Usefulness of the ankle-brachial index in assessing vascular function in normal individuals.
The ankle-brachial index (ABI) has been widely used in the diagnosis of established obstructive peripheral artery disease. However, its applicability in the earlier stages of vascular dysfunction lacks experimental demonstration. Our aim was thus to evaluate the potential of this indicator in the study of vascular function in a normal population. A total of 224 healthy male athletes were enrolled in a cross-sectional study. All underwent measurement of carotid-femoral pulse wave velocity (CFPWV) and carotid-radial pulse wave velocity (CRPWV). Central pulse pressure (PP) was extrapolated from CFPWV and CRPWV using a conversion algorithm (Complior, Colson, Paris). ABI was also calculated (adjusted for body surface area), and casual blood pressure and other relevant anthropometric data were recorded. The sample's mean age was 20+/-5.64 years, and systolic and diastolic blood pressure were 121+/-10.77 and 67+/-8.67 mmHg respectively. ABI showed a significant inverse correlation with CFPWV (r=-0.455; p<0.001) and with central PP (r=-0.465; p<0.001). Bivariate analysis of the correlation between ABI and left ventricular structural indicators revealed a significant inverse correlation with left ventricular mass (r=-0.43; p<0.05) and left ventricular systolic (r=-0.54; p<0.05) and diastolic (r--0.51; p<0.05) diameters, and with left atrial diameter (r--0.39; p<0.05). Repeated measures ANOVA showed a significant pulse pressure amplification (F (1,071,208,765) = 565.433; p<0.001), with lower values over the aorta (47.9+/-11.01), intermediate values over the brachial artery (54.2+11.66), and higher values over the ankle (74.1+/-15,17). Significant augmentation differences were found between brachial (5.4+/-2.99) and ankle (26.2+/-13.85) territories (F (1, 195) = 427.350; p<0.001). Significant correlations were found between ABI and aorta-ankle PP amplification (r=0.757; p<0.001), as well as with ankle PP (r=0.631; p<0.001). The strong association observed between ABI and arterial stiffness indicators, as well as with left ventricular and left atrial structural parameters, strongly supports the idea that this indicator may be useful in clinical practice by improving understanding and identification of potentially important hemodynamic adaptations. Thus, the arterial continuum strongly suggests a broad approach is advisable, integrating information from multiple sources, although the long-term value of the ABI as a potential risk marker remains to be determined in prospective studies.


Resolution of tracheostomy complications by decanulation and conversion to noninvasive management for a patient with high-level tetraplegia.
To report conversion from tracheostomy (TIV) to noninvasive intermittent positive pressure ventilation (NIV) for a continuously ventilator-dependent patient with high-level spinal cord injury (SCI) with no measurable vital capacity (VC = 0 mL) to resolve tracheostomy-associated complications. A case report of a 38-year-old female in a chronic care facility in Japan with a 10-year history of ventilator-dependent tetraplegia (C1 ASIA-A) presented for increasing difficulty vocalizing. She had been using a fenestrated cuffed tracheostomy tube to produce speech with the cuff deflated. Speech was increasingly hypophonic, because of tracheostoma enlargement, tube migration, and tracheal granulation. The NIV was provided via nasal and oral interfaces, the ostomy was surgically closed, and vocalization resumed. Airway secretions were expulsed using manually assisted coughing. The patient returned to the community. Conversion to NIV should be considered for ventilator-dependent patients with SCI who have adequate bulbar-innervated muscle function to permit effective speech and assisted coughing.


Transcriptional regulation by insulin: from the receptor to the gene.
Insulin, after binding to its receptor, regulates many cellular processes and the expression of several genes. For a subset of genes, insulin exerts a negative effect on transcription; for others, the effect is positive. Insulin controls gene transcription by modifying the binding of transcription factors on insulin-response elements or by regulating their transcriptional activities. Different insulin-signaling cascades have been characterized as mediating the insulin effect on gene transcription. In this review, we analyze recent data on the molecular mechanisms, mostly in the liver, through which insulin exerts its effect. We first focus on the key transcription factors (viz. Foxo, sterol-response-element-binding protein family (SREBP), and Sp1) involved in the regulation of gene transcription by insulin. We then present current information on the way insulin downregulates and upregulates gene transcription, using as examples of downregulation phosphoenolpyruvate carboxykinase (PEPCK) and insulin-like growth factor binding protein 1 (IGFBP-1) genes and of upregulation the fatty acid synthase and malic enzyme genes. The last part of the paper focuses on the signaling cascades activated by insulin in the liver, leading to the modulation of gene transcription.


