Evidence for separate carriers for purine nucleosides and for pyrimidine nucleosides in the renal brush border membrane.
The aim of the present study was to test if the transport of all nucleosides in rat renal brush border membranes occurs via a common carrier or if specific carriers exist for various groups of nucleosides. We measured the inward transport of radiolabeled nucleosides into brush border vesicles. The effect of unlabeled nucleosides present inside of the vesicles (trans-stimulation) or outside of the vesicles (cis-inhibition) was studied. Uphill influx of a nucleoside into the vesicles could be driven by the efflux of another nucleoside (trans-stimulation) if they were both purines or both pyrimidines but not if one nucleoside was a purine and the other one a pyrimidine. Thus, there exist a carrier that transports various purine nucleosides, and a carrier that transports various pyrimidine nucleosides, but the tested purine nucleosides and the tested pyrimidine nucleosides do not appear to be transported by the same carrier. Uridine and thymidine were similarly potent for the inhibition of cytidine transport whereas uridine was much more potent than thymidine for the inhibition of adenosine transport. This suggests that cytidine and adenosine can use different carriers. Preincubation of the vesicles with N-ethylmaleimide resulted in a marked decrease of the rate of transport of purine nucleosides but it had little effect on the transport of pyrimidine nucleosides. These data are best explained by the presence in the renal brush border membrane of two carriers, one for purine nucleosides, the other one for pyrimidine nucleosides.(ABSTRACT TRUNCATED AT 250 WORDS)


Dielectrophoretic capture voltage spectrum for measurement of dielectric properties and separation of cancer cells.
In this paper, a new dielectrophoresis (DEP) method based on capture voltage spectrum is proposed for measuring dielectric properties of biological cells. The capture voltage spectrum can be obtained from the balance of dielectrophoretic force and Stokes drag force acting on the cell in a microfluidic device with fluid flow and strip electrodes. The method was demonstrated with the measurement of dielectric properties of human colon cancer cells (HT-29 cells). From the capture voltage spectrum, the real part of Clausius-Mossotti factor of HT-29 cells for different frequencies of applied electric field was obtained. The dielectric properties of cell interior and plasma membrane were then estimated by using single-shell dielectric model. The cell interior permittivity and conductivity were found to be insensitive to changes in the conductivity of the medium in which the cells are suspended, but the measured permittivity and conductivity of cell membrane were found to increase with the increase of medium conductivity. In addition, the measurement of capture voltage spectrum was found to be useful in providing the optimum operating conditions for separating HT-29 cells from other cells (such as red blood cells) using dielectrophoresis.


Characterizing dynamic properties of retinal vessels in the rat eye using high speed imaging.
The dynamic properties of retinal vessels including pulse wave propagation and pulsatility index provide new perspective in retinal hemodynamic analysis. In this study we utilize a high speed imaging system to capture these characteristics in the rat eye for the first time. Retinal video images of 9 Wistar-Kyoto (WKY) rats were captured at a rate of 250 frames per second for 10s with a 50° field of view using a high speed camera (Optronis, Kehl, Germany). Two recordings were taken from each rat at the same sites for repeatability analysis. The electrocardiogram (ECG) was measured simultaneously with retinal images. Arterial retinal pulse wave velocity (rPWV) and arterial/venous pulse amplitude were calculated from recorded images. Arterial measurements were repeated in another normotensive strain of the same age (Sprague-Dawley, n=4). The average WKY rPWV was 11.4 ± 6.1 cm/s. The differences between repeated measures were not significant (-2.8 ± 2.9 cm/s, p=0.2). Sprague-Dawley animals had a similar rPWV (9.8 ± 2.2 cm/s, p=0.61). The average arterial and venous pulse amplitude was 7.1 ± 1.5 μm and 8.2 ± 2.0 μm respectively. There was a positive correlation between rPWV and heart rate in the WKY groups (r(2)=0.32). A positive correlation was also obtained between arterial and venous diameter and their pulse amplitude (r(2)=0.67 and r(2)=0.37 respectively). rPWV was associated with heart rate. Higher pulsation amplitude was also correlated with larger vessel diameter. High speed imaging of retinal vessels in the rat eye provides an accurate and robust method to study dynamic characteristics of these vessels and their relationship with ocular and systemic abnormalities.


Empirically derived lifespan polytraumatization typologies: A systematic review.
Polytraumatization classes based on trauma endorsement patterns relate to distinct clinical outcomes. Person-centered approaches robustly evaluate the nature, and construct validity of polytraumatization classes. Our review examined evidence for the nature and construct validity of lifespan polytraumatization typologies. In September 2016, we searched Pubmed, PSYCINFO, PSYC ARTICLES, Academic Search Complete, PILPTS, Web of Science, CINAHL, Medline, PsycEXTRA, and PBSC. Search terms included "latent profile," "latent class," "latent analysis," "person-centered," "polytrauma," "polyvictimization," "traumatization," "lifetime," "cooccurring," "complex," "typology," "multidimensional," "sequential," "multiple," "subtype," "(re)victimization," "cumulative," "maltreatment," "abuse," and "stressor." Inclusionary criteria included: peer-reviewed; latent class/latent profile analyses (LCA/LPA) of lifespan polytrauma classes; adult samples of size greater than 200; only trauma types as LCA/LPA indicators; mental health correlates of typologies; and individual-level trauma assessment. Of 1,397 articles, nine met inclusion criteria. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, research assistants completed a secondary reference search, and independently extracted data with standardized coding forms. Three-class (n = 5) or four-class (n = 4) solutions were found. Seven studies found a class characterized by higher trauma endorsement (high-trauma). All studies found a class characterized by lower trauma endorsement (low-trauma), and predominance of specific traumas (specific-trauma; e.g., childhood maltreatment). High-trauma versus low-trauma classes and specific-trauma versus low-trauma classes differed on mental health correlates. Evidence supports the prevalence of a high-trauma class experiencing poorer mental health, and the detrimental impact of aggregated interpersonal and other traumas. We highlight the clinical importance of addressing polytraumatization classes, and comprehensively assessing the impact of all traumas.


Glomerular hemodynamic and structural correlations in long-term experimental diabetic rats.
The glomerular functional and histologic alterations present in rats after 1 year of severe experimental diabetes mellitus were examined. Determination of single nephron function revealed a significant decline (27%) in glomerular plasma flow, primarily as a consequence of a significant increase in afferent arteriolar resistance. Single nephron filtration rate was not decreased proportionate to the decline in glomerular plasma flow, principally because of a significant increase (33%) in the ultrafiltration coefficient. As a result, single nephron filtration fraction was significantly increased by 24%. These functional changes in diabetic rats were similar to those observed after only 1 month of experimental diabetes; however, considerable progression in the glomerular histopathologic characteristics was evident in rats diabetic for 1 year. These changes were characterized by an increased glomerular mesangial matrix, focal glomerulosclerosis, and intense staining for rat IgG and C3 in mesangial regions. We propose that these histologic changes may be a consequence of long-term increases in the filtration fraction particularly associated with decreases in nephron blood flow, functional changes that may favor mesangial localization of phlogogenic macromolecules.


Alloactivated cytotoxic T cells recognize the carboxy-terminal domain of human immunodeficiency virus-1 gp120 envelope glycoprotein.
Infection with the human immunodeficiency virus (HIV) virus leads to clinical disease in humans but not in chimpanzees. Progression to disease is associated with activation of the immune system followed by loss of T helper cell function and a slow decline in CD4-positive lymphocytes. The presence of autoreactive and cytotoxic cells in humans but not chimpanzees suggests that mechanisms other than, or in addition to, direct virus-induced cell killing, are required for disease to develop. The observed changes are similar to those seen in chronic allogeneic disease. Here we show that a peptide from the carboxy terminus of gp120, predicted to have a structure similar to the major alpha-helices of major histocompatibility complex (MHC) class I and class II, acts as a cytolytic target when presented on syngeneic cells for alloactivated cytotoxic T effector cells. These data add further evidence to the hypothesis that HIV can act as an allostimulant due to its dual properties of CD4 binding and MHC mimicry. The ability to signal nonspecifically through the T cell receptor could explain the initially paradoxical responses of proliferation, anergy and apoptosis.


Rhabdomyolysis After Hyperemesis Gravidarum.
Hyperemesis gravidarum may lead to hypovolemia and substantial electrolyte abnormalities, including hypokalemia. Hypokalemia, when profound, may result in rare consequences, such as rhabdomyolysis. A 20-year-old woman with hyperemesis gravidarum at 19 weeks of gestation presented with extreme leg weakness and was found to have hypokalemia and hypophosphatemia. Her course was complicated by rhabdomyolysis, which, after excluding other causes, was attributed to hypokalemia and severe dehydration. After aggressive electrolyte and hydration repletion, she experienced resolution of her symptoms. Pregnancies complicated by hyperemesis gravidarum represent potentially high-risk clinical scenarios for electrolyte abnormalities and subsequent complications, including rhabdomyolysis.


The efficacy and safety of azithromycin in asthma: A systematic review.
Azithromycin is a potential therapeutic choice for asthma control, which is a heterogeneous airway inflammatory disease. Because of variable findings, we intend to evaluate the therapeutic effect and safety of azithromycin in asthma. Databases, including PubMed, EMBASE, Cochrane, and CNKI until 31 December 2017, were searched to identify available randomised controlled trials regarding azithromycin treatment for asthma. We identified seven studies involving 1520 cases that met our criteria. The mean difference for lung function (FEV1 , FVC, PEF), symptom assessment (ACQ, AQLQ), airway inflammation, and risk ratios for adverse events were extracted. Chi-square and I2 tests were applied to evaluate the heterogeneity among the studies towards each index with a random effect model or a fixed effect model. Pooled analysis shows that azithromycin administration results in no significant improvement in FEV1 (MD: 0.09, 95% CI -0.10 to 0.29, P = 0.36), PEF (MD: 11.76; 95% CI, -2.86 to 26.38, P = 0.11), total airway inflammatory cells (MD: -0.29; 95% CI, -1.38 to 0.80, P = 0.60), ACQ (MD: 0.05; 95% CI, -0.08 to 0.19, P = 0.44), and AQLQ (MD: 0.12; 95% CI, -0.02 to 0.26, P = 0.10). Moreover, no significant difference was detected in adverse events (Risk ratio 0.99; 95% CI, 0.82-1.19, P = 0.90). These findings demonstrate no beneficial clinical outcome of azithromycin in asthma control, and we propose that further prospective cohorts are warranted.


