the developing brain and requires neuronal circuits to reconfigure their functional connectivity depending upon activity patterns. To explore changes in neuronal function that occur downstream of altered activity, we performed an expression analysis in Drosophila mutants with acute or chronic alterations in neuronal activity. We find that seizure induction leads to an overproliferation of synaptic connections, indicating that activity-dependent neuronal rewiring occurs in Drosophila. To analyze transcriptional recoding during altered neuronal activity, we performed genome-wide DNA microarray analysis following multiple seizure induction and recovery paradigms. Approximately 250 genes implicated in cell adhesion, membrane excitability, and cellular signaling are differentially regulated, including the Kek 2 neuronal cell adhesion protein, which, as we demonstrate, functions as a regulator of synaptic growth. These data identify a collection of activity-regulated transcripts that may link changes in neuronal firing patterns to transcription-dependent modulation of brain function, including activity-dependent synaptic rewiring.


The mass mortality of blue mussels (Mytilus spp.) from the Atlantic coast of France is associated with heavy genomic abnormalities as evidenced by flow cytometry.
Since 2014, France's blue mussel industry has been facing heavy mortality outbreaks (90-100%) affecting both juveniles and adults. This report presents evidence of heavy genomic abnormalities associated with mortality outbreaks in blue mussels, Mytilus edulis-galloprovincialis, from the Atlantic coast of France. In this study, ploidy characteristics of hemic cells were investigated using Flow CytoMetry (FCM), revealing an unusual, broad continuum of ploidy distribution from hypodiploidy to tetraploidy. FCM was additionally used to evaluate, at individual and populations levels, different thresholds of genomic abnormality (GA%) using the percentage of non-diploid nuclei. Individual mussels were considered to be abnormal when more than 10% of hemocytes in S-G2/M phase were present. At the population level, a threshold of 6% for the mean intensity of the abnormality is proposed, which means in the population, more than 6% of individual mussels have to present with more than 10% of their hemocytes in S-G2/M phase. GA% was found to be significantly predictive of the final mortality. Based on the established thresholds, only two mussel stocks analyzed in this study were considered to have good cytogenetic quality, while all other stocks appeared to be affected. FCM offers a very powerful tool to help manage current blue mussel mortality in France. We also believe that annual and extensive determination of cytogenetic quality of wild and cultivated mussel beds along with exclusive use of FCM-qualified mussel seeds should be a priority.


Improved linkage map and thirty new microsatellite markers for rat Chromosome 10.
An improved linkage map for rat Chromosome (Chr) 10 with two F2 populations was constructed. Thirty new microsatellite markers were generated from a Chr 10-specific, small-insert genomic library and mapped to rat Chr 10. Among them were the rat homologs for the mouse gene for light and heavy chains of myeloperoxidase and human neurofibromatosis 1. Eight newly generated markers (D10Mco62, D10Mco63, D10Mco64, D10Mco65, D10Mco67, D10Mco68, D10Mco70, and D10Mco74) were mapped to the region of the rat Chr 10 blood pressure QTL. The availability of such markers may be instrumental in the search for genes responsible for the hypertension.


Profound hypotension and associated electrocardiographic changes during prolonged cord occlusion in the near term fetal sheep.
To determine whether the onset of fetal hypotension during profound asphyxia is reflected by alterations in the ratio between the T height, measured from the level of the PQ interval, and the QRS amplitude (T/QRS ratio) and ST waveform. Chronically instrumented near-term fetal sheep received complete occlusion of the umbilical cord for either 8 (n=6) or 15-min (n=9). Cord occlusion led to sustained bradycardia and severe acidosis. Mean arterial blood pressure initially rose and then fell to a nadir of 32.6 +/- 2.6 mm Hg in the 8-min group and 9.3 +/- 1.0 mm Hg in the 15-min group (P < .001). The T/QRS ratio rose initially in parallel with mean arterial blood pressure and then reduced as mean arterial blood pressure fell but remained significantly above baseline. Biphasic ST waveforms during occlusion occurred in only 2 fetuses, but biphasic and negative waveforms occurred during reperfusion in the 15-min group, with a significant rise in troponin T levels (0.58 +/- 0.46 versus 0.02 +/- 0.01 ng/mL at 6 h, P < .01). Elevation of the T/QRS ratio does not identify fetal hypotension during severe hypoxia, but abnormal waveforms in the recovery phase may indicate developing cardiac injury.


Internal polyadenylation of parvoviral precursor mRNA limits progeny virus production.
Aleutian Mink Disease Virus (AMDV) is the only virus in the genus Amdovirus of family Parvoviridae. In adult mink, AMDV causes a persistent infection associated with severe dysfunction of the immune system. Cleavage of AMDV capsid proteins has been previously shown to play a role in regulating progeny virus production (Fang Cheng et al., J. Virol. 84:2687-2696, 2010). The present study shows that AMDV has evolved a second strategy to limit expression of capsid proteins by preventing processing of the full-length capsid protein-encoding mRNA transcripts. Characterization of the cis-elements of the proximal polyadenylation site [(pA)p] in the infectious clone of AMDV revealed that polyadenylation at the (pA)p site is controlled by an upstream element (USE) of 200 nts in length, the AAUAAA signal, and a downstream element (DSE) of 40 nts. A decrease in polyadenylation at the (pA)p site, either by mutating the AAUAAA signal or the DSE, which does not affect the encoding of amino acids in the infectious clone, increased the expression of capsid protein VP1/VP2 and thereby increased progeny virus production approximately 2-3-fold. This increase was accompanied by enhanced replication of the AMDV genome. Thus, this study reveals correlations among internal polyadenylation, capsid production, viral DNA replication and progeny virus production of AMDV, indicating that internal polyadenylation is a limiting step for parvovirus replication and progeny virus production.


Abundant Fas expression by gastrointestinal stromal tumours may serve as a therapeutic target for MegaFasL.
Although the tyrosine kinase inhibitor imatinib has been shown to be an active agent in patients with gastrointestinal stromal tumours (GIST), complete remissions are almost never seen and most patients finally experience disease progression during their course of treatment. An alternative therapeutic option is to target death receptors such as Fas. We showed that a panel of imatinib-sensitive (GIST882) and imatinib-resistant (GIST48, GIST430 and GIST430K-) cell lines expressed Fas. MegaFasL, a recently developed hexameric form of soluble Fas ligand (FasL), appeared to be an active apoptosis-inducing agent in these cell lines. Moreover, MegaFasL potentiated the apoptotic effects of imatinib. Immunohistochemical evaluations, in 45 primary GISTs, underscored the relevance of the Fas pathway: Fas was expressed in all GISTs and was expressed strongly in 93%, whereas FasL was expressed at moderate and strong levels in 35 and 53% of GISTs, respectively. Fas and FasL expression were positively correlated in these primary GISTs, but there was no association between Fas or FasL expression and primary site, histological subtype, tumour size, mitotic index, risk classification, and KIT mutation status. The abundant immunohistochemical Fas and FasL expression were corroborated by western blot analysis. In conclusion, our data implicate Fas as a potential therapeutic target in GIST.