Fixed-Combination Eye Drops Based on Fluorometholone Nanoparticles and Bromfenac/Levofloxacin Solution Improve Drug Corneal Penetration.
The multi-instillation of three commercially available (CA) eye drops [fluorometholone (FL)-, bromfenac (BF)- and levofloxacin (LV)-eye drops] has been used to manage pain and inflammation post-intraocular surgery. However, the multi-instillation of these three eye drops causes corneal damage, and the FL drops have the disadvantage of low ocular bioavailability. To overcome these problems, we prepared fixed-combination eye drops based on FL nanoparticles (FL-NPs) and BF/LV solution (nFBL-FC), and evaluated the corneal toxicity and transcorneal penetration of the nFBL-FC eye drops. FL powder was mixed in 2-hydroxypropyl-β-cyclodextrin solution containing benzalkonium chloride, mannitol and methylcellulose, and milled with a Bead Smash 12 (5500 rpm for 30 s×30 times). The BF/LV solution was then added to the milled-dispersions to be used as nFBL-FC. The FL, BF and LV concentrations were measured by HPLC methods, and transcorneal penetration was evaluated in rabbits. The FL particle size in nFBL-FC was 40-150 nm, with only 0.0018% in liquid form. No aggregation of FL particles in the nFBL-FC was observed for 1 month. The viability of human corneal epithelial cells treated with nFBL-FC was remarkably higher than that of cells subjected to the multi-instillation of the corresponding three CA-eye drops. In addition, the corneal penetrations (AUC) of the FL, BF and LV in nFBL-FC were 4.9-, 1.8-, and 7.1-fold those of the corresponding CA-eye drops, respectively. Moreover, the caveolae-dependent endocytosis (CavME) inhibitor (nystatin) significantly prevented the transcorneal penetration of these drugs. We prepared fixed-combination eye drops based on FL-NPs and BF/LV solution (nFBL-FC), and show that high levels of FL-NPs and dissolved BF/LV (liquid drugs) can be delivered into the aqueous humor by the instillation of nFBL-FC. Further, we show that CavME is mainly related to the enhancement of transcorneal penetration of both the solid (NPs) and liquid drugs.


131I treatment of diffuse and nodular toxic goitre with or without antithyroid agents.
The results of 131I treatment in combination with pre- and post-treatment with carbimazole (n = 122) were compared to the results of 131I used as the only antithyroid treatment (n = 203). The two groups of patients were fully comparable in regard to age, size of goitre and time of observation, and the same diagnostic criteria and dosage regimen of 131I were used. The incidence of early myxoedema in patients with diffuse goitre was significantly reduced after combination therapy, 5 per cent, compared to 16 per cent after 131I as the only antithyroid therapy (P less than 0.05). The incidence of late myxoedema was 6 per cent in both groups 3 years after the last treatment, and fully compensated myxoedema was found in 13 and 22 per cent (n.s.). No severe acute side effects were observed after 131I therapy in any of the two groups. It is concluded that--in diffuse toxic goitre--a lower early incidence of myxoedema was obtained on the combined regimen because of either a possibly lower absorbed radiation dose or a more fractionate therapy. A major advantage of the combination therapy is also, that the patients are rendered euthyroid shortly after the diagnosis and remain so during the prolonged period of treatment. 131I treatment in combination with carbimazole is advocated in all patients with diffuse and nodular toxic goitre if the patient is above fertile age and thyroidectomy is not indicated.


Combination of Walnut Peptide and Casein Peptide alleviates anxiety and improves memory in anxiety mices.
Anxiety disorders continue to prevail as the most prevalent cluster of mental disorders following the COVID-19 pandemic, exhibiting substantial detrimental effects on individuals' overall well-being and functioning. Even after a search spanning over a decade for novel anxiolytic compounds, none have been approved, resulting in the current anxiolytic medications being effective only for a specific subset of patients. Consequently, researchers are investigating everyday nutrients as potential alternatives to conventional medicines. Our prior study analyzed the antianxiety and memory-enhancing properties of the combination of Walnut Peptide (WP) and Casein Peptide (CP) in zebrafish. Based on this work, our current research further validates their effects in mice models exhibiting elevated anxiety levels through a combination of gavage oral administration. Our results demonstrated that at 170 + 300 mg human dose, the WP + CP combination significantly improved performances in relevant behavioral assessments related to anxiety and memory. Furthermore, our analysis revealed that the combination restores neurotransmitter dysfunction observed while monitoring Serotonin, gamma-aminobutyric acid (GABA), dopamine (DA), and acetylcholine (ACh) levels. This supplementation also elevated the expression of brain-derived neurotrophic factor mRNA, indicating protective effects against the neurological stresses of anxiety. Additionally, there were strong correlations among behavioral indicators, BDNF (brain-derived neurotrophic factor), and numerous neurotransmitters. Hence, our findings propose that the WP + CP combination holds promise as a treatment for anxiety disorder. Besides, supplementary applications are feasible when produced as powdered dietary supplements or added to common foods like powder, yogurt, or milk.


Visualization, Interaction and Tractometry: Dealing with Millions of Streamlines from Diffusion MRI Tractography.
Recently proposed tractography and connectomics approaches often require a very large number of streamlines, in the order of millions. Generating, storing and interacting with these datasets is currently quite difficult, since they require a lot of space in memory and processing time. Compression is a common approach to reduce data size. Recently such an approach has been proposed consisting in removing collinear points in the streamlines. Removing points from streamlines results in files that cannot be robustly post-processed and interacted with existing tools, which are for the most part point-based. The aim of this work is to improve visualization, interaction and tractometry algorithms to robustly handle compressed tractography datasets. Our proposed improvements are threefold: (i) An efficient loading procedure to improve visualization (reduce memory usage up to 95% for a 0.2 mm step size); (ii) interaction techniques robust to compressed tractograms; (iii) tractometry techniques robust to compressed tractograms to eliminate biased in tract-based statistics. The present work demonstrates the need of correctly handling compressed streamlines to avoid biases in future tractometry and connectomics studies.