Integrated process approach for degradation of p-cresol pollutant under photocatalytic reactor using activated carbon/TiO2 nanocomposite: application in wastewater treatment.
Over the years, biodegradation has been an effective technique for waste water treatment; however, it has its own limitations. In order to achieve a higher degradation efficacy, integrated processes are being focus in this area. Therefore, the present study is targeted towards the coupling of biodegradation and photocatalytic degradation of p-cresol. The biodegradation of p-cresol was performed via lab isolate Serratia marcescens ABHI001. The obtained results confirmed that ~85% degradation of p-cresol was accomplished using Serratia marcescens ABHI001 strain in 18 h. Consequently, degradation of remaining residue (remaining p-cresol concentration initially used) was also examined in a batch reactor using activated carbon-TiO2 nanocomposite (AC/TiO2-NC) as a catalyst under the exposure of UV radiation. The AC/TiO2-NC was processed via sol-gel technique and characterized by various techniques, namely Brunauer-Emmett-Teller (BET), scanning electron microscope (SEM), X-ray diffraction (XRD), and Fourier transformed infrared spectroscopy (FT-IR). The investigation allowed p-cresol degradation further augment up to ~96% with the help of spectrophotometer trailed by high performance liquid chromatography (HPLC). This study demonstrates that integrated process (biodegradation-photodegradation) is the cost-effective bioremediation process to overcome such kinds of pollutant issues.


[Revision of the European pharmaceutical legislation].
In accordance with the Regulation N 2309/93/EC, the Commission shall produce a synopsis of European registration operating procedures no later than 2001. On July 18, 2001, after a wide open consultation, the College of Commissioners adopted a Proposed Revision elaborated by the "DG Enterprises". This Proposed Revision was guided by the desire to facilitate access of citizens of the European Union to innovating and safe medications, to limit fragmentation of the interior market, prejudicial to the community pharmaceutical industry, and to prepare widening of the community. This synopsis focused essentially on registration procedures and pharmacovigilance, on patient information, on reform of the European agency for administrative protection of recorded data. The Proposed Revision is following the codecision procedure and should come into force, in a more or less amended form, at the end of 2004 at the latest.


Immune hemolytic anemia associated with streptococcal preparation OK-432.
In the course of administration of an immunopotentiator, streptococcal agent OK-432, a patient with lung cancer was found to have severe anemia and a strongly positive antiglobulin test. In the absence of the drug, eluates from the patient's erythrocytes reacted strongly by the indirect antiglobulin test with a panel of washed Group O erythrocyte samples. The eluated antibody was composed of monoclonal IgG1-lambda. Upon discontinuing the drug the patient's hemoglobin level increased slowly with concomitant normalization of the reticulocyte count. Although very rare, drug-induced immune hemolytic anemia should be included in the list of adverse effects of immunopotentiators. This is the first reported case of immune hemolytic anemia associated with OK-432.


Influence of hydroxylation and conjugation of bile salts on their membrane-damaging properties--studies on isolated hepatocytes and lipid membrane vesicles.
To characterize the relative toxicity of different bile salts, isolated hepatocytes were incubated with different concentrations of one bile salt or with identical concentrations of different bile salts and their conjugates. Incubation lasted for 1 hr; samples were taken at intervals and studied for enzyme release, urea synthesis and stimulation by glucagon, and by electron microscopy. While the trihydroxylated bile salt, taurocholate, did not produce alterations at concentrations up to 1,500 microM, the dihydroxylated salts, chenodeoxy- and deoxycholate, caused enzyme release and membrane lysis, and inhibited urea synthesis at concentrations above 500 microM. In contrast, ursodeoxycholate was ineffective at concentrations up to 1,500 microM. Conjugation of these bile salts did not result in significant differences with the exception of deoxycholate conjugates which induced enzyme leakage more rapidly. Studies of lipid membrane vesicles revealed corresponding alterations. The monohydroxylated salt, taurolithocholate, caused cellular damage as indicated by enzyme loss and impairment of hormonal sensitivity of cells at low concentrations (30 to 100 microM). Dihydroxylated salts produced a different time course of membrane leakage, ultrastructural changes and release of volume marker and lipid in liposomes, suggesting a possible different mechanism of damage induced by this bile salt. Both systems can readily be used to study bile salt membrane interactions.


Efficacy of tivozanib treatment after sorafenib in patients with advanced renal cell carcinoma: crossover of a phase 3 study.
Tivozanib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 tyrosine kinases. This open-label, crossover clinical study (AV-951-09-902) provided access to tivozanib for patients who progressed on sorafenib in TIVO-1, comparing tivozanib with sorafenib in patients with advanced renal cell carcinoma (RCC). Patients enrolled in this single-arm, phase 2 crossover study were previously randomised to sorafenib on TIVO-1, progressed and then crossed over to tivozanib. Patients received tivozanib (1.5 mg/day orally; 3 weeks on/1 week off) within 4 weeks after their last sorafenib dose. Crossover patients were exposed to tivozanib for a median of eight cycles. From the start of tivozanib treatment, median progression-free survival was 11.0 months (95% confidence interval [CI]: 7.3-12.7) and median overall survival was 21.6 months (95% CI: 17.0-27.6). Best overall response was partial response in 29 (18%) patients and stable disease in 83 (52%) patients, with a median duration of response of 15.2 and 12.7 months, respectively. About 77% of patients experienced adverse events, most frequently hypertension (26%), followed by diarrhoea (14%) and fatigue (13%); 53% of patients had treatment-related adverse events, including 24% grade ≥3. About 9% and 16% of patients had dose reductions and dose interruptions due to adverse events, respectively. A total of 30% of patients had serious adverse events, and 4% had treatment-related serious adverse events. This crossover study of patients with advanced RCC demonstrated potent tivozanib anti-tumour activity. Safety and tolerability profiles were acceptable and consistent with the established adverse event profile of tivozanib.


Calix[4]arene-Functionalised Silver Nanoparticles as Hosts for Pyridinium-Loaded Gold Nanoparticles as Guests.
A series of lipophilic gold nanoparticles (AuNPs) circa 5 nm in diameter and having a mixed organic layer consisting of 1-dodecanethiol and 1-(11-mercaptoundecyl) pyridinium bromide was synthesised by reacting tetraoctylammonium bromide stabilised AuNPs in toluene with different mixtures of the two thiolate ligands. A bidentate ω-alkylthiolate calix[4]arene derivative was instead used as a functional protecting layer on AgNPs of approximately 3 nm. The functionalised nanoparticles were characterised by transmission electron microscopy (TEM), and by UV/Vis and X-ray photoelectron spectroscopy (XPS). Recognition of the pyridinium moieties loaded on the AuNPs by the calix[4]arene units immobilised on the AgNPs was demonstrated in solution of weakly polar solvents by UV/Vis titrations and DLS measurements. The extent of Au-AgNPs aggregation, shown through the low-energy shift of their surface plasmon bands (SPB), was strongly dependent on the loading of the pyridinium moieties present in the organic layer of the AuNPs. Extensive aggregation between dodecanethiol-capped AuNPs and the Ag calix[4]arene-functionalised NPs was also promoted by the action of a simple N-octyl pyridinium difunctional supramolecular linker. This linker can interdigitate through its long fatty tail in the organic layer of the dodecanethiol-capped AuNPs, and simultaneously interact through its pyridinium moiety with the calix[4]arene units at the surface of the modified AgNPs.


Carbon monoxide-releasing molecule-2 suppresses thrombomodulin and endothelial protein C receptor expression of human umbilical vein endothelial cells induced by lipopolysaccharide in vitro.
The aim of this study was to observe the counter-effect of carbon monoxide-releasing molecule-2 (CORM-2) on lipopolysaccharide (LPS)-suppressed thrombomodulin (TM) and endothelial protein C receptor (EPCR) expressions from human umbilical vein endothelial cell (HUVEC), and to reveal its mechanisms. HUVECs were divided into 5 treatment groups, wherein reagents were added simultaneously. TM and EPCR proteins of the cells and the culture medium levels of soluble TM, soluble EPCR, and matrix metalloproteinase-2 (MMP-2) were detected after administration, whereas mRNA levels of TM and EPCR, as well as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activity among groups, were also evaluated. No significant difference was observed in any indicator between CORM-2 and sham groups. Addition of LPS produced drastic increase in MMP-2 expression, NF-κB activity, shedding of TM and EPCR (into the culture medium), as well as remarkable decrease in both mRNA and protein expressions of TM and EPCR, and cell viability. LPS + CORM-2 treatment significantly reduced the increase in MMP-2, NF-κB activity, and TM/EPCR shedding, whereas maintained both mRNA and protein levels of TM and EPCR, and preserved cell viability. CORM-2 protects HUVEC from LPS-induced injury, by way of suppressing NF-κB activity, which downregulates TM and EPCR mRNAs. It also decreases MMP-2 expression and prevents the shedding of TM and EPCR from the surface of endothelial cells, so as to preserve their protective effect.


Heteroheptacenes with fused thiophene and pyrrole rings.
The preparation of conjugated heteroheptacenes using an electrophilic coupling reaction induced by a super acid is reported. The new molecules containing thiophene and/or pyrrole rings are bisbenzo[b,b']thienodithieno[3,2-b:2',3'-d]pyrrole, bisbenzo[b,b']thienocyclopenta[2,1-b:3,4-b']dithiophene, and bisthieno[3,2-b]thieno[2,3-f:5,4-f']carbazole. Dithieno[3,2-b:2',3'-d]pyrrole, cyclopenta[2,1-b:3,4-b']dithiophene, and carbazole are used as the aromatic cores. This versatility provides access to molecules with systematically controllable physicochemical properties. Single-crystal X-ray analyses demonstrate that the type and position of the alkyl substituents significantly changes the packing properties of the new molecules. The optical and optoelectronic properties of the heteroheptacenes vary considerably depending on the number and position of the sulfur or nitrogen linkages and reveal the improved environmental stability over their hydrocarbon counterparts. The analysis of the experimental results from UV/Vis absorption/photoluminescence (PL) spectroscopy and cyclic voltammetry were combined with DFT quantum-chemical calculations and compared with other model heteroheptacenes. The results suggest that among the acenes with the same number of fused rings, the thiophene ring fusion inside the skeleton stabilizes both HOMO and LUMO levels more effectively than pyrrole and benzene rings. The present study also shows that the new heteroheptacenes are promising candidates for the construction of electronic materials.