Generation of functional multipotent keratinocytes from mouse induced pluripotent stem cells.
Recent advances in reprogramming somatic cells into induced pluripotent stem cells (iPSCs) offer the possibility of developing new therapeutic approaches for the treatment of a variety of diseases, including inherited skin disorders. While the ultimate goal is the use of iPSCs in the treatment of human diseases, extensive research is still required with preclinical mouse models before iPSC technology can be introduced into the clinic. Therefore, the methodology for the derivation of multipotent keratinocytes from mouse iPSCs is of particular importance since it may allow for the assessment of the feasibility of using iPSCs in the treatment of inherited skin disorders using mouse models which mimic these diseases. Here, we describe two alternative protocols for the efficient differentiation of mouse iPSCs into functional keratinocytes capable of reconstituting a normal stratified epidermis, hair follicles, and sebaceous glands when grafted onto mice. Each protocol results in a different yield and efficiency of keratinocyte derivation depending on the mouse genetic background used in the study. Both protocols employ applications of retinoic acid and bone-morphogenetic protein-4 and growth on collagen type IV-coated dishes to induce iPSC differentiation toward a keratinocyte lineage.


Antibody persistence and immunologic memory after sequential pneumococcal conjugate and polysaccharide vaccination in HIV-infected children on highly active antiretroviral therapy.
The capacity of pneumococcal vaccination to confer memory in HIV-infected children is critical for durable protection. HIV-infected children 2-<19 years administered two doses of pneumococcal conjugate vaccine (PCV7) and one dose of polysaccharide vaccine (PPV) on HAART were randomized 4-5 years later to receive a PCV7 or PPV booster. Total and high avidity antibodies to serotypes 1 (PPV) and 6B and 14 (PCV7 and PPV) were determined by ELISA. Memory was defined as persistence of ≥ 0.5 mcg/mL of serotype-specific antibody on day 0 or change from <0.5 mcg/mL to ≥ 0.5 mcg/mL between day 0 and week 1, or, ≥ 4-fold antibody rise between day 0 and week 1. Prior to boosting, 4-5 years after the previous PCV7-PCV7-PPV series, geometric mean concentrations (GMCs) were 0.46 mcg/mL (serotype 1), 1.31 mcg/mL (serotype 6B), and 1.47 mcg/mL (serotype 14), with concentrations ≥ 0.5 mcg/mL in 41% (serotype 1) to 82% (serotypes 6B and 14). Memory based on antibody concentration ≥ 0.5 mcg/mL before or 1 week after boosting with PCV7 or PPV was demonstrated in 42-61% for serotype 1 and 87-94% for serotypes 6B and 14, with lower rates based on day 0 to week 1 ≥ 4-fold antibody rise (serotype 1, 3-13%; serotype 6B, 13-31%; serotype 14, 29-53%). Antibody concentrations post-boosting were greater following PCV7 than PPV for serotypes 6B and 14. Ratios of highly avid to total antibody pre- and post-boosting were 0.5-0.8. Predictors of memory included higher CD4% (nadir before HAART and at P1024 and P1061s entry), CD19% (at P1024 and P1061s entry), and antibody response after the PCV7-PCV7-PPV primary series and lower viral load (at P1024 and P1061s entry) and age. Protective antibody concentrations, high avidity, and booster responses to PCV7 or PPV indicative of memory were present 4-5 years after PCV7-PCV7-PPV in HIV-infected children on HAART.


Properties and affinity purification of the mixed-type putative acetylcholine receptor from wild and a mutant strain of hose flies.
Binding of decamethonium to a soluble preparation from house fly head (either wild or a mutant strain) showed a single kind of binding with values for wild strain of Kd = 0.095 micrometers and Bmax = 0.22 nmol/mg protein. The mutant had a four-fold greater affinity and a seven-fold lesser amount. The binding was blocked by both nicotinic and muscarinic drugs. The decamethonium binding migrated in sucrose gradients as a single peak, with sedimentation coefficient s20,w = 12.5 S and therefore a molecular weight of 342 000. Purification by affinity chromatography was achieved with only partial loss of activity, andthe purified material demonstrated a single band on analytical disc gel electrophoresis. Electrophoresis in sodium dodecyl sulphate gels showed two subunits of molecular wegiths 94 000 and 64 000. Both subunits had an isoelectric point of 4.8.


The role of miRNA in stem cell pluripotency and commitment to the vascular endothelial lineage.
Vascular endothelial cells derived from human pluripotent stem cells have substantial potential for the development of novel vascular therapeutics and cell-based therapies for the repair of ischemic damage. To gain maximum benefit from this source of cells, a complete understanding of the changes in gene expression and how they are regulated is required. miRNAs have been demonstrated to play a critical role in controlling stem cell pluripotency and differentiation and are important for mature endothelial cell function. Specific miRNAs that determine stem cell fate have been identified for a number of different cell lineages; however, in the case of differentiation and specification of vascular endothelial cells, this is yet to be fully elucidated.


Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study.
Few large-scale epidemiologic studies have enrolled older adults; hence, little is known about the feasibility of recruiting this group for long-term population-based studies. In this article we present the recruitment experience of the Cardiovascular Health Study (CHS), a population-based, longitudinal study of cardiovascular diseases in adults 65 years and older. Participants were sampled from the Health Care Financing Administration's (HCFA) Medicare eligibility lists in four US communities. Letters were mailed to 11,955 sampled individuals. Persons recruited were required to complete an extensive home interview and then a 4-hour in-clinic examination. Excluded were persons who were expected to be able to complete the baseline examination and who were not expected to return for the 3-year follow-up. Some 3654 participants were recruited from those randomly selected from the Medicare sampling frame. In addition, 1547 other age-eligible persons living in the household with the sampled individuals also participated, yielding a total of 5201 participants. Of those who were contacted, 9.6% were ineligible and 34.9% refused participation. Among those eligible, 38.6% refused and 57.3% were enrolled (the remaining did not refuse but were not enrolled before the recruitment ended). Data from a subsample indicate that compared to those who were ineligible or who refused, enrolled participants were younger, more highly educated, more likely to be married, and less likely to report limitations in activity. Compared to those who were eligible but refused, enrolled participants were less likely to have high blood pressure and stroke and more likely to have quit smoking and to perceive their health status as very good or excellent.(ABSTRACT TRUNCATED AT 250 WORDS)


Conditioning of behavioural effects produced by an intermediate dose of apomorphine: hypokinesia, ptosis and stereotypies.
Apomorphine, in an intermediate dose (0.18 mg/kg s.c.) decreased dopamine turnover and produced signs generally attributed to a decrease in dopaminergic neurotransmission, e.g. ptosis and yawning, as well as signs of an increased stimulation of dopamine receptors in dopaminoceptive target neurones, e.g. stereotyped sniffing. In contrast, the former signs were exclusively observed after smaller doses and the latter after larger doses of apomorphine. Since it had been shown in previous studies that these signs, except yawning, could be conditioned in association with discriminative stimuli in the environment, the present study using conditioning experiments with this intermediate dose aimed at determining, 1. the time course of each conditioned response, 2. the interaction of conditioned and unconditioned responses, and 3. the conditions under which hypokinesia occurred. In each series, conditioned animals were compared with pseudoconditioned controls. Rats were conditioned for 8 days with apomorphine, and on day 9, treated with saline in presence of the conditional stimuli (a test cage in combination with acoustic and olfactory stimuli). In contrast to pseudoconditioned controls, ptosis and stereotyped behaviour were observed in conditioned rats, sometimes occurring alternatingly. These signs closely resembled the direct, unconditioned pharmacological effects. In addition, akinesia occurred after conditioning, although it was never manifest as a pure drug response, nor during the conditioning period. In contrast, yawning was observed in pseudoconditioned as well as in conditioned rats, although slightly more frequently in the former animals. Subsequently, the rats were again conditioned (or pseudoconditioned) on days 10-14 with apomorphine and both groups tested with the same dose (0.18 mg/kg) of apomorphine in the presence of the conditioned stimuli.(ABSTRACT TRUNCATED AT 250 WORDS)