Evolution of white matter tract microstructure across the life span.
The human brain undergoes dramatic structural change over the life span. In a large imaging cohort of 801 individuals aged 7-84 years, we applied quantitative relaxometry and diffusion microstructure imaging in combination with diffusion tractography to investigate tissue property dynamics across the human life span. Significant nonlinear aging effects were consistently observed across tracts and tissue measures. The age at which white matter (WM) fascicles attain peak maturation varies substantially across tissue measurements and tracts. These observations of heterochronicity and spatial heterogeneity of tract maturation highlight the importance of using multiple tissue measurements to investigate each region of the WM. Our data further provide additional quantitative evidence in support of the last-in-first-out retrogenesis hypothesis of aging, demonstrating a strong correlational relationship between peak maturational timing and the extent of quadratic measurement differences across the life span for the most myelin sensitive measures. These findings present an important baseline from which to assess divergence from normative aging trends in developmental and degenerative disorders, and to further investigate the mechanisms connecting WM microstructure to cognition.


The effect of HBB: c.*+96T>C (3'UTR +1570 T>C) on the mild b-thalassemia intermedia phenotype.
Hemoglobin beta (HBB): c.*+96T>C substitution is very rare among β-globin gene mutations and its clinical significance remains to be clarified. The present study aimed to investigate the role of HBB: c.*+96T>C in the β-thalassemia intermedia phenotype in a Turkish family. The proband and parents were screened for β-globin gene mutations via direct sequencing. Hematological and physical examination results were recorded, and correlated according to genotype. The proband was compound heterozygous for Cod 8 (-AA) and HBB: c.*+96T>C, whereas his mother and father were heterozygous for Cod 8 (-AA) and HBB: c.*+96T>C, respectively. The father had almost normal hematological findings, whereas the mother had the typical β-thalassemia trait phenotype. The proband was diagnosed as mild β-thalassemia intermedia based on hepatosplenomegaly and hematological findings. To the best of our knowledge this is the first report of HBB: c.*+96T>C mutation in a Turkish family. HBB: c.* 96T>C substitution is a very rare, but clinically relevant β-globin gene mutation. Additionally, we think that if 1 spouse is a carrier for β-globin gene mutation the other should be screened for silent mutations, such as HBB: c.*+96T>C mutation of the β-globin gene, even if she/he does not have any clinical or hematological signs of the β-thalassemia trait phenotype.


Describing the readiness for interprofessional education among university students attending healthcare programs: insights from a monocentric cross-sectional study.
Readiness for interprofessional education (IPE) was recognized by international authorities as a key approach for educating students attending healthcare programs. Thus far, there are no descriptions of readiness for IPE in the Albanian context. For this reason, this study aimed to describe readiness for IPE, assessed by measuring "teamwork and collaboration" and "positive professional identity, roles, and responsibilities" among students attending healthcare programs in an Italian-speaking university based in Albania, and describe the correlations between readiness for IPE and the characteristics of the respondents. This study had a descriptive observational design, a cross-sectional data collection, and a convenience sampling procedure performed in a single centre. The study was accomplished between April 2020 and June 2021, involving 688 students, 38.2% of the entire population of students attending healthcare programs in the context of the investigation. The teamwork and collaboration mean score was 4.40 (standard deviation = 0.56), and no differences were found between programs (p-value=0.159). The positive professional identity, roles, and responsibilities mean score was 4.33 (standard deviation = 0.64) with no differences between programs (p-value=0.340). Females attending nursing or midwifery reported higher positive professional identity, roles, and responsibilities scores (p-value=0.020), and females in dentistry reported higher teamwork and collaboration scores than males (p-value=0.045). Future research should evaluate readiness for IPE longitudinally to ascertain its trajectories over time and analyze any potential individual- or organizational-level variables that may impact IPE and sex-related differences regarding factors influencing IPE.


Depressive realism from the perspective of cognitive-experiential self-theory.
To explain why the depressive realism effect has been found in trivial, artificial laboratory but not in more realistic or emotionally engaging situations, the authors hypothesized that depressed people overcompensate for a tendency toward maladaptive experiential (intuitive) processing by exercising excessive rational control in trivial situations. In more consequential situations, they are unable to control their maladaptive experiential processing because it is excessive, or their rational control is insufficient, or both. As predicted, a subclinically depressed group (n = 39) made more optimal decisions than a nondepressed control group (n = 36) under trivial conditions, and the groups converged under more consequential conditions, with the depressed group responding less and the control group more optimally. Also, the depressed group reported engaging in less rational processing and in more maladaptive experiential processing in everyday life than did the control group.


Comparison of Langevin and Markov channel noise models for neuronal signal generation.
The stochastic opening and closing of voltage-gated ion channels produce noise in neurons. The effect of this noise on the neuronal performance has been modeled using either an approximate or Langevin model based on stochastic differential equations or an exact model based on a Markov process model of channel gating. Yet whether the Langevin model accurately reproduces the channel noise produced by the Markov model remains unclear. Here we present a comparison between Langevin and Markov models of channel noise in neurons using single compartment Hodgkin-Huxley models containing either Na+ and K+, or only K+ voltage-gated ion channels. The performance of the Langevin and Markov models was quantified over a range of stimulus statistics, membrane areas, and channel numbers. We find that in comparison to the Markov model, the Langevin model underestimates the noise contributed by voltage-gated ion channels, overestimating information rates for both spiking and nonspiking membranes. Even with increasing numbers of channels, the difference between the two models persists. This suggests that the Langevin model may not be suitable for accurately simulating channel noise in neurons, even in simulations with large numbers of ion channels.