Interaction between adrenaline and epidermal growth factor in the control of liver glycogenolysis in mouse.
Epidermal growth factor (EGF) stimulates glycogenolysis in mouse liver, but the effect requires concentrations that are only achieved in plasma upon adrenergic stimulation of EGF release from submandibular salivary glands. Thus, we studied the interaction between adrenaline and EGF in liver glycogen metabolism, both in whole animals and in isolated hepatocytes. Adrenaline administered to anesthetized mice stimulated both the endocrine secretion of EGF from submandibular salivary glands and the degradation of glycogen in the liver. In sialoadenalectomized mice, adrenaline administration did not increase plasma EGF concentration. In these animals, the glycogenolytic response to adrenaline was enhanced. The sensitivity of hepatocytes to adrenaline was similar in cells from sialoadenalectomized and sham-operated mice. EGF, added to isolated hepatocytes, reduced the glycogenolytic effect of adrenaline (the maximal effect but not the ED50). Adrenaline stimulated glycogen degradation through both an alpha1-adrenergic mediated Ca2+ increase and a beta-adrenergic-mediated cAMP increase. EGF did not interfere with the rise of cytosolic Ca2+ but decreased the cAMP signal. EGF did not decrease the glycogenolytic effect of phenylephrine or VP (which increased cytosolic Ca2+ but not cAMP), but EGF decreased both the glycogenolytic effect and the cAMP signal generated by glucagon or forskolin. EGF did not interfere with the glycogenolytic effect of CPT-cAMP or bt2-cAMP. The effect of EGF on cAMP was blocked by 3-isobutyl-1-methylxanthine. These results demonstrate that the effect of EGF on the glycogenolytic action of adrenaline involves interference with the generation of the cAMP signal. We suggest that EGF induces such an effect through the activation of a phosphodiesterase.


'Y' connector system for prevention of peritonitis in CAPD: a controlled study.
To compare the efficacy of the standard Oreopoulos CAPD system with that of a new method consisting of a Y-shaped set filled with sodium hypochlorite during the dwelling time, a randomised controlled study was performed in 62 new CAPD patients. Life table analysis showed a significantly (p less than 0.001) less frequent incidence of peritonitis in the group treated with the Y connector system. This study shows that the Y system appears to be effective in reducing the incidence of peritonitis, as compared with the standard technique, in patients on the CAPD programme. The method is simple and economical and the incidence and the severity of side effects appear to be acceptable.


What should be the data sharing policy of cognitive science?
There is a growing chorus of voices in the scientific community calling for greater openness in the sharing of raw data that lead to a publication. In this commentary, we discuss the merits of sharing, common concerns that are raised, and practical issues that arise in developing a sharing policy. We suggest that the cognitive science community discuss the topic and establish a data-sharing policy.


Virions and virus-associated structures within dendrites in an experimental flavovirus encephalomyelitis.
In experimental yellow fever virus encephalomyelitis of adult albino mice, virions, and virus-associated structures were observed not only inside neuronal perikarya but also within dendrites of varied size. The finding permits the following explanations: (1) either the viral agent is synthesized in the nerve cell bodies and transported intradendritically in a proximodistal direction; or (2) virus morphogenesis takes place in neuronal perikarya and dendrites as well; or (3) both possiblities are equally valid. Some incidental findings were suggestive of virus release at postsynaptic dendrite membranes. They are discussed with reference to a hypothetical long-distance pathway of viral dissemination involving endocytosis of the agent by presynaptic axon terminals, intraaxonal virus decoating, and retrograde axoplasmic transport of the infectious nucleic acid to the cell soma.


Reducing gait speed affects axial coordination of walking turns.
Turning is a common feature of daily life and dynamic coordination of the axial body segments is a cornerstone for safe and efficient turning. Although slow walking speed is a common trait of old age and neurological disorders, little is known about the effect of walking speed on axial coordination during walking turns. The aim of this study was to investigate the influence of walking speed on axial coordination during walking turns in healthy elderly adults. Seventeen healthy elderly adults randomly performed 180° left and right turns while walking in their self-selected comfortable pace and in a slow pace speed. Turning velocity, spatiotemporal gait parameters (step length and step time), angular rotations and angular velocity of the head and pelvis, head-pelvis separation (i.e. the angular difference in degrees between the rotation of the head and pelvis) and head-pelvis velocity were analyzed using Wilcoxon signed-rank tests. During slow walking, turning velocity was 15% lower accompanied by shorter step length and longer step time compared to comfortable walking. Reducing walking speed also led to a decrease in the amplitude and velocity of the axial rotation of the head and pelvis as well as a reduced head-pelvis separation and angular velocity. This study demonstrates that axial coordination during turning is speed dependent as evidenced by a more 'en bloc' movement pattern (i.e. less separation between axial segments) at reduced speeds in healthy older adults. This emphasizes the need for matching speed when comparing groups with diverse walking speeds to differentiate changes due to speed from changes due to disease.


Clinical evaluation of a deep-learning-based computer-aided detection system for the detection of pulmonary nodules in a large teaching hospital.
To evaluate a deep-learning-based computer-aided detection (DL-CAD) software system for pulmonary nodule detection on computed tomography (CT) images and assess its added value in the clinical practice of a large teaching hospital. A retrospective analysis was performed of 145 chest CT examinations by comparing the output of the DL-CAD software with a reference standard based on the consensus reading of three radiologists. For every nodule in each scan, the location, composition, and maximum diameter in the axial plane were recorded. The subgroup of chest CT examinations (n = 97) without any nodules was used to determine the negative predictive value at the given clinical sensitivity threshold setting. The radiologists found 91 nodules and the CAD system 130 nodules of which 80 were true positive. The measured sensitivity was 88% and the mean false-positive rate was 1.04 false positives/scan. The negative predictive value was 95%. For 23 nodules, there was a size discrepancy of which 19 (83%) were measured smaller by the radiologist. The agreement of nodule composition between the CAD results and the reference standard was 95%. The present study found a sensitivity of 88% and a false-positive rate of 1.04 false positives/scan, which match the vendor specification. Together with the measured negative predictive value of 95% the system performs very well; however, these rates are still not good enough to replace the radiologist, even for the specific task of nodule detection. Furthermore, a surprisingly high rate of overestimation of nodule size was observed, which can lead to too many follow-up examinations.


The ubiquitin ligase SCFFBXW7α promotes GATA3 degradation.
GATA3 is a key transcription factor in cell fate determination and its dysregulation has been implicated in various types of malignancies. However, how the abundance and function of GATA3 are regulated remains unclear. Here, we report that GATA3 is physically associated with FBXW7α, and FBXW7α destabilizes GATA3 through assembly of a SKP1-CUL1-F-box E3 ligase complex. Importantly, we showed that FBXW7α promotes GATA3 ubiquitination and degradation in a GSK3 dependent manner. Furthermore, we demonstrated that FBXW7α inhibits breast cancer cells survival through destabilizing GATA3, and the expression level of FBXW7α is negatively correlated with that of GATA3 in breast cancer samples. This study indicated that FBXW7α is a critical negative regulator of GATA3 and revealed a pathway for the maintenance of GATA3 abundance in breast cancer cells.


Blood Pressure, Heart Rate, and CNS Stimulant Medication Use in Children with and without ADHD: Analysis of NHANES Data.
It is estimated that 2-3% of children in the US have hypertension (HTN) and 8% of children ages 4-17 carry the diagnosis of attention-deficit hyperactivity disorder (ADHD). The prevalence of HTN and cardiovascular (CV) risk factors in children with ADHD on CNS stimulant treatment (stimulants) compared to no treatment and compared to their healthy counterparts is not well described. Using National Health and Nutrition Survey data, we examined demographic, blood pressure (BP) and CV risk factors of 4,907 children aged 12-18 years with and without the diagnosis of ADHD, and further examined the CV risk in a subgroup of ADHD patients on stimulants. Three hundred eighty-three (10.7%) children were reported to have ADHD, of whom 111 (3.4%) were on stimulants. Children with ADHD on stimulants were significantly younger, male, and white compared to those with ADHD not on medication and those without ADHD. Body mass index (BMI), eGFR, cholesterol, the prevalence of albuminuria, and poverty were not significantly different between the three groups. One hundred sixty (2.7%) had BP in the hypertensive and 637 (12.4%) in the pre-hypertensive range. The prevalence of elevated BP (HTN and/or pre-HTN range) was not different between children with ADHD on stimulants compared to ADHD without medication and those without ADHD. Heart rate (HR) was significantly higher in the ADHD group on stimulants vs. the groups ADHD on no stimulants and without ADHD. When the relationship between stimulants and the risk of abnormal BP was examined, there was a significant interaction between having BP in the HTN range and sex. After adjusting for BMI, race, and age, females with ADHD on stimulants tended to be older and had significantly more BP in the hypertensive range. On the other hand, males were more likely to be of a white race and older, but not hypertensive. Children with ADHD on stimulants have significantly higher HR than children with ADHD on no stimulants and children without ADHD. On the other hand, the prevalence of abnormal BP classification is comparable between the three groups.


Drug resistant tuberculosis in Saudi Arabia: an analysis of surveillance data 2014-2015.
There is limited data that investigates the national rates of drug-resistant tuberculosis (TB) in Saudi Arabia.This study aimed to estimate the rates of multi-drug-resistant tuberculosis (MDR-TB), rifampicin-resistant tuberculosis (RR-TB), and monoresistance (MR) in Saudi Arabia. A retrospective cohort study was conducted on all TB cases reported to the National TB Control and Prevention Program (NTCPP) registry at the Saudi Ministry of Health between January 1, 2014 and December 31, 2015. A total of 2098 TB patients with positive TB cultures were included in the study. Subgroup analyses and multivariate binary logistic regression models were performed with IBM SPSS 23.0. Of the total TB cases, 4.4% (95% CI: 3.59%-5.40%) were found to have MDR-TB. The rates of MR were 3.8% (95% CI: 2.99%-4.67%) for ethambutol, 5.4% (95% CI: 4.50%-6.49%) for pyrazinamide, 10.2% (95% CI: 5.89%-11.52%) for isoniazid, 11% (95% CI: 9.70%-12.43%) for streptomycin, and 5.9% (95% CI: 4.90%-6.96%) for rifampicin. The high rates of MDR and RR-TB were found among the younger age group, female gender, and those who had a previous history of TB. We also discovered that renal failure tends to increase the risk of rifampicin resistance. National TB data in Saudi Arabia shows that the rate of MDR-TB was similar to the global rate reported by the World Health Organization (WHO). It is a relatively high rate as compared to Western countries. The proportion of MDR/RR-TB patients tends to be higher in the younger age group, female gender, and in patients with a previous history of TB treatment. Effective strategies for prevention of all multi-drug-resistant TB cases are warranted.