The Phenotypes and Mechanisms of NOTCH2NLC-Related GGC Repeat Expansion Disorders: a Comprehensive Review.
The human-specific gene NOTCH2NLC is primarily expressed in radial glial cells and plays an important role in neuronal differentiation and cortical neurogenesis. Increasing studies were conducted to verify the relationship between NOTCH2NLC gene and many neurological diseases, such as neuronal intranuclear inclusion disease, essential tremor, multiple system atrophy, Parkinson's disease, Alzheimer's disease, and even oculopharyngodistal myopathy. Thus, we support the concept, NOTCH2NLC-related GGC repeat expansion disorders (NRED), to summarize all diseases with the GGC repeat expansion in the 5'UTR of NOTCH2NLC gene, regardless of their various clinical phenotypes. Here, we discuss the reported cases to analyze the clinical features of NOTCH2NLC-related GGC repeat expansion disorders, including dementia, parkinsonism, peripheral neuropathy and myopathy, leukoencephalopathy, and essential tremor. In addition, we outline radiological and pathological manifestations of NOTCH2NLC-related GGC repeat expansion disorders, and then present possible mechanisms, such as toxic polyG protein, toxic repeat RNA, the GGC repeat size, and the size and types of trinucleotide interruption. Therefore, this review provides a systematic description of NOTCH2NLC-related GGC repeat expansion disorders and emphasizes the significance for understanding this type of repeat expansion disease.


A comparative study between full-dose and half-dose intravesical immune bacille Calmette-Guérin injection in the management of superficial bladder cancer.
To determine whether a half-dose of bacille Calmette-Guérin (BCG) can reduce toxicity without affecting its efficacy in the management of non-muscle-invasive bladder cancer. From January 2012 to January 2014, 80 patients with superficial bladder cancer and in the intermediate-risk group were simply randomised to receive two different doses of BCG, i.e., a full dose of 90 mg (group A) or a half-dose of 45 mg (group B). There were no significant differences in clinical and pathological characteristics between the groups. At completion of the study, 40 patients could be evaluated in each group. All patients were evaluated for a follow-up of 12 months after treatment. There was no significant difference in recurrence rate (15 patients, 38%, in group A and 16, 40%, in group B) in the two groups, and no difference in progression rate of the disease, at eight patients (20%) in each group. There were significant differences between groups A and B in toxicity (grade 1 adverse events, 70% vs. 60%; grade 2, 18% vs. 7.5%, respectively). Grade 3 adverse events were only reported in group A (2.5%). The half dose of intravesical BCG instillation can reduce the toxicity and side-effects that are associated with the treatment of superficial bladder cancer, without affecting the efficacy of therapy.


Incremental weight loss improves cardiometabolic risk in extremely obese adults.
Excessively obese adults often acquire many metabolic disorders that put them at high risk for developing type 2 diabetes mellitus and cardiovascular disease. We investigated the hypothesis that cardiometabolic risk in a primary care cohort of 208 excessively obese adults (body mass index 40-60 kg/m(2), 48 with type 2 diabetes mellitus) would deteriorate with additional weight gain and improve incrementally beginning with 5% weight reduction. Further analysis of the Louisiana Obese Subjects Study of excessively obese patients enrolled and followed during 2005-2008 is reported. Weight loss correlated significantly with improvements in fasting plasma glucose, triglycerides, high- and low-density lipoprotein cholesterol, uric acid, alanine aminotransferase, lactate dehydrogenase, and high-sensitivity C-reactive protein. Most parameters deteriorated with weight gain and progressively improved with 5% or more weight loss. Except for low-density lipoprotein cholesterol, all risk factors significantly improved with ≥ 20% loss of body weight. Among patients who had not been diagnosed with type 2 diabetes mellitus and had normoglycemia at baseline, median fasting plasma glucose increased significantly (13%) with stable or gained weight at 1 year, but did not change significantly with reduced weight. Although glucose levels did not change significantly in patients with type 2 diabetes mellitus who gained weight, a decline beginning after 5% weight reduction culminated in 25% glucose reduction with ≥ 20% weight loss. Resting blood pressure declined independently of weight change. Very obese adults can improve their cardiometabolic risk under primary care weight management. Incremental success may help motivate further therapeutic weight reduction.


Novel oral anticoagulants for thromboprophylaxis after orthopaedic surgery.
The direct thrombin inhibitor, dabigatran, and the selective factor Xa inhibitors, rivaroxaban and apixaban, are new oral anticoagulants that are approved in many countries for prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty. All have a rapid onset of action, a low potential for food and drug interactions and a predictable anticoagulant effect that obviates the need for routine coagulation monitoring. These agents offer a convenient alternative to conventional anticoagulant drug regimens, including parenteral low-molecular-weight heparins and fondaparinux, and oral adjusted-dose vitamin K antagonists, for the prevention of venous thromboembolism in this surgical setting. This review summarizes the pharmacology, clinical trial results, bleeding risk and practical use of these new oral anticoagulants in clinical orthopaedic practice. Potential issues to be considered when using these oral anticoagulants include renal impairment, potential drug interactions, neuraxial anaesthesia and management of bleeding.


GIP and insulin release in relation to gastric emptying of a mixed meal in man.
To clarify the role of GIP (gastric inhibitory polypeptide) as an incretin, we related temporally the gastric emptying of fat, protein and glucose to plasma levels of glucose, GIP and insulin in man. Five healthy volunteers with a multiple lumen duodenal tube ingested a mixed meal with phase-specific markers for the aqueous phase, liquid fat and the solid protein phase. Duodenal passage was determined by intraduodenal infusion of a second set of phase-specific non-absorbable markers. Plasma insulin rose rapidly from a basal value of 59 pM to 300 pM at 60 min, and then declined to reach basal levels after 180 min. By contrast, plasma GIP rose more slowly than insulin, from a basal value of 9.4 pM, and remained elevated, in the range of 14-18 pM, throughout the 240 min observation period. The time course of plasma insulin concentration paralleled gastric emptying of the aqueous phase, containing most of the meal's glucose (r = 0.952, P less than 0.001). The time course of plasma GIP concentrations paralleled the gastric emptying of fat and protein (r = 0.763-0.834; P less than 0.01-0.05). Plasma insulin concentrations showed no correlation to the rate of emptying of fat and protein (r = 0.142-0.420; n.s.) and to plasma levels of GIP (r = 0.365; n.s.). The threshold for plasma glucose at which GIP would exert an incretin effect only reached at one time point, 30 min after ingestion of the meal. Our findings of simultaneously tracked gastric emptying of meal nutrients, hormone release and plasma glucose levels do not support an important physiological role for GIP as an insulinotropic hormone after ingestion of mixed meals in man.