Inhibition of fructose-1,6-bisphosphatase by aminoimidazole carboxamide ribotide prevents growth of Salmonella enterica purH mutants on glycerol.
The enzyme fructose-1,6-bisphosphatase (FBP) is key regulatory point in gluconeogenesis. Mutants of Salmonella enterica lacking purH accumulate 5-amino-4-imidazole carboxamide ribotide (AICAR) and are unable to utilize glycerol as sole carbon and energy sources. The work described here demonstrates this lack of growth is due to inhibition of FBP by AICAR. Mutant alleles of fbp that restore growth on glycerol encode proteins resistant to inhibition by AICAR and the allosteric regulator AMP. This is the first report of biochemical characterization of substitutions causing AMP resistance in a bacterial FBP. Inhibition of FBP activity by AICAR occurs at physiologically relevant concentrations and may represent a form of regulation of gluconeogenic flux in Salmonella enterica.


Cherenkov radiation versus X-shaped localized waves.
Localized waves (LW) are nondiffracting ("soliton-like") solutions to the wave equations and are known to exist with subluminal, luminal, and superluminal peak velocities V. For mathematical and experimental reasons, those that have attracted more attention are the "X-shaped" superluminal waves. Such waves are associated with a cone, so that one may be tempted-let us confine ourselves to electromagnetism-to look [Phys. Rev. Lett.99, 244802 (2007)] for links between them and the Cherenkov radiation. However, the X-shaped waves belong to a very different realm: For instance, they can be shown to exist, independently of any media, even in vacuum, as localized non-diffracting pulses propagating rigidly with a peak-velocity V>c [Hernández et al., eds., Localized Waves (Wiley, 2008)]. We dissect the whole question on the basis of a rigorous formalism and clear physical considerations.


SpyTag/SpyCatcher Functionalization of E2 Nanocages with Stimuli-Responsive Z-ELP Affinity Domains for Tunable Monoclonal Antibody Binding and Precipitation Properties.
E2 nanocages functionalized with Z-domain-elastin-like polypeptide affinity ligands (Z-ELP40) using Sortase A (SrtA) ligation have been shown to be a promising scaffold for purifying monoclonal antibodies (mAbs) based on affinity precipitation. However, the reversible nature of SrtA reaction has been attributed to the low ligation efficiency (<25%) and has significantly limited the practical utility of the technology. Here, we reported an improved conjugation platform using the SpyTag/SpyCatcher pair to form a spontaneous isopeptide bond between SpyTag-E2 and Z-ELP-SpyCatcher fusion proteins of two different ELP chain-lengths. Using this system, E2 ligation efficiencies exceeding 90% were obtained with both 40- and 80-repeat Z-ELP-SpyCatcher fusions. This enabled the production of nanocages fully functionalized with Z-ELP for improved aggregation and mAb binding. Compared to the 50% decorated Z-ELP40-E2 nanocages produced by SrtA ligation, the fully decorated Z-ELP80-Spy-E2 nanocages exhibited a 10 °C lower transition temperature and a 2-fold higher mAb binding capacity. The improved transition property of the longer Z-ELP80 backbone allowed for >90% recovery of Z-ELP80-Spy-E2 nanocages at room temperature using 0.1 M ammonium sulfate after mAb elution. The flexibility of customizing different affinity domains onto the SpyTag-E2 scaffold should expand our ability to purify other non-mAb target proteins based on affinity precipitation.


Computational Insights into ADAMTS4, ADAMTS5 and MMP13 Inhibitor Selectivity.
The results obtained by means of Molecular Dynamics simulations and Multiway Explorative Data Analysis on ADAMTS4, ADAMTS5 and MMP13 complexed with Marimastat and two cis-1(S)2(R)-amino-2-indanol ligands suggest that determinant characteristics for ligand binding and selectivity among the three enzymes are to be found in the different protein conformation flexibility. Moreover, the role of the TS-domain in the inhibitor binding to ADAMTS enzymes has been investigated for the first time in this work. The results obtained suggest that the influence of the TS-domain on the S1' loop fluctuations of ADAMTS4 and ADAMTS5 could be exploited for the design of therapeutics for chronic osteoarthritis diseases.


Higher Levels of Psychopathy Predict Poorer Motor Control: Implications for Understanding the Psychopathy Construct.
A review of the literature suggests that higher levels of psychopathy may be linked to less effective behavioral control. However, several commentators have urged caution in making statements of this type in the absence of direct evidence. In two studies (total N = 142), moment-to-moment accuracy in a motor control task was examined as a function of dimensional variations in psychopathy in an undergraduate population. As hypothesized, motor control was distinctively worse at higher levels of psychopathy relative to lower levels, both as a function of primary and secondary psychopathy and particularly their shared variance. These novel findings provide support for the idea that motor control systematically varies by psychopathy, in a basic manner, consistent with views of psychopathy emphasizing lesser control.