In situ observation of ZnO nanowire growth on zinc film in environmental scanning electron microscope.
In situ uniform growth of ZnO nanowires was realized and monitored at real time by heating zinc film in an environmental scanning electron microscope. Better controllability and repeatability were obtained by using zinc film as source material compared to traditionally used zinc powder. Morphology of the as-grown ZnO nanowires was found to depend on both the growth temperature and holding time. Low temperature (500 degrees C) and short growth time (approximately 20 min) favor one-dimensional nanowire growth, whereas longer holding time (>40 min) or higher temperature (700 degrees C) lead to nanosheet growth. The results suggest that the zinc vapor partial pressure is vital in determining the final morphology. These results help to give more insights into the mechanism of ZnO nanowire synthesis.


MEASURING THE EFFECTS OF PAIRING SUCCESS, EXTRA-PAIR COPULATIONS AND MATE QUALITY ON THE OPPORTUNITY FOR SEXUAL SELECTION.
Sexual selection can act through variation in the number of social mates obtained, variation in mate quality, or variation in success at obtaining extra-pair fertilizations. Because within-pair fertilizations (WPF) and extra-pair fertilizations (EPF) are alternate routes of reproduction, they are additive, rather than multiplicative, components of fitness. We present a method for partitioning total variance in reproductive success (a measure of the opportunity for selection) when fitness components are both additive and multiplicative and use it to partition the variance into components that correspond to each mechanism of sexual selection. Computer simulations show that extra-pair fertilizations can either increase or decrease total variance, depending on the covariance between within-pair and extra-pair success. Simulations also suggest that for socially monogamous species, extra-pair fertilizations have a greater effect than variation in mate quality or pairing status on the opportunity for selection. Application of our model to data gathered for a population of red-winged blackbirds (Agelaius phoeniceus) indicates that most of the variance in male reproductive success was attributable to within-pair sources of variance. Nevertheless, extra-pair copulations increased the opportunity for selection because males varied both in the proportion of their social young that they sired and in the number of extra-pair mates that they obtained. Furthermore, large and positive covariances existed between the number of extra-pair mates a male obtained and both social pairing success and within-pair paternity, indicating that, in this population, males preferred as social mates also were preferred as extra-pair mates.


Effects of Estrogen Therapy on the Serotonergic System in an Animal Model of Perimenopause Induced by 4-Vinylcyclohexen Diepoxide (VCD).
Chronic exposure to 4-vinylcycloxene diepoxide (VCD) in rodents accelerates the natural process of ovarian follicular atresia modelling perimenopause in women. We investigated why estrogen therapy is beneficial for symptomatic women despite normal or high estrogen levels during perimenopause. Female rats (28 d) were injected daily with VCD or oil for 15 d; 55-65 d after the first injection, pellets of 17β-estradiol or oil were inserted subcutaneously. Around 20 d after, the rats were euthanized (control rats on diestrus and estradiol-treated 21 d after pellets implants). Blood was collected for hormone measurement, the brains were removed and dorsal raphe nucleus (DRN), hippocampus (HPC), and amygdala (AMY) punched out for serotonin (5-HT), estrogen receptor β (ERβ), and progesterone receptor (PR) mRNA level measurements. Another set of rats was perfused for tryptophan hydroxylase (TPH) immunohistochemistry in the DRN. Periestropausal rats exhibited estradiol levels similar to controls and a lower progesterone level, which was restored by estradiol. The DRN of periestropausal rats exhibited lower expression of PR and ERβ mRNA and a lower number of TPH cells. Estradiol restored the ERβ mRNA levels and number of serotonergic cells in the DRN caudal subregion. The 5-HT levels were lower in the AMY and HPC in peristropausal rats, and estradiol treatment increased the 5-HT levels in the HPC and also increased ERβ expression in this area. In conclusion, estradiol may improve perimenopause symptoms by increasing progesterone and boosting serotonin pathway from the caudal DRN to the dorsal HPC potentially through an increment in ERβ expression in the DRN.


Impact of low-carbon city pilot policies on urban green innovation from the perspective of spatial and temporal heterogeneity.
The low-carbon city pilot policy (LCPP) in China is an active response to climate change, with cities serving as the main agents of action. Enhancing green innovation at a city-wide level can effectively support the promotion of pilot cities' efforts towards sustainable growth. Using panel data from 204 prefectures collected from 2005 to 2019, we adopted the time-varying difference-in-differences (DID) model and the spatial Durbin model combined with time-varying DID (SDM-DID) to determine the impact of the LCPP on urban green innovation and its temporal and spatial heterogeneity. Empirical findings showed that (1) LCPP had a significant positive impact on urban green innovation, and green invention patents had a greater green innovation effect than green utility model patents. (2) Heterogeneity analysis revealed that in terms of geographical location, the pilot policy was more effective in promoting urban green innovation in the eastern and central regions in comparison to the western region. At the city level, the pilot policy had a greater impact on green innovation in first- and second-tier cities. With regard to city scale, large-scale cities showed a greater impact on green innovation than small- and medium-sized cities. (3) Mechanistic testing revealed that LCPPs stimulated urban green innovation by talent aggregation, increasing government support for innovation, and public participation; but the mechanism for alleviating financing constraints has yet to be effectively validated. (4) The LCPP showed a spatial spillover effect, whereby one city's low-carbon governance yielded institutional dividends for neighboring cities both geographically and economically, and the impact was more pronounced in those cities that were not resource-based. This study presents empirical evidence at the urban and spatial levels, supporting the comprehensive promotion of low-carbon city construction and development in China.


The quinolone family: from antibacterial to anticancer agents.
The present review focuses on the structural modifications responsible for the transformation of an antibacterial into an anticancer agent. Indeed, a distinctive feature of drugs based on the quinolone structure is their remarkable ability to target different type II topoisomerase enzymes. In particular, some congeners of this drug family display high activity not only against bacterial topoisomerases, but also against eukaryotic topoisomerases and are toxic to cultured mammalian cells and in vivo tumor models. Hence, these cytotoxic quinolones represent an exploitable source of new anticancer agents, which might also help addressing side-toxicity and resistance phenomena. Their ability to bind metal ion co-factors represents an additional means of modulating their pharmacological response(s). Moreover, quinolones link antibacterial and anticancer chemotherapy together and provide an opportunity to clarify drug mechanism across divergent species.


Contributions of memory and brain development to the bioregulation of naps and nap transitions in early childhood.
The transition from multiple sleep bouts each day to a single overnight sleep bout (i.e., nap transition) is a universal process in human development. Naps are important during infancy and early childhood as they enhance learning through memory consolidation. However, a normal part of development is the transition out of naps. Understanding nap transitions is essential in order to maximize early learning and promote positive long-term cognitive outcomes. Here, we propose a novel hypothesis regarding the cognitive, physiological, and neural changes that accompany nap transitions. Specifically, we posit that maturation of the hippocampal-dependent memory network results in more efficient memory storage, which reduces the buildup of homeostatic sleep pressure across the cortex (as reflected by slow-wave activity), and eventually, contributes to nap transitions. This hypothesis synthesizes evidence of bioregulatory mechanisms underlying nap transitions and sheds new light on an important window of change in development. This framework can be used to evaluate multiple untested predictions from the field of sleep science and ultimately, yield science-based guidelines and policies regarding napping in childcare and early education settings.


Undetected αKlotho in serum is associated with the most aggressive phenotype of breast cancer.
Klotho, a cellular anti-senescence protein, is related to antitumor actions, growth regulation, proliferation and invasiveness in several types of tumor, including breast cancer. The present study aimed to analyze the serum levels of αKlotho in patients with breast cancer according to histopathological and immunohistochemical variables. A total of 74 patients and 60 healthy controls were recruited. Peripheral blood samples were collected and serum levels were assessed by sandwich ELISA. Clinical and diagnostic data were obtained from medical records and databases of the Clinical Hospital of the Federal University of Uberlândia (Uberlândia, Brazil). The results indicated no difference in the levels of αKlotho between patients and controls (P=0.068); however, the number of patients with breast cancer with undetectable αKlotho was high (n=52). Thus, the variables that were associated with the lowest survival rates were analyzed, relating them to undetectable αKlotho. Among cases of metastatic tumors or tumors with poor differentiation, positive lymph node status and triple-negative status, patients with undetectable αKlotho predominated and had unfavorable overall survival. Due to the significant results obtained in triple-negative patients, an in vitro analysis was performed to determine whether estrogen receptors (ERs) have a role in αKlotho production. Treatment of MCF-7 cells with ER agonists, estradiol (E2) and diarylpropionitrile (DPN), resulted in increases in αKlotho expression and supernatant levels of both agonists, demonstrating a direct association between the ER and Klotho production; of note, the ERβ-specific agonist DPN tripled αKlotho expression when compared to E2 (P=0.078). These data suggested that undetectable αKlotho in the serum of patients with breast cancer is related to unfavorable histopathological variables and poor prognosis and ERs possibly have an important role in maintaining adequate quantities of αKlotho.


Dolichoperoides macalpini (Nicoll, 1914) (Digenea: Dolichoperoididae) infecting venomous snakes (Elapidae) across Australia: molecular characterisation and infection parameters.
Specimens of Dolichoperoides macalpini (Nicoll, 1914) (Digenea: Dolichoperoididae) were collected from Australian venomous snakes (Elapidae): Notechis scutatus Peters, 1861 and Austrelaps superbus (Günther, 1858) from Tasmania and surrounding islands and N. s. occidentalis Glauert, 1948 from wetlands near Perth, Western Australia. Despite variation in morphological measurements, genetic analysis showed that the one species of digeneans infected the snakes from all locations. This study presents the first DNA sequences for D. macalpini (internal transcribed spacer, 18S, 28S), confirming its placement in a family separate from the Reniferidae and Telorchiidae. Analysis of the infection dynamics of infection in Western Australian snakes showed significant differences in levels of infection between wetland locations, season and year of collection. Infection of D. macalpini was reported in the gastrointestinal tract, including the mouth, in freshly euthanised snakes in Western Australia, and in the lung in Tasmanian snakes, consistent with earlier reports. Differences in morphology and site of infection are suggested to be due to a combination of season and maturity of the digenean, with infection potentially occurring early in the season, as the snakes emerge from torpor. The need for research on the seasonal dynamics of infection with this parasite is discussed.