Concurrent learning of multiple oddity discrimination in rats.
This experimental series examines rats' concurrent learning of multiple oddity discrimination and its transfer to novel stimuli. Three rats were trained to discriminate an odd object from five identical objects in a row. After acquisition of the AAAAAB problem, the BBBBBA set was added to training. At the start of concurrent training with both sets, performance on BBBBBA was significantly below chance, suggesting that rats had acquired a tendency to respond to and/or avoid specific features of objects during the initial AAAAAB training. Although all rats learned the two problems reliably, no transfer effect was observed during tests with novel sets CCCCCD and DDDDDC. After the first transfer test, rats performed reliably for stimulus sets AAAAAB, BBBBBA, CCCCCD, and DDDDDC concurrently. Although one rat showed reliable transfer for novel test problems EEEEEF and FFFFFE, the possibility of biased test performance between stimulus sets, by choosing one of two test objects, could not be excluded. However, following the transfer tests, all rats responded significantly to 20 novel problems immediately after they were introduced into training. These findings offer evidence of rats' capacity for concurrent oddity discrimination using multiple stimulus sets, as well as preliminary evidence of relational oddity learning in rats.


Seroepidemiology of human parvovirus B19 in Taiwan.
In order to determine the prevalence and risk factors of human parvovirus B19 (B19) infection in Taiwan, a seroepidemiological study was carried out in 19 townships. Serum samples were collected from 862 healthy residents, who were selected by stratified random sampling from various study areas. They were chosen from four different ethnic groups including aborigines, Fukien Taiwanese, Hakka Taiwanese, and mainland Chinese. Serum samples were screened for B19 IgG antibody by indirect antibody capture enzyme-linked immunosorbent assay (ELISA) and B19 IgM by IgM antibody capture (MAC)-ELISA, respectively. The overall prevalence of anti-B19 IgG and anti-B19 IgM was 32.8% and 0.35%, respectively. The anti-B19 seropositive rate in females was significantly higher than that of males (36.4% vs. 29.4%, P < .001). The age-sex-adjusted seropositive rate in urban townships (39.9%) was higher than that in aboriginal townships (30.5%, P < .001). The seropositive rate increased significantly with age showing a dose-response relationship (P=0.0001 based on a trend test). Blood transfusion was found to be associated with an increased seropositive rate showing a multivariate-adjusted odds ratios of 1.6.


Duplex carotid sonography: correlation with digital subtraction angiography and conventional angiography.
Duplex sonography is a relatively new technique for noninvasive evaluation of the extracranial carotid arteries. In a prospective, double-blind study of 453 vessels (229 patients) over a one-year period, an excellent correlation was found with intravenous digital subtraction angiography (DSA) in 66.3 per cent of vessels, good correlation in an additional 28.4 per cent of vessels, and poor correlation in only 5.3 per cent. Duplex was compared with conventional biplane angiography in 86 vessels (45 patients); there was excellent correlation in 71 per cent, good correlation in 20 per cent, and poor agreement in 9 per cent of vessels. Duplex sonography is a highly accurate method of evaluating the cervical carotid system and it has a complementary role with DSA.


The correlation between anergy, malnutrition and clinical outcome in an elderly hospital population.
The nutritional state of 482 out of 501 newly admitted elderly patients was assessed by anthropometry, serum protein analyses and the delayed hypersensitivity skin test (DH) on admission and after 8 and 26 weeks. The mean age of the women was 81.3 +/- 7.7 and of the men 77.9 +/- 9.3. Protein-energy malnutrition (PEM) was initially defined as three or more subnormal criteria, one in each of the three categories of measurement. The data was then reanalysed excluding anergy and using the two other criteria only. The prevalence of PEM on the first assessment was 28.5% and was 10% higher when anergy was excluded as a criterion. PEM was more common in women and increased with age. The anergic patients had lower mean values in serum protein and anthropometry than those with normal reactivity. Anergic patients had a higher mortality rate and more pressure sores than the reactive group. Nutritional supplementation was associated with an increase in skin reactivity.


Matrix metalloproteinase inhibitors (MMPIs) as attractive therapeutic targets: Recent progress and current challenges.
Matrix metalloproteinase (MMP) plays an essential role in many physiological and pathological processes. An increase in MMP activity contributes to excessive degradation and remodeling of the extracellular matrix (ECM), which has been correlated with invasion and metastasis of tumors. Matrix metalloproteinase inhibitor (MMPI) has been developed as an attractive therapeutic target for decades, suggesting inspiring therapeutic effects in preclinical studies. However, achieving specificity remains an important challenge in the development of MMPIs, limiting their clinical application and bringing about the risk of biosafety. Nanomaterials can be used as alternative candidates for MMPI design, providing a new strategy for this problem. This report reviewed the research about MMPIs, summarized their MMPs activity regulation mechanisms, and discussed their failures in clinical trials. Furthermore, we outlined several schemes of MMPIs screening and design. Finally, we reviewed the therapeutic application prospects of MMPIs and discussed the remaining challenges and solutions, which may offer new insights for the development of MMPIs studies.


Polymorphisms in schizophrenia candidate gene UFD1L may contribute to cognitive deficits.
We aimed to investigate UFD1L polymorphisms in schizophrenia and in relation to cognition. A total of 299 cases and 363 controls were genotyped, and 130 patients completed nine neuropsychological tests. We found that rs5992403 AA-genotype carriers showed lower scores on the set-shifting task. Therefore, UFD1L may participate in the core cognitive deficits observed in schizophrenia.


Three-dimensionally slanted illusory contours capture stereopsis.
In stereo capture a stereogram of a crossed illusory figure pulls a texture bounded by the illusory contours to the same depth plane with the illusory figure. We investigated whether three-dimensionally curved and slanted illusory figures could capture a repeating background texture. According to results, stereoscopic capture was perceived when a disparate illusory contour was slanted provided that the period of the background texture was consistent with the three-dimensional geometry of the illusory surface. We suggest that stereo capture is actually induced by disparate rows of points defined by vertical cut-out sectors and the induced disparity spread is constrained by illusory contours and possible discrete matches of the background texture.