Heteromeric TRPV4/TRPC1 channels mediate calcium-sensing receptor-induced relaxations and nitric oxide production in mesenteric arteries: comparative study using wild-type and TRPC1-/- mice.
We have previously provided pharmacological evidence that stimulation of calcium-sensing receptors (CaSR) induces endothelium-dependent relaxations of rabbit mesenteric arteries through activation of heteromeric TRPV4/TRPC1 channels and nitric oxide (NO) production. The present study further investigates the role of heteromeric TRPV4/TRPC1 channels in these CaSR-induced vascular responses by comparing responses in mesenteric arteries from wild-type (WT) and TRPC1-/- mice. In WT mice, stimulation of CaSR induced endothelium-dependent relaxations of pre-contracted tone and NO generation in endothelial cells (ECs), which were inhibited by the TRPV4 channel blocker RN1734 and the TRPC1 blocking antibody T1E3. In addition, TRPV4 and TRPC1 proteins were colocalised at, or close to, the plasma membrane of endothelial cells (ECs) from WT mice. In contrast, in TRPC1-/- mice, CaSR-mediated vasorelaxations and NO generation were greatly reduced, unaffected by T1E3, but blocked by RN1734. In addition, the TRPV4 agonist GSK1016790A (GSK) induced endothelium-dependent vasorelaxations which were blocked by RN1734 and T1E3 in WT mice, but only by RN1734 in TRPC1-/- mice. Moreover, GSK activated cation channel activity with a 6pS conductance in WT ECs but with a 52 pS conductance in TRPC1-/- ECs. These results indicate that stimulation of CaSR activates heteromeric TRPV4/TRPC1 channels and NO production in ECs, which are responsible for endothelium-dependent vasorelaxations. This study also suggests that heteromeric TRPV4-TRPC1 channels may form the predominant TRPV4-containing channels in mouse mesenteric artery ECs. Together, our data further implicates CaSR-induced pathways and heteromeric TRPV4/TRPC1 channels in the regulation of vascular tone.


The presence of eosinophil leucocytes in cervicovaginal smears with Actinomyces-like organisms: Light microscopic examination.
Actinomyces species are part of mucosal surfaces of oral cavity, gastrointestinal and genital tracts. When these mucosal surfaces disrupt, Actinomyces become pathogen and cause infection. Eosinophil leucocytes participate in host defense against helminthic infestation and they generally play a role in asthma and allergy. However, the role of eosinophil leucocytes in host defense against bacteria is conflicting. To determine whether there is a relationship between Actinomyces-like organisms (ALOs) and eosinophil leucocytes at light microscopic level. Cervicovaginal samples obtained from 200 patients were examined by both Pap smear microscopy and anaerobic culturing. Since the results obtained by these methods were not concordant for diagnosis of genital Actinomyces, 6 of 200 patients (3%) diagnosed with ALOs by Pap smear microscopy became the study group. Patients without any infectious agents (n=134) were the control group. Statistical analyses were conducted with χ(2) test using SPSS program. The study and control groups were compared statistically in view of the presence of eosinophil leucocytes and it was found that there was a significant correlation between the presence of ALOs and eosinophil leucocytes (P<0.05). Abundant polymorphonuclear leucocytes (PMNLs) and macrophages were also detected in the study group. This study implies that eosinophil leucocytes might have a role in host defense against Actinomyces in addition to PMNLs and macrophages.


Mechanism of active renal tubular efflux of tenofovir.
Tenofovir (TFV) undergoes renal elimination by a combination of glomerular filtration and active tubular secretion. While transporter-mediated uptake of TFV from the blood into proximal-tubule cells has been well characterized, comparatively little is known about the efflux system responsible for transporting TFV into the lumen during active tubular secretion. Therefore, members of the ATP-binding cassette family of efflux pumps expressed at the apical side of proximal-tubule cells were studied for the ability to transport TFV. Studies in multiple independent in vitro systems show TFV not to be a substrate for P glycoprotein (Pgp) or multidrug resistance protein type 2 (MRP2). In contrast to Pgp and MRP2, TFV was observed to be a substrate for MRP4. TFV accumulated to fivefold lower levels in MRP4-overexpressing cells, and its accumulation could be increased by an MRP inhibitor. Furthermore, MRP4-overexpressing cells were found to be 2.0- to 2.5-fold less susceptible to cytotoxicity caused by TFV. ATP-dependent uptake of TFV was observed in membrane vesicles containing MRP4 but not in vesicles lacking the transporter. On the basis of these and previous results, the molecular transport pathway for the active tubular secretion of TFV through renal proximal-tubule cells involves uptake from the blood mediated by human organic anion transporters 1 and 3 and efflux into urine by MRP4. A detailed understanding of the molecular mechanism of TFV active tubular secretion will facilitate the assessment of potential renal drug-drug interactions with coadministered agents.


A Salmonella enterica subspecies enterica serovar Choleraesuis outbreak in weaned piglets in Serbia: clinical signs, pathologic changes, and microbiologic features.
Salmonella enterica subspecies enterica serovar Choleraesuis is rarely detected in Europe, but the clinical disease has been reported in wild boars. We describe here the clinical findings, pathologic changes, and microbiologic features of swine salmonellosis caused by S. enterica serovar Choleraesuis in weaned piglets in Serbia. In April 2019, on a large farrow-to-finish pig farm, increased mortality was reported in weaned piglets, marked by lethargy, anorexia, pyrexia, and respiratory distress. Gross pathology revealed dermal cyanosis, mesenteric lymphadenopathy, splenomegaly, hepatomegaly, interstitial pneumonia, and colitis. By direct culturing of lung, liver, spleen, and lymph nodes, S. enterica ser. Choleraesuis variant Kunzendorf was isolated after years of absence of the disease in pig farms in Europe. The source of this salmonellosis outbreak caused by S. enterica ser. Choleraesuis remains unknown.