[Not Available].
New biographical facts are submitted concerning Anastasia Golovina, the first female doctor among the Bessarabia Bulgarians. The data, made available from the Soviet and Bulgarian archives, makes reference to the life and studies of Golovina in Kishinev, Zürich and Paris, her contacts with the progressive, revolutionary circles in Russia and Bulgaria in the middle of the seventies of the 19th century.


Spontaneous and induced interferon production by peripheral blood leucocytes from control population and patients with herpes genitalis.
The spontaneous and PHA induced levels of interferon were measured in peripheral blood leucocyte cultures of twenty-eight individuals diagnosed as positive for herpes genitalis, and in a group of control subjects. As reported by Cunningham and Merigan [1983] for herpes labialis, leucocytes from individuals with herpes genitalis produced low levels of interferon spontaneously; however, similar results were found for individuals within the control population. No statistically significant difference could be found for PHA induced interferon levels, antigen induced interferon levels, or helper/suppressor cell ratios between the herpes genitalis population and control population. Our results indicate that interferon does not play a major role in the latency or recurrence of herpes genitalis.


Effect of Structured Cognitive-Behavioral Group Therapy on Body Weight, Mental Status and the Quality of Life in Obese and Overweight Individuals: A 16-Week Follow Up Study.
It was aimed in this study to investigate the effects of group cognitive and behavioral therapy (CBT) on the body weight, depression, anxiety, quality of life, self-esteem, dietary cognitive distortions and eating behavior of obese and overweight people. The study was carried out at the Department of Psychiatry, Gazi University Faculty of Medicine, between 01.07.2017 and 31.12.2017. The participants attended group CBT sessions once weekly for eight weeks. Reinforcement sessions took place at the 12th and 16th weeks. At the first, 8th, 12th and the 16th weeks, body weights were measured and the participants were asked to complete the Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), the Obese Individuals Specific Quality of Life Scale (OISQLS), the Dutch Eating Behavior Questionnaire (DEBQ), the Rosenberg Self-Esteem Scale (RSES) and the Diet Related Dysfunctional Attitudes Scale (DRDAS). The group mean age was 41.71±4.46 years, 32 (91.4%) being female. Significant improvements were found in body weight and the scores on the BDI, BAI, DEBQ, OISQLS, DRDAS, and the RSES (p<0.001 for each). The average percent weight loss was 10.2%. The BDI score was the best predictor of the change in body mass index (BMI). CBT-based group treatments for obese and overweight people are effective in losing weight. Therapy participants with less depression symptoms benefit more from treatment and lose more weight. These results should be re-evaluated in randomized controlled trials.


Identification and validation of a seven-gene prognostic marker in colon cancer based on single-cell transcriptome analysis.
Colon cancer (CC) is one of the most commonly diagnosed tumours worldwide. Single-cell RNA sequencing (scRNA-seq) can accurately reflect the heterogeneity within and between tumour cells and identify important genes associated with cancer development and growth. In this study, scRNA-seq was used to identify reliable prognostic biomarkers in CC. ScRNA-seq data of CC before and after 5-fluorouracil treatment were first downloaded from the Gene Expression Omnibus database. The data were pre-processed, and dimensionality reduction was performed using principal component analysis and t-distributed stochastic neighbour embedding algorithms. Additionally, the transcriptome data, somatic variant data, and clinical reports of patients with CC were obtained from The Cancer Genome Atlas database. Seven key genes were identified using Cox regression analysis and the least absolute shrinkage and selection operator method to establish signatures associated with CC prognoses. The identified signatures were validated on independent datasets, and somatic mutations and potential oncogenic pathways were further explored. Based on these features, gene signatures, and other clinical variables, a more effective predictive model nomogram for patients with CC was constructed, and a decision curve analysis was performed to assess the utility of the nomogram. A prognostic signature consisting of seven prognostic-related genes, including CAV2, EREG, NGFRAP1, WBSCR22, SPINT2, CCDC28A, and BCL10, was constructed and validated. The proficiency and credibility of the signature were verified in both internal and external datasets, and the results showed that the seven-gene signature could effectively predict the prognosis of patients with CC under various clinical conditions. A nomogram was then constructed based on features such as the RiskScore, patients' age, neoplasm stage, and tumor (T), nodes (N), and metastases (M) classification, and the nomogram had good clinical utility. Higher RiskScores were associated with a higher tumour mutational burden, which was confirmed to be a prognostic risk factor. Gene set enrichment analysis showed that high-score groups were enriched in 'cytoplasmic DNA sensing', 'Extracellular matrix receptor interactions', and 'focal adhesion', and low-score groups were enriched in 'natural killer cell-mediated cytotoxicity', and 'T-cell receptor signalling pathways', among other pathways. A robust seven-gene marker for CC was identified based on scRNA-seq data and was validated in multiple independent cohort studies. These findings provide a new potential marker to predict the prognosis of patients with CC.


Localization of two unique heparin binding domains of human plasma fibronectin with monoclonal antibodies.
Monoclonal antibodies to human plasma fibronectin were used to study the topological arrangement of several biologically active sites on the 220,000-dalton fibronectin subunit. Plasma fibronectin was cleaved into a number of biologically active fragments by trypsin and cathepsin D. Fragments that bind gelatin and heparin bind to both gelatin and heparin were isolated by affinity chromatography. These fragments were further characterized by their ability to bind to two different monoclonal antibodies: monoclonal 2-8 and monoclonal 180-8. Using this approach, we have established the positions of two unique heparin-, a gelatin-, and two monoclonal antibody-binding sites on the fibronectin subunit.


Prognostic value of copeptin and mid-regional proadrenomedullin in COVID-19-hospitalized patients.
Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality. Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC). Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p < 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p < 0.01) for copeptin values > 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p < 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p < 0.001) for MR-proADM values > 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p < 0.001, and r = 0.46, p < 0.001). Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.


Studies on haem alpha-methenyl oxygenase. Isomeric structure of formylbiliverdin, a possible precursor of biliverdin.
1. The enzyme from guinea-pig liver that degrades pyridine-haemochromogen into formylbiliverdin, a possible precursor of biliverdin, breaks the porphyrin ring exclusively at the alpha-methene bridge. The enzyme is therefore appropriately named haem alpha-methenyl oxygenase. 2. It is deduced that this enzyme plays an essential role in haemoglobin catabolism in vivo.


Endothelial function in obstructive sleep apnea and response to treatment.
Impaired endothelium-dependent vascular relaxation is a prognostic marker of atherosclerosis and cardiovascular disease. We evaluated endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin (NTG)-induced dilation of the brachial artery with Doppler ultrasound in 28 men with obstructive sleep apnea (OSA) and 12 men without OSA. Subjects with OSA (apnea-hypopnea index; mean +/- SD, 46.0 +/- 14.5) had lower FMD compared with subjects without OSA (5.3 +/- 1.7% vs. 8.3 +/- 1.0%, p < 0.001), and major determinants of FMD were the apnea-hypopnea index and age. There was no significant difference in NTG-induced dilation. Subjects with OSA were randomized to nasal continuous positive airway pressure (nCPAP) or observation for 4 weeks. Subjects on nCPAP had significant increase in FMD, whereas those on observation had no change (4.4% vs. -0.8%, difference of 5.2%, p < 0.001). Neither group showed significant change in NTG-induced vasodilation. Eight subjects who used nCPAP for over 3 months were reassessed on withdrawing treatment for 1 week. On nCPAP withdrawal, FMD became lower than during treatment (p = 0.02) and were similar to baseline values. Our findings demonstrated that men with moderate/severe OSA have endothelial dysfunction and treatment with nCPAP could reverse the dysfunction; the effect, however, was dependent on ongoing use.


cDNA cloning and expression of a soluble epoxide hydrolase from human liver.
We report the cloning and expression of a cDNA that encodes a soluble epoxide hydrolase from human liver. The 2101-base clone predicts a 554-residue protein (M(r) 62,640) with an apparently imperfect peroxisomal targeting signal of Ser-Lys-Met at the carboxy terminus. The cDNA was expressed in the baculovirus system in the Spodoptera frugiperda 21 cell line. The recombinant protein was similar to soluble epoxide hydrolase isolated from human liver in terms of molecular weight, hydrolytic activity, inhibition, and immunoreactivity.


STRAP reduces endoplasmic reticulum stress and apoptosis in cardiomyocytes and attenuates myocardial ischemia-reperfusion injury by activating PI3K/PDK1/Akt signaling pathway.
Myocardial ischemia-reperfusion injury (MIRI) is a common problem in heart-related diseases. The aim of this study was to explore the protective effects of STRAP on cardiomyocytes in the MIRI process and its mechanisms. We used SD rats to construct a MIRI model and increased the expression of STRAP in myocardial tissue by Entranster to detect the effect of STRAP on rat myocardial tissue. In addition, we cultured rat cardiomyocyte cell line H9c2 cells and constructed a hypoxia-reoxygenation model to detect the protective effect of STRAP on H9c2 cells. LY294002, an inhibitor of the PI3K/PDK1/Akt signaling pathway, was used to validate the mechanism by which STRAP protects cardiomyocytes. Overexpression of STRAP significantly reduced the activity of MDA in myocardial tissue and increased the activity of SOD. STRAP also substantially lowered CK and LDH levels in rat serum and increased Na+-K+-ATPase and Ca2+-Mg2+-ATPase activity. In addition, overexpression of STRAP considerably reduced endoplasmic reticulum stress (ERS) and apoptosis levels in H9c2 cells. However, LY294002 attenuated the protective effect of STRAP on cardiomyocytes. STRAP reduces ERS and apoptosis in cardiomyocytes by activating the PI3K/PDK1/Akt signaling pathway, thereby reducing myocardial MIRI.