LysoPC-acyl C16:0 is associated with brown adipose tissue activity in men.
Brown adipose tissue (BAT) recently emerged as a potential therapeutic target in the treatment of obesity and associated disorders due to its fat-burning capacity. The current gold standard in assessing BAT activity is [18F]FDG PET-CT scan, which has severe limitations including radiation exposure, being expensive, and being labor-intensive. Therefore, indirect markers are needed of human BAT activity and volume. We aimed to identify metabolites in serum that are associated with BAT volume and activity in men. We assessed 163 metabolites in fasted serum of a cohort of twenty-two healthy lean men (age 24.1 (21.7-26.6) years, BMI 22.1 (20.5-23.4) kg/m2) who subsequently underwent a cold-induced [18F]FDG PET-CT scan to assess BAT volume and activity. In addition, we included three replication cohorts consisting of in total thirty-seven healthy lean men that were similar with respect to age and BMI compared to the discovery cohort. After correction for multiple testing, fasting concentrations of lysophosphatidylcholine-acyl (LysoPC-acyl) C16:1, LysoPC-acyl C16:0 and phosphatidylcholine-diacyl C32:1 showed strong positive correlations with BAT volume (β= 116 (85-148) mL, R2 = 0.81, p = 4.6 × 10-7; β = 79 (93-119) mL, R2 = 0.57, p = 5.9 × 10-4 and β= 91 (40-141) mL, R2 = 0.52, p = 1.0 × 10-3, respectively) as well as with BAT activity (β= 0.20 (0.11-0.29) g/mL, R2 = 0.59, p = 1.9 × 10-4; β = 0.15 (0.06-0.23) g/mL, R2 = 0.47, p = 2.0 × 10-3 and β= 0.13 (0.01-0.25) g/mL, R2 = 0.28, p = 0.04, respectively). When tested in three independent replication cohorts (total n = 37), the association remained significant between LysoPC-acyl C16:0 and BAT activity in a pooled analysis (β= 0.15 (0.07-0.23) g/mL, R2 = 0.08, p = 4.2 × 10-4). LysoPC-acyl C16:0 is associated with BAT activity in men. Since BAT is regarded as a promising tool in the battle against obesity and related disorders, the identification of such a noninvasive marker is highly relevant.


Prevalence of beta-lactam nonsusceptible Gram-negative bacilli and use and interpretation of current susceptibility breakpoints: a survey of infectious disease physicians.
Beta-lactam-resistant Enterobacteriaceae represent an important public health problem; however, questions exist about their prevalence and the impact of recent breakpoint changes on clinical practice. We surveyed infectious disease physicians to better understand these issues. Many reported encountering resistant Enterobacteriaceae; respondents generally favored a more conservative interpretation of antimicrobial susceptibility results.


The association of insomnia with gastroesophageal reflux symptoms in biopsy-proven nonalcoholic fatty liver disease.
It is suggested that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), can be associated with insomnia and gastro-esophageal reflux disease (GERD). The relationship between GERD and insomnia in subjects with biopsy-proven NAFLD was investigated. This study enrolled 123 patients with biopsy-proven NAFLD. Insomnia was assessed by the Athens Insomnia Scale (AIS), a self-assessment psychometric instrument designed to quantify sleep difficulty based on ICD-10 criteria; AIS scores ≥ 6 were considered positive for insomnia. GERD symptoms were evaluated using a frequency scale for the symptoms of GERD (FSSG); FSSG scores ≥ 8 were considered positive. Logistic regression models were used to evaluate the association of insomnia with GERD, after adjusting for potential confounders. Thirteen patients with GERD were treated with the proton pump inhibitor rabeprazole (RPZ; 10 mg/day), for 12 weeks. Of the 123 patients, 76 (62%) were female and 87 (71%) were obese, with 34 (28%) having AIS scores ≥ 6 and 31 (25%) having FSSG scores ≥ 8. Liver biopsy revealed that 40 patients (33%) had NAFL and 83 (67%) had NASH. FSSG and AIS scores were similar in the two groups. HOMA-IR, FSSG scores and γGT (GGT) concentrations were significantly higher in insomniacs than in non-insomniacs. Logistic regression analysis demonstrated that FSSG score and GGT concentration were independently associated with insomnia. RPZ treatment resulted in significantly reductions in both AIS and FSSG scores. Nearly 30% of patients with biopsy-proven NAFLD had insomnia, which was related to GGT and GERD and could be relieved by RPZ treatment.


[The role of atherosclerotic plaque stability and inflammation in the pathogenesis of acute coronary syndrome].
To elucidate the effect of inflammation and coronary atherosclerotic plaque destabilization in the pathogenesis of acute coronary syndromes (ACS). Twenty-eight patients with ACS and 13 patients with stable angina pectoris (SA) were examined by intravascular ultrasound (IVUS). Coronary plaque morphology and areas in culprit lesions were analyzed. The serum levels of hs-CRP, MMP-9, TIMP-1, sCD40L were also measured. Soft plaques were dominant in culprit lesions of ACS patients (71.4%, 20/28), and hard plaques were dominant in culprit lesions of SA patients [76.9% (10/13), P = 0.004]. At the culprit site, plaque area, plaque burden and remodeling index were all significantly larger in culprit lesions of ACS patients than those of SA patients (all P < 0.05). Positive remodeling was more frequent in ACS patients than in SA patients, whereas negative remodeling was more frequent in SA patients (P < 0.05). The serum levels of hs-CRP, MMP-9, sCD40L were higher in ACS group compared with SA group (P < 0.05, respectively). Moreover, hs-CRP level was positively correlated with MMP-9 (r = 0.671, P = 0.000) and sCD40L (r = 0.494, P = 0.008), respectively, in ACS patients. There was no difference in TIMP-1 between two groups (P = 0.234). These results suggest that structurally vulnerable plaques are essential element in the pathogenesis of ACS and inflammation might play an important role in plaque vulnerability.


Determination of urinary steroid sulfate metabolites using ion paired extraction.
The need for laboratories accredited by the World Anti-Doping Agency (WADA) to develop methods of analysis for steroids excreted primarily as their sulfate conjugates has faced significant analytical challenges. One of the issues relates to the extraction of these metabolites from urine in a relatively pure state. The use of (-)-N,N-dimethylephedrinium bromide as an ion pairing reagent was optimised to produce a method that is selective for the extraction of steroid sulfates prior to GC-MS or LC-MS analysis, with minimal contributions from the urine matrix. The recovery of androsterone from its sulfate conjugate was determined to be 67% with a relative quantitative uncertainty of +/-14% (k = 2).


Cloning of a cDNA encoding porcine brain natriuretic peptide.
Complimentary DNA (cDNA) clones encoding porcine brain natriuretic peptide (BNP) were isolated from a porcine atrial cDNA library. The longest of the cDNA clones (1507 nucleotides) apparently originated from an unprocessed messenger RNA, since the nucleotide sequence encoding BNP-26 was interrupted by an intron of 554 nucleotides. A partial cDNA clone representing processed BNP mRNA was prepared by polymerase chain reaction. A comparison of the sequence of these two cDNAs reveals the presence of an additional intron within the sequence encoding the BNP precursor. The identification of these introns suggests that the BNP gene structure differs from the atrial natriuretic peptide gene in the location of intron 2. BNP mRNA encodes a propeptide of 131 amino acids, including a signal peptide domain (25 amino acids) and a prohormone domain (106 amino acids). Like atrial natriuretic peptide, the bioactive BNP sequence is localized at the carboxyl terminus of the prohormone. Although the carboxyl-terminal peptide sequences of porcine atrial natriuretic peptide and BNP are well conserved, there is relatively little homology within their propeptide regions.


[Generalized and lethal pentastomiasis due to Armillifer grandis (Hett, 1915)].
The authors described a case of generalised and lethal Pentastomiasis by a five years old girl. The most heavy parasitised organs are the lungs and the brain. Considering the age of the child and the uncommon density of the parasites, the authors suggest that the symptoms may follow the casual ingestion of a gravid female worm.