"Diminishing returns" and leaf area-biomass scaling of ferns in subtropical ecosystems.
Foliage leaves are the primary photosynthetic organ of the majority of vascular plants, and their area vs. biomass scaling relationships provide valuable insights into the capacity and investment in light interception, which is critical to plant growth and performance. The "diminishing returns" hypothesis (DRH), which is based primarily on data from gymnosperms and angiosperms, posits that leaf (lamina) area scales with leaf dry mass. on average with a scaling exponent less than 1.0. However, it remains uncertain whether DRH applies to ferns or whether ecological factors affect the scaling exponents governing fern leaf morphometrics. To address this issue, 182 individuals of 28 subtropical ferns species were studied at low, medium, and high elevations (i.e., 600 m, 900 m, and 1200 m, respectively) in Mount Wuyi National Park, Jiangxi Province, China. The scaling relationships between leaf area and leaf biomass for individual and total leaf of ferns at different elevations were examined by using standardized major axis regression protocols. Analyses of the 28 fern species (using Blomberg K-value protocols) indicated no phylogenetic biases among the species compositions of the three different elevations. In addition, at the individual plant level, individual leaf area (ILA) did not differ significantly among the three different elevations (P > 0.05). However, individual leaf mass (ILM) was significantly higher at 900m than at 1200m (P < 0.05), resulting in a significantly higher leaf mass per area (LMA) at the 900m elevation than at the 600m and 1200m elevations (P < 0.05). The ILA and ILM at the 900m elevation were significantly higher than at the 600m elevation (P < 0.05). At the species level, ILA and ILM did not differ significantly among the three elevations (P > 0.05). The total leaf area per individual (TLA) did not differ significantly across the different elevations (P > 0.05). However, total leaf mass per individual (TLM) did differ significantly (P < 0.05). At the individual plant level, the scaling exponents for ILA vs. ILM and TLA vs. TLM at the three different elevations were all significantly less than 1.0 (P < 0.05), which was consistent with the DRH. At the species level, the scaling exponents for the ILA vs. ILM were significantly less than 1.0 at the middle and high elevations, but not at the low elevation. The scaling exponents of the TLA and TLM were numerically highest in the middle elevation, and all were less than 1.0 for the three elevations. These results indicate that the scaling relationships of leaf area versus mass of subtropical ferns at different elevations support the DRH hypothesis. The study further informs our understanding of the resource allocation strategies of an ancient and diverse plant lineage.


Corneal donor tissue preparation for Descemet's membrane endothelial keratoplasty.
Descemet's Membrane Endothelial Keratoplasty (DMEK) is a form of corneal transplantation in which only a single cell layer, the corneal endothelium, along with its basement membrane (Descemet's membrane) is introduced onto the recipient's posterior stroma(3). Unlike Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK), where additional donor stroma is introduced, no unnatural stroma-to-stroma interface is created. As a result, the natural anatomy of the cornea is preserved as much as possible allowing for improved recovery time and visual acuity(4). Endothelial Keratoplasty (EK) is the procedure of choice for treatment of endothelial dysfunction. The advantages of EK include rapid recovery of vision, preservation of ocular integrity and minimal refractive change due to use of a small, peripheral incision(1). DSAEK utilizes donor tissue prepared with partial thickness stroma and endothelium. The rapid success and utilization of this procedure can be attributed to availability of eye-bank prepared precut tissue. The benefits of eye-bank preparation of donor tissue include elimination of need for specialized equipment in the operating room and availability of back up donor tissue in case of tissue perforation during preparation. In addition, high volume preparation of donor tissue by eye-bank technicians may provide improved quality of donor tissue. DSAEK may have limited best corrected visual acuity due to creation of a stromal interface between the donor and recipient cornea. Elimination of this interface with transplantation of only donor Descemet's membrane and endothelium in DMEK may improve visual outcomes and reduce complications after EK(5). Similar to DSAEK, long term success and acceptance of DMEK is dependent on ease of availability of precut, eye-bank prepared donor tissue. Here we present a stepwise approach to donor tissue preparation which may reduce some barriers eye-banks face in providing DMEK grafts.


[Quality of life in multiple sclerosis--association with clinical features, fatigue and depressive syndrome].
The aim of the study was to assess the health related quality of life in patients suffering from multiple sclerosis (MS) in association with clinical features, fatigue and depressive symptoms. The examined group consisted of 61 patients (45 women and 16 men) in the mean age of 38.6 +/- 11.4. The mean duration of disease was 7.1 +/- 6.1 years. The control group consisted of 30 healthy volunteers. The following questionnaires were used: EuroQol (EQ5D) with visual scale EuroQol-VAS, Modified Impact Fatigue Scale (MIFS) and Beck Depression Inventory (BDI). The quality of life in the examined group of MS patients was significantly lower in comparison to the control group. Results of EQ-5D and EQ-VAS were influenced by age, disease course, level of disability and carried treatment. Statistically significant association was also found between results of the questionnaires assessing quality of life and either fatigue or depressive symptoms. The used questionnaires confirmed that quality of life in patients with MS is significantly worse, especially in the older people with secondary progressive course of the disease, more disable and not treated. Presence of fatigue and depressive symptoms influenced the self-assessment of quality of life. Complex care of MS patient should consider diagnosis and treatment of fatigue and depression which could improve their quality of life.