Five shared decision-making tools in 5 months: use of rapid reviews to develop decision boxes for seniors living with dementia and their caregivers.
Decision support tools build upon comprehensive and timely syntheses of literature. Rapid reviews may allow supporting their development by omitting certain components of traditional systematic reviews. We thus aimed to describe a rapid review approach underlying the development of decision support tools, i.e., five decision boxes (DB) for shared decision-making between seniors living with dementia, their caregivers, and healthcare providers. We included studies based on PICO questions (Participant, Intervention, Comparison, Outcome) describing each of the five specific decision. We gave priority to higher quality evidence (e.g., systematic reviews). For each DB, we first identified secondary sources of literature, namely, clinical summaries, clinical practice guidelines, and systematic reviews. After an initial extraction, we searched for primary studies in academic databases and grey literature to fill gaps in evidence. We extracted study designs, sample sizes, populations, and probabilities of benefits/harms of the health options. A single reviewer conducted the literature search and study selection. The data extracted by one reviewer was verified by a second experienced reviewer. Two reviewers assessed the quality of the evidence. We converted all probabilities into absolute risks for ease of understanding. Two to five experts validated the content of each DB. We conducted descriptive statistical analyses on the review processes and resources required. The approach allowed screening of a limited number of references (range: 104 to 406/review). For each review, we included 15 to 26 studies, 2 to 10 health options, 11 to 62 health outcomes and we conducted 9 to 47 quality assessments. A team of ten reviewers with varying levels of expertise was supported at specific steps by an information specialist, a biostatistician, and a graphic designer. The time required to complete a rapid review varied from 7 to 31 weeks per review (mean ± SD, 19 ± 10 weeks). Data extraction required the most time (8 ± 6.8 weeks). The average estimated cost of a rapid review was C$11,646 (SD = C$10,914). This approach enabled the development of clinical tools more rapidly than with a traditional systematic review. Future studies should evaluate the applicability of this approach to other teams/tools.


Rapid parameter estimation for selective inversion recovery myelin imaging using an open-source Julia toolkit.
Magnetic resonance imaging (MRI) is used extensively to quantify myelin content, however computational bottlenecks remain challenging for advanced imaging techniques in clinical settings. We present a fast, open-source toolkit for processing quantitative magnetization transfer derived from selective inversion recovery (SIR) acquisitions that allows parameter map estimation, including the myelin-sensitive macromolecular pool size ratio (PSR). Significant progress has been made in reducing SIR acquisition times to improve clinically feasibility. However, parameter map estimation from the resulting data remains computationally expensive. To overcome this computational limitation, we developed a computationally efficient, open-source toolkit implemented in the Julia language. To test the accuracy of this toolkit, we simulated SIR images with varying PSR and spin-lattice relaxation time of the free water pool (R 1f) over a physiologically meaningful scale from 5% to 20% and 0.5 to 1.5 s-1, respectively. Rician noise was then added, and the parameter maps were estimated using our Julia toolkit. Probability density histogram plots and Lin's concordance correlation coefficients (LCCC) were used to assess accuracy and precision of the fits to our known simulation data. To further mimic biological tissue, we generated five cross-linked bovine serum albumin (BSA) phantoms with concentrations that ranged from 1.25% to 20%. The phantoms were imaged at 3T using SIR, and data were fit to estimate PSR and R 1f. Similarly, a healthy volunteer was imaged at 3T, and SIR parameter maps were estimated to demonstrate the reduced computational time for a real-world clinical example. Estimated SIR parameter maps from our Julia toolkit agreed with simulated values (LCCC > 0.98). This toolkit was further validated using BSA phantoms and a whole brain scan at 3T. In both cases, SIR parameter estimates were consistent with published values using MATLAB. However, compared to earlier work using MATLAB, our Julia toolkit provided an approximate 20-fold reduction in computational time. Presented here, we developed a fast, open-source, toolkit for rapid and accurate SIR MRI using Julia. The reduction in computational cost should allow SIR parameters to be accessible in clinical settings.


Dual functioning of plant arginases provides a third route for putrescine synthesis.
Two biosynthetic routes are known for putrescine, an essential plant metabolite. Ornithine decarboxylase (ODC) converts ornithine directly to putrescine, while a second route for putrescine biosynthesis utilizes arginine decarboxylase (ADC) to convert arginine to agmatine, and two additional enzymes, agmatine iminohydrolase (AIH) and N-carbamoyl putrescine aminohydrolase (NLP1) to complete this pathway. Here we show that plants can use ADC and arginase/agmatinase (ARGAH) as a third route for putrescine synthesis. Transformation of Arabidopsis thaliana ADC2, and any of the arginases from A. thaliana (ARGAH1, or ARGHA2) or the soybean gene Glyma.03g028000 (GmARGAH) into a yeast strain deficient in ODC, fully complemented the mutant phenotype. In vitro assays using purified recombinant enzymes of AtADC1 and AtARGAH2 were used to show that these enzymes can function in concert to convert arginine to agmatine and putrescine. Transient expression analysis of the soybean genes (Glyma.06g007500, ADC; Glyma.03g028000 GmARGAH) and the A. thaliana ADC2 and ARGAH genes in leaves of Nicotiana benthamiana, showed that these proteins are localized to the chloroplast. Experimental support for this pathway also comes from the fact that expression of AtARGAH, but not AtAIH or AtNLP1, is co-regulated with AtADC2 in response to drought, oxidative stress, wounding, and methyl jasmonate treatments. Based on the high affinity of ARGAH2 for agmatine, its co-localization with ADC2, and typically low arginine levels in many plant tissues, we propose that these two enzymes can be major contributors to putrescine synthesis in many A. thaliana stress responses.


Technical considerations for lower limb multidetector computed tomographic angiography.
Multidetector computed tomography (MDCT) enables imaging of the entire arterial tree non-invasively. Optimal technical considerations for performing MDCT angiography (MDCTA) are essential for accurate diagnosis and atherosclerotic disease stratification. This review article focuses on the various technical aspects necessary for peripheral computed tomographic angiography (CTA) acquisition. Common clinical indications for peripheral MDCTA and the latest scan protocols are described. The essential issue of radiation dose reduction is discussed, along with methods of optimal contrast bolus detection and delivery. Post-processing techniques are also presented. Previously, digital subtraction angiography was the only established reliable imaging technique to quantify atherosclerotic disease load; however, MDCTA may now challenge this old gold standard, along with other non-invasive techniques such as magnetic resonance angiography (MRA).


Catalytic, asymmetric, and stereodivergent synthesis of non-symmetric β,β-diaryl-α-amino acids.
We report a concise, enantio- and diastereoselective route to novel nonsymmetrically substituted N-protected β,β-diaryl-α-amino acids and esters, through the asymmetric hydrogenation of tetrasubstituted olefins, some of the most challenging examples in the field. Stereoselective generation of an E- or Z-enol tosylate, when combined with stereoretentive Suzuki-Miyaura cross-coupling and enantioselective hydrogenation catalyzed by (NBD)2RhBF4 and a Josiphos ligand, allows for full control over the two vicinal stereogenic centers. High yields and excellent enantioselectivities (up to 99% ee) were obtained for a variety of N-acetyl, N-methoxycarbonyl, and N-Boc β,β-diaryldehydroamino acids, containing a diverse and previously unreported series of heterocyclic and aryl substituted groups (24 examples) and allowing access to all four stereoisomers of these valuable building blocks.


Depletion of Host Cell Focal Adhesion Kinase Increases the Susceptibility to Invasion by Trypanosoma cruzi Metacyclic Forms.
Focal adhesion kinase (FAK), a cytoplasmic protein tyrosine kinase (PTK), is implicated in diverse cellular processes, including the regulation of F-actin dynamics. Host cell F-actin rearrangement is critical for invasion of Trypanosoma cruzi, the protozoan parasite that causes Chagas disease. It is unknown whether FAK is involved in the internalization process of metacyclic trypomastigote (MT), the parasite form that is important for vectorial transmission. MT can enter the mammalian host through the ocular mucosa, lesion in the skin, or by the oral route. Oral infection by MT is currently a mode of transmission responsible for outbreaks of acute Chagas disease. Here we addressed the question by generating HeLa cell lines deficient in FAK. Host cell invasion assays showed that, as compared to control wild type (WT) cells, FAK-deficient cells were significantly more susceptible to parasite invasion. Lysosome spreading and a disarranged actin cytoskeleton, two features associated with susceptibility to MT invasion, were detected in FAK-deficient cells, as opposed to WT cells that exhibited a more organized F-actin arrangement, and lysosomes concentrated in the perinuclear area. As compared to WT cells, the capacity of FAK-deficient cells to bind a recombinant protein based on gp82, the MT surface molecule that mediates invasion, was higher. On the other hand, when treated with FAK-specific inhibitor PF573228, WT cells exhibited a dense meshwork of actin filaments, lysosome accumulation around the nucleus, and had increased resistance to MT invasion. In cells treated with PF573228, the phosphorylation levels of FAK were reduced and, as a consequence of FAK inactivation, diminished phosphorylation of extracellular signal-regulated protein kinases (ERK1/2) was observed. Fibronectin, known to impair MT invasion, induced the formation of thick bundles of F-actin and ERK1/2 dephosphorylation.


Comparative promoting activities of phosphate salts on rat two-stage bladder carcinogenesis under conditions of equivalent urinary Na+ or K+ levels.
Promoting effects of Na or K phosphate salts on rat two-stage bladder carcinogenesis were compared. Animals were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) in their drinking water for 4 weeks and thereafter received 1.4% Na3PO4, 2.0% NaH2PO4, 1.0% K3PO4, or 2.5% KH2PO4, these dietary concentrations being selected because they result in approximately equal levels of Na+ and K+ in the urine, equivalent to moderate natriuresis or kaluresis in comparison with our previous data. Treatment with Na3PO4 or K3PO4 induced significant increase in urinary pH compared with control values, whereas urinary pH in the NaH2PO4 and KH2PO4 groups was comparable to control values. With regard to preneoplastic lesion development, both incidences and multiplicity were significantly increased in the groups given Na3PO4 or K3PO4 compared with both controls and NaH2PO4 or KH2PO4 groups, respectively. Furthermore, treatment with Na3PO4 significantly increased multiplicity of papillomas, accompanied by a tendency to increased incidence. No statistically significant difference in promoting potential between Na3PO4 and K3PO4 groups was evident. The present results thus suggest that tumor promotion under conditions of moderate natriuresis or kaluresis depends primarily on high urinary pH.


Interstrand DNA Cross-Links Derived from Reaction of a 2-Aminopurine Residue with an Abasic Site.
Efficient methods for the site-specific installation of structurally defined interstrand cross-links in duplex DNA may be useful in a wide variety of fields. The work described here developed a high-yield synthesis of chemically stable interstrand cross-links resulting from a reductive amination reaction between an abasic site and the noncanonical nucleobase 2-aminopurine in duplex DNA. Results from footprinting, liquid chromatography-mass spectrometry, and stability studies support the formation of an N2-alkylamine attachment between the 2-aminopurine residue and the Ap site. The reaction performs best when the 2-aminopurine residue on the opposing strand is offset 1 nt to the 5'-side of the abasic site. The cross-link confers substantial resistance to thermal denaturation (melting). The cross-linking reaction is fast (complete in 4 h), employs only commercially available reagents, and can be used to generate cross-linked duplexes in sufficient quantities for biophysical, structural, and DNA repair studies.