Milieu therapy under the primary caretaker system at the University of Michigan's Children's Psychiatric Hospital.
The inpatient service at the University of Michigan's Children Psychiatric Hospital is a multidisciplined program whose purpose is to create a therapeutic milieu in which emotionally disturbed children can live while being effectively treated. The work of the primary staff as milieu therapist on the ward is a key factor in the success or failure of many cases. This paper describes the therapeutic milieu, the primary caretaker system of staffing, and the specific role of the primary staff as milieu therapist at the hospital.


Differential effects of adenosine A1 receptor on pain-related behavior in normal and nerve-injured rats.
This study investigated the effects of N6-cyclopentyladenosine (CPA), a potent and selective adenosine A1 receptor (A1R) agonist in normal and nerve-injured rats and mechanisms of its action by behavioral tests and electrophysiological technique. The results showed: (1) In normal rats, intraperitoneal administration of CPA (1mg/kg) increased paw withdrawal latencies, in a way blocked by a selective A1R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 3mg/kg, i.p.), but had no influence on the threshold of mechanical stimulation. (2) In rats with neuropathic pain induced by spinal nerve ligation (SNL), CPA reduced thermal hyperalgesia and mechanical allodynia, which could last 6h and 10h, respectively (n=6/group, P<0.05). Both of the effects could be blocked by pretreatment of DPCPX intraperitoneally. (3) The baseline of C-fiber but not A-fiber evoked field potentials was depressed by spinal application of CPA (0.01 mM), and this effect was prevented by application of DPCPX (0.02 mM) 30 min before CPA. (4) Spinal application of CPA depressed long-term potentiation (LTP) of A- and C-fiber evoked field potentials, and both the depression could be blocked by pretreatment of DPCPX 30 min before CPA. These results suggested that the activation of A1R has different influences on normal and neuropathic rats probably due to the absence and presence of central sensitization in spinal dorsal horn.


Comparison of Modified Transtibial and Outside-In Techniques in Anatomic Single-Bundle Anterior Cruciate Ligament Reconstruction.
To compare the bending angle of anterior cruciate ligament (ACL) graft at femoral tunnel, graft maturation, and tunnel positions and the clinical outcomes of the modified transtibial (mTT) and outside-in (OI) techniques. Patients who met the inclusion criteria were divided into the mTT group (n = 50) and the OI group (n = 50). Using 3-dimensional computed tomography (3-D CT), tunnel placement and femoral tunnel bending angle were analyzed. The 3.0-T magnetic resonance imaging (MRI) was used to assess the graft signal intensity (indicative of maturation) with signal/noise quotient (SNQ). Graft tension and synovialization were evaluated with second-look arthroscopy in all cases. Clinical and functional tests were completed at 36 months of follow-up. When tunnel placements were analyzed using the quadrant method, no significant differences were found between the mTT group and the OI group. The femoral graft bending angle was reduced in the mTT group, and the total mean of SNQ values and mean SNQ values at the femoral intraosseous and proximal graft of the mTT group were significantly lower than in the OI group (P < .001), respectively. The femoral graft bending angle on the coronal and axial planes showed moderate-to-strong correlation with the SNQ values at the femoral intraosseous and proximal graft. Second-look arthroscopy revealed better synovialization in the mTT group than in the OI group (P = .040), with no significant difference in graft tension between the 2 groups (P = .328). Anatomic tunnel placements did not vary between the mTT group and the OI group. However, the mTT group had more benefits in femoral graft bending angle and showed higher graft maturity and better synovial coverage than the OI group, although there were no significant differences in clinical outcomes. The acute femoral graft bending angle might negatively affect the maturation of proximal graft. LEVEL OF EVIDENCE: Level III, retrospective comparative study.


High glucose induces renal mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which is inhibited by resveratrol.
Renal hypertrophy and extracellular matrix accumulation are early features of diabetic nephropathy. Hyperglycemia-induced oxidative stress is implicated in the etiology of diabetic nephropathy. Resveratrol has potent antioxidative and protective effects on diabetic nephropathy. We aimed to examine whether high glucose (HG)-induced NADPH oxidase activation and reactive oxygen species (ROS) production contribute to glomerular mesangial cell proliferation and fibronectin expression and the effect of resveratrol on HG action in mesangial cells. By using rat mesangial cell line and primary mesangial cells, we found that NADPH oxidase inhibitor (apocynin) and ROS inhibitor (N-acetyl cysteine) both inhibited HG-induced mesangial cell proliferation and fibronectin expression. HG-induced elevation of NADPH oxidase activity and production of ROS in mesangial cells was inhibited by apocynin. These results suggest that HG induces mesangial cell proliferation and fibronectin expression through NADPH oxidase-mediated ROS production. Mechanistic studies revealed that HG upregulated NADPH oxidase subunits p22(phox) and p47(phox) expression through JNK/NF-κB pathway, which resulted in elevation of NADPH oxidase activity and consequent ROS production. Resveratrol prevented HG-induced mesangial cell proliferation and fibronectin expression through inhibiting HG-induced JNK and NF-κB activation, NADPH oxidase activity elevation and ROS production. These results demonstrate that HG enhances mesangial cell proliferation and fibronectin expression through JNK/NF-κB/NADPH oxidase/ROS pathway, which was inhibited by resveratrol. Our findings provide novel therapeutic targets for diabetic nephropathy.


Spray-on magnetic skin for robotic actuation.
A minimalist robot construction strategy offers versatility and compatibility in actuating diverse objects on demand.


Synthesis and in vitro antitumor activity of asperphenamate derivatives as autophagy inducer.
In an effort to improve the aqueous solubility and the antitumor activity of natural product asperphenamate, we have designed and synthesized three series of asperphenamate derivatives, including series I (simplifying molecular skeleton series), series II (introducing a hydroxyl group to A-phenyl ring series) and series III (disrupting molecular planarity series). All derivatives have displayed a significantly increased solubility compared with asperphenamate. Their growth inhibitory activities in vitro were screened by the standard MTT method in MCF-7, HeLa, and BEL-7402 cell lines. With the exception of the derivatives in series I, most of derivatives in series II and series III showed growth inhibitory activity. Among all derivatives, IM23b in series III showed the greatest potency in human breast cancer MCF-7 cells. The cellular potency of IM23b was approximately 1.5-fold more potent than that of cisplatin. The mechanism of cell death induced by IM23b in human breast cancer MCF-7 cells was further investigated. We concluded that the cell death was induced by autophagy instead of apoptosis or cell cycle arrest.


Contact with mothers for children in out-of-home-care: Group-based trajectory modelling from the Pathways of Care Longitudinal Study (POCLS).
Good quality contact with birth parents is considered important to successful out-of-home care (OOHC) placements. There is, however, an absence of empirical evidence about contact needs of children in the OOHC system and how these needs change over time. The current analysis analyzed four waves of data from the Pathways of Care Longitudinal Study in Australia relating to 1507 children on yearly frequency of contact with mothers, relationship quality with mothers, and the extent that contact met the needs of the child. Group-based trajectory modelling was used to examine in what ways frequency of contact, child-mother relationships and child's needs for maintaining family contact were associated over time. The analysis showed a positive association between these three outcomes that also held true as the children aged, with five distinct patterns: (1) low frequency and poor relationship (low poor) (14.5 % of the sample); (2) moderate frequency and poor relationship (moderate poor) (30.3 %); (3) increasing frequency and improving relationship (improving) (19.8 %); (4) declining frequency and declining relationship (declining) (19.5 %); and (5) high frequency, good relationship (high good) (15.9 %). Care type, child demographics, child socioemotional wellbeing and unsupervised contact arrangements were significantly associated with trajectory group membership. These results can be used to inform policy and practice around contact and to better match the heterogenous contact needs for children in OOHC.