Breastfeeding articles in the Australian press: 1996-1999.
The mass print media provide an opportunity to promote health messages to the general community. This paper examines articles on breastfeeding in the mass print media available to a low socioeconomic area in Australia over a four-year period from 1996 to 1999. Between January 1996 and December 1999, 334 breastfeeding articles were identified in the four main newspapers available in a low socioeconomic metropolitan area. Breastfeeding messages presented by the articles were examined using content analysis. While most articles presented a neutral message about breastfeeding (43%), more articles presented a positive message (35%) than a negative message (14%). Twenty-two percent of the articles were letters to the editor, and only 1.3% of the articles were accompanied by photos of a baby being breastfed. Fifty-five articles discussed breastfeeding in public making it the most common breastfeeding issue mentioned. Breastfeeding is an emotive issue and could be more actively supported and promoted by publishing more newspaper articles that present a positive message of breastfeeding, more positive headlines, and more breastfeeding photos.


City sanitation and socioeconomics predict rat zoonotic infection across diverse neighbourhoods.
Rat-associated zoonoses transmitted through faeces or urine are of particular concern for public health because environmental exposure in homes and businesses may be frequent and undetected. To identify times and locations with greater public health risks from rats, we investigated whether rat characteristics, environmental features, socioeconomic factors, or season could predict rat infection risk across diverse urban neighbourhoods. In partnership with a pest management company, we sampled rats in 13 community areas along an income gradient in Chicago, a large city where concern about rats has increased in recent years. We collected kidneys for Leptospira spp. testing and colon contents for aerobic bacteria such as Salmonella spp. and Escherichia coli. Of 202 sampled rats, 5% carried Leptospira spp. and 22% carried E. coli. Rats were significantly more likely to carry Leptospira spp. on blocks with more standing water complaints in higher-income neighbourhoods (OR = 6.74, 95% CI: 1.54-29.39). Rats were significantly more likely to carry E. coli on blocks with more food vendors (OR = 9.94, 2.27-43.50) particularly in low-income neighbourhoods (OR = 0.26, 0.09-0.82) and in the spring (OR = 15.96, 2.90-88.62). We detected a high diversity of E. coli serovars but none contained major virulence factors. These associations between environmental features related to sanitation and infection risk in rats support transmission through water for Leptospira spp. and faecal-oral transmission for E. coli. We also found opposing relationships between zoonotic infection risk and income for these two pathogens. Thus, our results highlight the importance of sanitation for predicting zoonotic disease risks and including diverse urban areas in pathogen surveillance to mitigate public health risks from rats.


Penicillin's Discovery and Antibiotic Resistance: Lessons for the Future?
Undoubtedly, the discovery of penicillin is one of the greatest milestones in modern medicine. 2016 marks the 75th anniversary of the first systemic administration of penicillin in humans, and is therefore an occasion to reflect upon the extraordinary impact that penicillin has had on the lives of millions of people since. This perspective presents a historical account of the discovery of the wonder drug, describes the biological nature of penicillin, and considers lessons that can be learned from the golden era of antibiotic research, which took place between the 1940s and 1960s. Looking back at the history of penicillin might help us to relive this journey to find new treatments and antimicrobial agents. This is particularly relevant today as the emergence of multiple drug resistant bacteria poses a global threat, and joint efforts are needed to combat the rise and spread of resistance.


Do routine outcome monitoring measures tell the same story? Evaluating outcome trajectories and clinical outcomes for the outcome rating scale and outcome questionnaire - 45.
Routine outcome monitoring (ROM) of psychotherapy improves client outcomes and reduces premature terminations. Two ROM systems with the most empirical support are the OQ System (Lambert, 2010) and the Partners for Change Outcome Management System (PCOMS; Duncan, 2012; Miller et al., 2005). We evaluated if the global distress measures, the Outcome Rating Scale (ORS; PCOMS) and the Outcome Questionnaire-45.2 (OQ-45; OQ System) show similar outcome trajectories and rates of reliable and clinically significant change when completed by the same clients. Participants (N = 290) were clients from archived data collected in a training clinic for a psychology doctoral program in the western United States, who completed both the ORS and OQ-45 across treatment. Bi-variate correlations between the ORS and OQ-45 were highly correlated at the first session (r = -.73), and for later sessions linear and quadratic estimates were only moderately related (rs = -.31 to -.57). Statistically significantly more clients indicated both reliable change and clinically significant change on the ORS compared to the OQ-45. The results indicate that these measures are correlated but not interchangeable in relation to the conclusions they generate about treatment outcomes. Measurement tools should be carefully considered given the potential for different conclusions to be drawn regarding treatment progress and outcomes.


The Perception of Art among Patients and Staff on a Renal Dialysis Unit.
This study investigated the purpose and effectiveness of giving outpatients an opportunity to engage in art activities while receiving dialysis treatment. A mixed method study was conducted. 21 semi-structured interviews were conducted with outpatients attending the dialysis unit and 13 surveys of clinicians were completed. The principle reasons to partake in the art activity programme included: to pass time, to relieve boredom, to be creative, to try something new, distraction from concerns, to stay positive and to achieve something new. Patients who did not participate in the programme pass their time primarily by watching TV or sleeping. All staff who partook in the survey were satisfied with the programme and wanted it to continue. Our findings indicate that the creative arts programme is viewed positively by staff and patients alike, and might be useful in other hospital departments. Further in depth qualitative research would be useful to interrogate the potential effect of engagement in art on positive mental health and quality of life for patients with chronic conditions.