Occupational class differences in long sickness absence: a register-based study of 2.1 million Finnish women and men in 1996-2013.
Sickness absence is consistently higher in lower occupational classes, but attempts to analyse changes over time in socioeconomic differences are scarce. We examined trends in medically certified sickness absence by occupational class in Finland from 1996 to 2013 and assessed the magnitude and changes in absolute and relative occupational class differences. Population-based, repeated cross-sectional study. A 70% random sample of Finns aged between 25 and 63 years in the years 1996-2013. The study focused on 25- to 63 year-old female (n between 572 246 and 690 925) and male (n between 525 698 and 644 425) upper and lower non-manual and manual workers. Disability and old age pensioners, students, the unemployed, entrepreneurs and farmers were excluded. The analyses covered 2 160 084 persons, that is, 77% of the random sample.For primary and secondary outcome measures, we examined yearly prevalence of over 10 working days long sickness absence by occupational class. The Slope Index of Inequality (SII) and the Relative Index of Inequality (RII) were used to assess the magnitude and changes in occupational class differences. Compared with mid-1990s, sickness absence prevalence was slightly lower in 2013 in all occupational classes except for female lower non-manual workers. Hierarchical occupational class differences in sickness absence were found. Absolute differences (SII) peaked in 2005 in both women (0.12, 95% CI 0.12 to 0.13) and men (0.15, 95% CI 0.14 to 0.15) but reached the previous level in women by 2009 and decreased modestly in men until 2013. Relative differences narrowed over time (p<0.001) but levelled off by 2013. Sickness absence prevalence is currently slightly lower in almost all occupational classes than in the mid-1990s, but occupational class differences have remained large. Ill health and poor working conditions especially in the lower occupational classes should be targeted in order to reduce sickness absence and to achieve longer working lives.


Risk markers for poor developmental attainment in young children: results from a longitudinal national survey.
To evaluate social and environmental determinants of poor developmental attainment among preschool children by means of longitudinal data from a population-based sample of Canadian children. Secondary analysis of data from cycles 1 (1994-1995) and 2 (1996-1997) of the National Longitudinal Survey of Children and Youth using a cohort design with 2-year follow-up. A total of 4987 children aged 1 to 5 years at baseline, whose biological mother completed risk factor information and who were included in both cycles. Poor developmental attainment (developing unusually slowly) was defined as scores more than 1 SD below the age-standardized mean for the Motor and Social Development Scale, revised Peabody Picture Vocabulary Test, or Canadian Achievement Tests in mathematics and reading/comprehension, depending on the child's age. The prevalence of sustained poor developmental attainment after 2 years of follow-up was 4.6%. Factors found to be associated with poor developmental attainment included male sex (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.10-1.70), maternal depression (OR, 1.64; 95% CI, 1.25-2.15), low maternal education (OR, 1.57; 95% CI, 1.19-2.08), maternal immigrant status (OR, 1.93; 95% CI, 1.38-2.71), and household low income adequacy (OR, 1.43; 95% CI, 1.11-1.83). Having a mother who has symptoms of depression, has low education, or is an immigrant, and living in a household with low income adequacy increase the risk of poor developmental attainment in children aged 1 to 5 years. The notable risks associated with these factors indicate them as possible targets for screening and interventions to prevent poor developmental attainment.


Highly efficient concerted evolution in the ribosomal DNA repeats: total rDNA repeat variation revealed by whole-genome shotgun sequence data.
Repeat families within genomes are often maintained with similar sequences. Traditionally, this has been explained by concerted evolution, where repeats in an array evolve "in concert" with the same sequence via continual turnover of repeats by recombination. Another form of evolution, birth-and-death evolution, can also explain this pattern, although in this case selection is the critical force maintaining the repeats. The level of intragenomic variation is the key difference between these two forms of evolution. The prohibitive size and repetitive nature of large repeat arrays have made determination of the absolute level of intragenomic repeat variability difficult, thus there is little evidence to support concerted evolution over birth-and-death evolution for many large repeat arrays. Here we use whole-genome shotgun sequence data from the genome projects of five fungal species to reveal absolute levels of sequence variation within the ribosomal RNA gene repeats (rDNA). The level of sequence variation is remarkably low. Furthermore, the polymorphisms that are detected are not functionally constrained and seem to exist beneath the level of selection. These results suggest the rDNA is evolving via concerted evolution. Comparisons with a repeat array undergoing birth-and-death evolution provide a clear contrast in the level of repeat array variation between these two forms of evolution, confirming that the rDNA indeed does evolve via concerted evolution. These low levels of intra-genomic variation are consistent with a model of concerted evolution in which homogenization is very rapid and efficiently maintains highly similar repeat arrays.


[Immunologic properties of malignant and benign L cell sublines. IV. Immune response of C3Hf mice].
Malignant LS cells obtained from benign L cells by selection retained their immunogenicity in syngeneic recipients. Nevertheless, such selection resulted in a partial change in their antigenic structure, which was manifested by the fact that only partial cross reactivity existed between L and LS cells on the level of both humoral and cellular immunity. The preliminary inoculation of L cells induced statistically significant lymphocytic reaction in the animals against LS cells, sufficient to protect 30% of mice inoculated with these cells.


The Friday evening case of acute kidney injury: a crystal dilemma.
We report a case of acute kidney injury (AKI) induced by amoxycillin crystalluria suggested by massive amounts of urinary crystals of unusual morphology. This hypothesis was further reinforced by a particular solubility pattern when the urine sample was exposed to various temperatures, alkali, acids and alcohol. We therefore suspended amoxycillin, which produced a rapid and complete recovery of kidney function. Infrared spectroscopy later confirmed the amoxycillin composition of the crystals. Since infrared spectroscopy is not easily available, we propose that these solubility tests of urinary crystals be used as a first-step investigation when amoxycillin crystalluria is suspected.


A mild method for the isolation of folded chromosomes from Escherichia coli.
Until now it has not been possible to obtain nuclear bodies from Escherichia coli after treatment with rifampicin. It was generally assumed that the cross-connections between the DNA double strands which are sensitive towards ribonuclease are destroyed under the influence of inhibitors of RNA synthesis like rifampicin. In this paper a new lysis procedure is described for preparing nuclear bodies from E. coli. These particles differ in some respects, especially in salt sensitivity from those prepared by earlier methods. Using the new lysis method it is also possible to obtain folded chromosomes from cells after treatment with rifampicin. These nuclear bodies can be destroyed by ribonuclease. Therefore, it has to be postulated that a fraction of RNA being sufficient to hold the chromosome in the folded shape is not susceptible to the action of rifampicin.


Chemical Synthesis of Human Insulin-Like Peptide-6.
Human insulin-like peptide-6 (INSL-6) belongs to the insulin superfamily and shares the distinctive disulfide bond configuration of human insulin. In this report we present the first chemical synthesis of INSL-6 utilizing fluorenylmethyloxycarbonyl-based (Fmoc) solid-phase peptide chemistry and regioselective disulfide bond construction protocols. Due to the presence of an oxidation-sensitive tryptophan residue, two new orthogonal synthetic methodologies were developed. The first method involved the identification of an additive to suppress the oxidation of tryptophan during iodine-mediated S-acetamidomethyl (Acm) deprotection and the second utilized iodine-free, sulfoxide-directed disulfide bond formation. The methodologies presented here offer an efficient synthetic route to INSL-6 and will further improve synthetic access to other multiple-disulfide-containing peptides with oxidation-sensitive residues.


Wounding in the plant tissue: the defense of a dangerous passage.
Plants are continuously exposed to agents such as herbivores and environmental mechanical stresses that cause wounding and open the way to the invasion by microbial pathogens. Wounding provides nutrients to pathogens and facilitates their entry into the tissue and subsequent infection. Plants have evolved constitutive and induced defense mechanisms to properly respond to wounding and prevent infection. The constitutive defenses are represented by physical barriers, i.e., the presence of cuticle or lignin, or by metabolites that act as toxins or deterrents for herbivores. Plants are also able to sense the injured tissue as an altered self and induce responses similar to those activated by pathogen infection. Endogenous molecules released from wounded tissue may act as Damage-Associated Molecular Patterns (DAMPs) that activate the plant innate immunity. Wound-induced responses are both rapid, such as the oxidative burst and the expression of defense-related genes, and late, such as the callose deposition, the accumulation of proteinase inhibitors and of hydrolytic enzymes (i.e., chitinases and gluganases). Typical examples of DAMPs involved in the response to wounding are the peptide systemin, and the oligogalacturonides, which are oligosaccharides released from the pectic component of the cell wall. Responses to wounding take place both at the site of damage (local response) and systemically (systemic response) and are mediated by hormones such as jasmonic acid, ethylene, salicylic acid, and abscisic acid.


Efficacy of a Web-Based Psychoeducational Intervention for Young Adults With Fertility-Related Distress Following Cancer (Fex-Can): Randomized Controlled Trial.
Threatened fertility following cancer diagnosis in the reproductive age may severely impact emotional and psychosocial well-being in survivorship. Effective web-based interventions for fertility-related distress have been lacking. This study aims to test whether the Fertility and Sexuality following Cancer (Fex-Can) intervention is superior to standard care in reducing fertility-related distress and related psychosocial outcomes in young adults with cancer. This randomized controlled trial evaluated a 12-week, web-based, automated self-help intervention for fertility-related distress following cancer-Fex-Can Fertility. Individuals were identified via Swedish national quality registries, and those reporting fertility-related distress 1.5 years after diagnosis were invited. A total of 100 women and 24 men (aged 19-40 years) answered self-administered surveys at baseline (T0), directly after the intervention (T1), and 3 months later (T2). The main outcome was fertility-related distress, which was measured by using the 6-dimension Reproductive Concerns After Cancer (RCAC) scale. The secondary outcomes were health-related quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire), emotional distress (Hospital Anxiety and Depression Scale), fertility-related knowledge, and fertility self-efficacy. In addition, the intervention group (IG) reported self-perceived changes in problems related to fertility after cancer (T1). 2-tailed t tests and linear mixed models, including intention-to-treat and subgroup analyses, were performed to compare the effects of the intervention with those of standard care. Although 62% (31/50) of the participants in the IG stated that their concerns about fertility were fewer after the intervention, there were few statistically significant group differences in the main outcome (RCAC) at T1 and T2. Compared with controls, the IG rated lower distress concerning the dimension child's health at T2 (P=.003; effect size [ES]=0.64). This difference was maintained when adding group and time interactions (intention-to-treat: P=.003; ES=0.58). The IG also had better self-perceived cancer-related fertility knowledge at T1 (P=.05; ES=0.35) and T2 (P=.01; ES=0.42) than the control group. Subgroup analyses based on dose or adherence and baseline RCAC scores did not substantially alter these results. Overall, the use of the web-based program was low. The Fex-Can intervention had small to moderate positive effects on cancer-related fertility knowledge and distress related to child's health. The lack of group differences in other dimensions of fertility distress and related secondary outcomes contrasted with reports on self-perceived improvement after the intervention. The Fex-Can Fertility program may be a useful complement to routine psychosocial support in the clinical care of young women and men with cancer. ISRCTN Registry 36621459; https://www.isrctn.com/ISRCTN36621459.