An exon skipping in a SEPALLATA-Like gene is associated with perturbed floral and fruits development in cucumber.
We isolated a mutant showing perturbations in the development of male and female floral organs and fruits. Analysis of the single nucleotide polymorphisms from bulked F2 pools identified the causative variant occurring in Csa4G126690. Csa4G126690 shows high homology to Arabidopsis SEPALLATA2 (SEP2) thus being designated CsSEP2. The causative variant was located on the splicing site of CsSEP2, resulting in the skipping of exon 6 and abolishment of the transcriptional activity. Our data suggest that CsSEP2 is involved in the floral organ and fruits development by conferring transcriptional activity.


Prevention of acute lung allograft rejection in rat by the janus kinase 3 inhibitor, tyrphostin AG490.
Tyrphostin AG490 (AG490) potently and selectively inhibits gammac/Janus kinase 3-dependent signaling pathways, including downstream Stat5a/b activation and subsequent T cell proliferation by alloantigen stimulation. We evaluated the effects of AG490 on acute rat lung allograft rejection. A 7-day course of an intraperitoneal (IP) injection with 10 mg/kg, 15 mg/kg, or 20 mg/kg AG490 was administered to inhibit the rejection of orthotopically transplanted Brown Norway (RT1n) rat lung allografts in Fischer 344 (RT1(1vl)) rat recipients. The progression of allograft rejection was evaluated by X-ray with a semi-quantitative scoring system and was evaluated histologically with a semi-quantitative rejection scoring system for acute lung allograft rejection. Moreover, to determine whether AG490 regulates CD4+ T cell differentiation during acute rejection, flow cytometry was used to investigate Th1 (interferon-gamma) and Th2 (interleukin [IL]-4, IL-10) intracellular cytokine profiles and the CD4+CD25+ T cell population in recipient splenocytes. Results of radiology and histology confirmed that treatment with AG490 significantly suppressed acute lung allograft rejection. Furthermore, the splenocytes of the AG490-treated recipients had significantly lower production of interferon-gamma and relatively higher production of IL-10, implying that a Th2 shift was induced by AG490. In addition, AG490-treated recipients had a significantly increased population of CD4+CD25+ T cells in their splenocytes on Day 6 after transplantation. These findings suggest that treatment with AG490 prevents acute lung allograft rejection in rats. The effects of AG490 may contribute to development of CD4+CD25+ T cells and a Th2 shift of CD4+ T cells.


Evaluating Partitioned Survival and Markov Decision-Analytic Modeling Approaches for Use in Cost-Effectiveness Analysis: Estimating and Comparing Survival Outcomes.
The objective of this study was to assess long-term survival outcomes for nivolumab and everolimus in renal cell carcinoma predicted by three model structures, a partitioned survival model (PSM) and two variations of a semi-Markov model (SMM), for use in cost-effectiveness analyses. Three economic model structures were developed and populated using parametric curves fitted to patient-level data from the CheckMate 025 trial. Models consisted of three health states: progression-free, progressed disease, and death. The PSM estimated state occupancy using an area under-the-curve approach from overall survival (OS) and progression-free survival (PFS) curves. The SMMs derived transition probabilities to calculate patient flow between health states. One SMM assumed that post-progression survival (PPS) was independent of PFS duration (PPS Markov); the second SMM assumed differences in PPS based on PFS duration (PPS-PFS Markov). All models provide a reasonable fit to the observed OS data at 2 years. For estimating cost effectiveness, however, a more relevant comparison is between estimates of OS over the modeling horizon, because this will likely impact differences in costs and quality-adjusted life-years. Estimates of the incremental mean survival benefit of nivolumab versus everolimus over 20 years were 6.6 months (PSM), 7.6 months (PPS Markov), and 7.4 months (PPS-PFS Markov), reflecting non-trivial differences of + 14% and + 11%, respectively, compared with PSM. The evidence from this study and previous work highlights the importance of the assumptions underlying any model structure, and the need to validate assumptions regarding survival and the application of treatment effects against what is known about the characteristics of the disease.


Physiotherapists' experiences of osteoarthritis guidelines in primary health care - an interview study.
Osteoarthritis is a common joint disease, globally. Guidelines recommend information, exercise and, if needed, weight reduction as core treatment. There is a gap between evidence-based recommended care for osteoarthritis and clinical practice. To increase compliance to guidelines, implementation was conducted. The aim of the study was to explore physiotherapists' experiences of osteoarthritis guidelines and their experiences of implementation of the guidelines in primary health care in a region in southern Sweden. Eighteen individual, semi-structured interviews with physiotherapists in primary health care were analysed with inductive qualitative content analysis. The analysis resulted in two categories and four subcategories. The physiotherapists were confident in their role as primary assessors for patients with osteoarthritis and the guidelines were aligned with their professional beliefs. The Supported Osteoarthritis Self-Management Programme, that is part of the guidelines, was found to be efficient for the patients. Even though the physiotherapists followed the guidelines they saw room for improvement since all patients with hip and/or knee osteoarthritis did not receive treatment according to the guidelines. Furthermore, the physiotherapists emphasised the need for management's support and that guidelines should be easy to follow. The physiotherapists believed in the guidelines and were confident in providing first line treatment to patients with osteoarthritis. However, information about the guidelines probably needs to be repeated to all health care providers and management. Data from a national quality register on osteoarthritis could be used to a greater extent in daily clinical work in primary health care to improve quality of care for patients with osteoarthritis.


Mitochondrial genomic analyses provide new insights into the "missing" atp8 and adaptive evolution of Mytilidae.
Mytilidae, also known as marine mussels, are widely distributed in the oceans worldwide. Members of Mytilidae show a tremendous range of ecological adaptions, from the species distributed in freshwater to those that inhabit in deep-sea. Mitochondria play an important role in energy metabolism, which might contribute to the adaptation of Mytilidae to different environments. In addition, some bivalve species are thought to lack the mitochondrial protein-coding gene ATP synthase F0 subunit 8. Increasing studies indicated that the absence of atp8 may be caused by annotation difficulties for atp8 gene is characterized by highly divergent, variable length. In this study, the complete mitochondrial genomes of three marine mussels (Xenostrobus securis, Bathymodiolus puteoserpentis, Gigantidas vrijenhoeki) were newly assembled, with the lengths of 14,972 bp, 20,482, and 17,786 bp, respectively. We annotated atp8 in the sequences that we assembled and the sequences lacking atp8. The newly annotated atp8 sequences all have one predicted transmembrane domain, a similar hydropathy profile, as well as the C-terminal region with positively charged amino acids. Furthermore, we reconstructed the phylogenetic trees and performed positive selection analysis. The results showed that the deep-sea bathymodiolines experienced more relaxed evolutionary constraints. And signatures of positive selection were detected in nad4 of Limnoperna fortunei, which may contribute to the survival and/or thriving of this species in freshwater. Our analysis supported that atp8 may not be missing in the Mytilidae. And our results provided evidence that the mitochondrial genes may contribute to the adaptation of Mytilidae to different environments.