Understanding the role of aluminium in determining the surface structure and electrochemical performance of layered cathodes.
The electrochemical properties of layered cathodes can be enhanced by doping with aluminium. However, understanding of the underlying mechanism of Al ion behaviour is deficient, which obstructs its further application. Herein, we adjusted the aluminium content in model LiNi0.85-xCo0.15AlxO2 (LNCA) materials; the sample with the optimum aluminium content (x = 0.05) exhibited excellent electrochemical performance (98.6% capacity retention at 275 mA g-1). Meanwhile, for the samples with excessive aluminium (x = 0.15, 0.30), fast decay of the cycling stability could be observed. Meanwhile, their reversible capacities in the initial cycles were also greatly inferior to the theoretical values. These abnormal phenomena can be attributed to structure cracking and the impedance of Li-ion migration in samples with higher aluminium content. According to the microstructure observations, an unexpected beneficial heterostructure was found to cover the samples with optimum aluminium content, while in the samples with higher aluminium content, this heterostructure was not present. Furthermore, as confirmed by activation barrier calculations, Al ions were found to prefer to thermodynamically occupy the tetrahedral interstices instead of the octahedral sites in Li layers in a high delithiation state. Due to this selective occupancy, proper aluminium content can improve the stability of layered cathodes during cycling. However, excessive aluminium content instead impedes the formation of beneficial surface heterogeneity during synthesis and deeply affects Li-ion migration during cycling. Therefore, the electrochemical performance of the samples with higher aluminium content suffered severe decay. These results and discoveries significantly advance the guidance of microstructural design for next-generation layered cathode materials.


In vivo toxicity of prion protein in murine scrapie: ultrastructural and immunogold studies.
Prion protein (PrP) is a cell surface, host coded, sialoglycoprotein which accumulates in excess in scrapie, Creutzfeldt-Jakob disease, bovine spongiform encephalopathy and other transmissible spongiform encephalopathies. Infection of mice with the 87 V or ME7 scrapie strains results in distinctive and very different light microscopical patterns of vacuolation and disease specific PrP accumulation. In both of these scrapie strains immunogold electron microscopy was used to locate PrP to the plasmalemma of neurons from where it was released into the neuropil. Initial PrP accumulation around neurons and in early plaques lacking amyloid fibrils was generally not associated with morphological changes either of the neuron or dendrite releasing the PrP or in the adjacent neuropil in which excess PrP accumulated. However, accumulation of pre-amyloid PrP in some brain areas was associated with specific degeneration of dendritic spines and axon terminals. Initial PrP aggregation into fibrils was also associated with tissue damage with both ME7 and 87 V plaques and diffuse accumulations. Tissue damage associated with fibrillogenesis was localized and would not be expected to have clinical significance. We conclude that pre-amyloid PrP release and accumulation is not invariably toxic, either to the neuron releasing PrP or to the neuropil into which it is released. However, axon terminal degeneration and dendritic spine loss in some neuroanatomical areas may be indicative of specific PrP toxicity and may be the main cause of neurological dysfunction in murine scrapie.


Nonparametric testing of lack of dependence in functional linear models.
An important inferential task in functional linear models is to test the dependence between the response and the functional predictor. The traditional testing theory was constructed based on the functional principle component analysis which requires estimating the covariance operator of the functional predictor. Due to the intrinsic high-dimensionality of functional data, the sample is often not large enough to allow accurate estimation of the covariance operator and hence causes the follow-up test underpowered. To avoid the expensive estimation of the covariance operator, we propose a nonparametric method called Functional Linear models with U-statistics TEsting (FLUTE) to test the dependence assumption. We show that the FLUTE test is more powerful than the current benchmark method (Kokoszka P,2008; Patilea V,2016) in the small or moderate sample case. We further prove the asymptotic normality of our test statistic under both the null hypothesis and a local alternative hypothesis. The merit of our method is demonstrated by both simulation studies and real examples.


Mortality benefit of beta blockade in patients with acute coronary syndromes undergoing coronary intervention: pooled results from the Epic, Epilog, Epistent, Capture and Rapport Trials.
The effects of beta blocker therapy in the settings of heart failure and coronary artery disease have been well described, although little data exist in patients presenting with acute coronary syndromes undergoing percutaneous coronary intervention. The current study will attempt to evaluate the efficacy of beta blocker therapy in this setting. Pooled data from five randomized, controlled trials of abciximab during coronary intervention were used to analyze the clinical efficacy of beta blocker therapy. The pooled analysis evaluated the end points of all-cause mortality, myocardial infarction, repeat revascularization, and the combined endpoint of death and myocardial infarction in 2,894 patients. At 30 days, death occurred in 12 of 1,939 (0.6%) patients receiving beta blocker therapy and in 19 of 955 (2.0%) patients not receiving beta blocker therapy, (P < 0.001). At 6 months, death occurred in 33 of 1,939 (1.7%) patients receiving beta blocker therapy and 35 of 955 (3.7%) not receiving beta blocker therapy, (P < 0.001). After creating a propensity model and adjusting for variables predictive of mortality in the multivariable analysis, beta blocker therapy continued to be associated with a significant reduction in mortality. The findings were similar to those shown for the effects of beta blocker therapy in separate subgroups of patients with unstable angina and acute myocardial infarction. This analysis demonstrates a lower short-term mortality in patients receiving beta blocker therapy who undergo percutaneous coronary intervention for unstable angina or acute myocardial infarction.


Isolation and characterization of a post-proline cleaving enzyme and its inhibitor from sperm of the ascidian, Halocynthia roretzi.
A post-proline cleaving enzyme and its endogenous inhibitor have been demonstrated to be present in sperm of the ascidian, Halocynthia roretzi. The enzyme was extracted with artificial sea water from frozen and thawed sperm and isolated from accompanying acrosin-like and chymotrypsin-like enzymes by DEAE-cellulose chromatography. It was then separated from the endogenous inhibitor by ammonium sulfate fractionation and DEAE-Sephacel chromatography. Three subsequent chromatographic operations using hydroxylapatite, Sephadex G-150 and Z-Gly-Pro-Leu-Gly-aminohexyl-Sepharose yielded the highly purified enzyme. The molecular weight and isoelectric point of the enzyme were estimated to be 66,000 and 5.5, respectively. The pH optimum of the activity was 7.0. The enzyme was inactivated with diisopropylphosphorofluoridate, phenylmethylsulfonyl fluoride, Z-Gly-Pro-chloromethyl ketone and sulfhydryl-directed reagents; these inhibitor susceptibilities were similar to those reported for the enzymes of mammalian origins. The ascidian enzyme hydrolyzed oxytocin, angiotensin II, luteinizing hormone releasing hormone and neurotensin at the carboxyl side of proline residues. The endogenous inhibitor was heat stable. The molecular weight of its main component was estimated to be about 8,000. The presence of salt at high concentrations weakened the enzyme-inhibitor interaction. Z-Gly-Pro-chloromethyl ketone inhibited fertilization of the ascidian, suggesting possible involvement of the post-proline cleaving enzyme in fertilization.


[Expression of HLA-G protein in placental tissues and its influence on Th1/Th2 cytokines in peripheral blood in patients with intrahepatic cholestasis of pregnancy].
To investigate the changes of human leukocyte antigen-G (HLA-G) protein expression and Th1/Th2 type cytokines in intrahepatic cholestasis of pregnancy (ICP) and their relativity to the etiology of ICP. Peripheral blood and placental tissues were obtained from 26 ICP patients (the ICP group) and 22 normal pregnant women (the NP group) in the operation room for Cesarean birth. Immunohistochemistry was used to detect the expression of HLA-G protein in the placental tissues. Meanwhile we tested the concentrations of tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4) by enzyme-linked immunosorbent assay (ELISA) in the peripheral blood and checked the levels of TBA in the serum. TBA level in the ICP group was (27.05+/-6.08) micromol/L, significant higher than that in the NP group (4.35+/-2.68) micromol/L (P<0.01). The positive expression of HLA-G protein in extravillous trophoblast in the ICP group was significantly lower than that in the NP group (P<0.01). The mean optical density (MOD) of positive expression of HLA-G protein in the placenta tissues in the ICP group (52.91+/-7.19) was significantly lower than that in the NP group (69.26+/-7.72) (P<0.01). The concentration of TNF-alpha was significantly higher in the ICP group (101.31+/-19.30) pg/mL than that in the NP group (54.51+/-23.72) pg/mL (P<0.01). The concentration of IL-4 was lower in the ICP group (22.16+/-6.55) pg/mL than that in the NP group (31.69+/-8.25) pg/mL (P<0.01). The ratio of TNF-alpha/IL-4 was higher in the ICP group (4.52+/-1.91) than that in the NP group (1.72+/-0.61) (P<0.01). There was a negative correlation between the MOD of HLA-G protein and TNF-alpha (r=-0.98, P<0.01) in the ICP group. No correlation with IL-4 and TNF-alpha/IL-4 was seen (P>0.05). There was a positive correlation between TBA and TNF-alpha (r=0.99, P<0.01), and a negative correlation between TBA and the MOD of HLA-G protein (r=-1.00, P<0.01) in the ICP group. No correlation with IL-4 and TNF-alpha/IL-4 was seen (P>0.05). There is an imbalance of Th1/Th2 cytokines to the Th1 type in the peripheral blood of ICP patients. The expression of HLA-G protein in the placenta of ICP patients decreases, leading to an increase of Th1 type cytokines that may be one of the reasons for liver destroy in ICP.