Search for hepatitis delta virus (HDV) infection in hepatitis C patients in north-eastern Poland. Comparison with anti-HDV prevalence in chronic hepatitis B.
Hepatitis C virus and hepatitis D virus have been shown to suppress HBsAg synthesis. Thus it is possible that HDV infection occurs despite the lack of detectable HBsAg. The aim of our study was to (a) determine the prevalence of HDV infection in patients with chronic hepatitis C (b) compare it with the prevalence of HDV infection in HBsAg positive patients with hepatitis B. The study group consisted of 51 chronic hepatitis C patients, 30 HIV infected drug addicts (27 of them were also positive for anti-HCV) and 102 hepatitis B patients. The participants were tested for anti-HDV, anti-HCV and HBsAg. All anti-HCV positive patients were negative for anti-HDV. Four individuals with anti-HDV belonged to hepatitis B group and constituted 3.9% of all HBsAg positive subjects. We conclude that (a) there is currently no evidence of HDV infection among HCV infected patients in our region (b) hepatitis delta infection is rare in north-eastern Poland.


A 3D characterization method of geometric variation in edentulous mandibles.
The aim of this study was to perform an exploratory analysis of the morphological variations of mandibles at diverse states of edentulousness using tridimensional geometric morphometrics. Twelve cadaveric mandibles were selected and divided in three groups: dentate (G1), partially edentate (G2) and totally edentate (G3). CT scans, segmentation and digital reconstruction of 3D surfaces of each specimen was made. Thirteen landmarks were defined; the measurement error was determined and 3D morphometrics exploratory analysis by principal components (PCs) and PC scores was performed. The principal shape variations in G2 and G3 compared to G1 can be summarized as follows: (1) decrease in the mid body mandibular height of 24% in G2 and 41% in G3, (2) decrease of symphysis height of 16% in G2 and 37% in G3, (3) a decrease in posterior mandibular height of 30% in both G1 and G2, (4) a deeper sigmoid notch also in both groups and finally (5) a widening of 7.7% in the cross sectional morphology on the symphysis in G3. The 3D morphometric methods, combined with surface morphing tools confirmed the main patterns of bone changes in edentulous mandibles, referenced in the literature. The average 3D mandibular morphologies of each edentulousness state group was also defined. These methods could offer more accurate definition of shape variations, which is critical in a clinical context. This study provides clinicians with highlights of 3D morphological mandibular variations at different states of edentulism and not only in 2D projections as they are currently described. The 3D surface model for each group in PDF3D file format, are include in supplementary material.


Physiologic Growth Hormone-Replacement Therapy and Craniopharyngioma Recurrence in Pediatric Patients: A Meta-Analysis.
A systematic review and meta-analysis were conducted to examine the effect of growth hormone-replacement therapy (GHRT) on the recurrence of craniopharyngioma in children. PubMed, Embase, and Cochrane databases were searched through April 2017 for studies that evaluated the effect of GHRT on the recurrence of pediatric craniopharyngioma. Pooled effect estimates were calculated with fixed- and random-effects models. Ten studies (n = 3487 patients) met all inclusion criteria, including 2 retrospective cohorts and 8 case series. Overall, 3436 pediatric patients were treated with GHRT after surgery and 51 were not. Using the fixed effect model, we found that the overall craniopharyngioma recurrence rate was lower among children who were treated by GHRT (10.9%; 95% confidence interval 9.80%-12.1%; I2 = 89.1%; P for heterogeneity <0.01; n = 10 groups) compared with those who were not (35.2%; 95% confidence interval 23.1%-49.6%; I2 = 61.7%; P for heterogeneity = 0.11; n = 3); the P value comparing the 2 groups was <0.01. Among patients who were treated with GHRT, subgroup analysis revealed that there was a greater prevalence of craniopharyngioma recurrence among studies conducted outside the United States (P < 0.01), single-center studies (P < 0.01), lower impact factor studies (P = 0.03), or studies with a lower quality rating (P = 0.01). Using the random-effects model, we found that the results were not materially different except for when stratifying by GHRT, impact factor, or study quality; this led to nonsignificant differences. Both Begg's rank correlation test (P = 0.7) and Egger's linear regression test (P = 0.06) indicated no publication bias. This meta-analysis demonstrated a lower recurrence rate of craniopharyngioma among children treated with GHRT than those who were not.


Early signs of neurolipidosis-related behavioural alterations in a murine model of metachromatic leukodystrophy.
Arylsulfatase A (ASA)-deficient mice represent an animal model for the lysosomal storage disorder metachromatic leukodystrophy (MLD). Although the model has been applied in pathophysiological and therapeutic studies, the behavioural phenotype of ASA(-/-) mice is only partially characterized, and the most decisive outcome measures for therapy evaluation only emerge beyond 1 year of age. Presently, ASA(-/-) mice and ASA(+/-) control mice were studied at 6 and 12 months of age on an extensive battery including tests of neuromotor ability, exploratory behaviour, and learning and memory. Overt signs of ataxia were not observed in 6-month-old ASA(-/-) mice, but quantitative gait analysis during open-field exploration revealed that ASA(-/-) mice displayed increased hind base width and increased stride lengths for all paws. Their covert motor incoordination was evident in a correlation analysis which unveiled decreased harmonisation of concurrent gait parameters. For example, while ASA(+/-) controls demonstrated substantial convergence of front and hind base width (r=0.54), these variables actually diverged in ASA(-/-) mice (r=-0.37). Furthermore, various behavioural observations indicated emotional alterations in ASA(-/-) mice. Six-month-old ASA(-/-) mice also showed decreased response rates in scheduled operant responding. The present findings could provide relevant behavioural outcome measures for further use of this murine MLD model in preclinical studies.


Evaluation of the curing depth of two translucent composite materials using a halogen and two LED curing units.
This in vitro study evaluated the influence of one halogen and two light-emitting diode (LED) curing units on the curing depth of a conventional hybrid and two translucent resin composites by measuring the Knoop microhardness. In the first part of the study, a conventional hybrid resin composite and three curing units (one halogen: 40 s polymerization time, two LEDs: 10 and 20 s) were used. Ten cylindrical resin composite samples were prepared for each curing unit and each polymerization time tested. After polymerization, the soft part of the samples was removed. The samples were embedded in a polyacrylic resin and separated in the middle towards the direction, top-bottom. On the section plane, Knoop microhardness measurements were performed every 1 mm, starting at 0.5 mm under the surface. In the second part of the study, two translucent resin composites and a conventional hybrid composite resin were cured with the three curing units, and the microhardness was measured as mentioned above. The difference between the curing units tested was found statistically significant (p = 0.0009), as well as the difference between the materials concerning curing depth (p = 0.0001). Both translucent materials achieved microhardness values equal to the 80% of the surface values, in depths 3.5-5.5 mm, depending on the curing units used.