Use of a free gracilis flap for coverage of medium size defects over the ankle and foot.
We report the use of a free gracilis flap in six cases of medium size tissue loss over the ankle and foot. All the procedures were done under spinal or epidural block. A muscle flap was used twice and a musculocutaneous flap four times. The skin paddle was reliable in three cases for evaluation of the vascularity of the musculocutaneous flaps, but in one case there was necrosis of 70% of the surface. In three cases the fatty skin paddle was removed at two weeks and the entire muscle surface was mesh skin grafted. The advantages of the use of a gracilis flap are easy dissection and low donor site morbidity. This flat and thin muscle is well-suited for medium size defects from 8-15 cm. The length of the pedicle could be extended to 8 cm by dissecting it as far as the profunda femoris vessels.


Population Characteristics and Progressive Disability in Neurofibromatosis Type 2.
To characterize the clinical features of patients with neurofibromatosis type 2 (NF2) and determine prognostic risk factors for progressive disabilities. In this retrospective cohort study of the Japanese national NF2 registry between 2009 and 2013, clinical data (demographic, history, oncologic, and neurologic) of 807 patients with a diagnosis of NF2 were analyzed. The overall severity of neurologic disability was assessed using a comprehensive 25-point scoring system encompassing a wide variety of neurologic deficits. In 587 patients in whom longitudinal disability data were available, multivariate logistic regression was performed to identify risk factors for significant progression of disability. The clinical characteristics of the Japanese NF2 population were heterogeneous. The median age of onset was 24 years (range, 1-80 years), the male:female ratio was 1:1.29, and the initial severity score was 4 (range, 0-22) out of 25 points. A family history of NF2 was present in 33% of the patients. Most frequent clinical features were bilateral cranial nerve VIII nerve sheath tumor (NST) in 87%, spinal NST in 80%, hearing loss in 65%, spinal dysfunction in 50%, intracranial meningioma in 49%, and facial paresis in 36%. The disability score progressed by ≥5 points in 6.1% of patients over the study period. Based on multivariate logistic regression analyses, the significant independent risk factors of progression (P value) included age of onset <25 years (P = 0.015), positive family history (P = 0.007), positive treatment history (P = 0.026), hearing loss (P = 0.014), facial paresis (P = 0.015), blindness (P = 0.011), and hemiparesis (P = 0.025). The Japanese NF2 population has heterogeneous clinical features. Risk factors for progressive disability include younger age of onset, positive family history, positive treatment history, and specific neurologic deficits.


[Prognostic biomarkers and targeted therapies for gastric cancer].
Gastric cancer patients with the same clinical stage may vary greatly in prognosis, which makes the improvement of current staging-based treatment imperative. The systematic biology approaches are the solution for systematic identification of biomarkers for prognostic evaluation and targeted therapy. These markers will be applied to classify the patients by molecular traits and then to guide the individualized medication. Although HER-2 antibody is currently the only targeted drug in guideline, more drugs are now addressed in early phases of clinical trials and parts of them will be eventually approved.


Long term effects of low protein diet on depressive symptoms and quality of life in elderly Type 2 diabetic patients.
The long term effects of a low protein diet (LPD) on depressive symptoms and the quality of life in elderly Type 2 diabetic are unclear. 38 elderly Type 2 diabetic patients with CRD (Stage 3 - 4) were enrolled in the study. After 4 weeks on a normal protein diet regimen (NPD) providing 1.0 g/kg per day, all participants were assigned for 30 months, randomly, to a LPD (0.7 g/kg per day), either 7 days a week (LPD 7/7) or 6 days a week (LPD 6/7). Mini mental state examination (MMSE), activities daily living (ADL), cumulative illness severity (CIRS-IS), geriatric depression scale (GDS-15) and short-form healthy survey (SF- 36) were evaluated every 3 months. Before the LPD regimen creatinine clearance (CrCl), MMSE, ADL, CIRS-IS, GDS-15 and SF-36 were similar in both LPD 7/7 and LPD 6/7 groups. After 30 months, the mean GDS- 15 increased significantly more in LPD 7/7 group than in LPD 6/7 group (p < 0.05). Both mean SF-36 MCS and SF-36 PCS were decreased significantly more in LPD 7/7 group than in LPD 6/7 group (p < 0.05). After 30 months, the decline in CrCl observed was similar in LPD 7/7 and LPD 6/7 groups (2.77 ± 0.3 and 2.84 ± 0.3 ml/min/year, respectively). In elderly Type 2 diabetic patients, long term effects of LPD 6/7 regimen in comparison to LPD 7/7 are associated with a similar decline in CrCl, but with decreased depressive symptoms and a better quality of life.


Anti-MuSK Antibody-positive Myasthenia Gravis Mimicking Amyotrophic Lateral Sclerosis.
We herein investigated the clinical features of three patients with anti-muscle-specific tyrosine kinase (MuSK) antibody-positive myasthenia gravis (MG), which was initially difficult to distinguish from amyotrophic lateral sclerosis (ALS). The patients exhibited dropped head syndrome or dysphagia as initial symptoms. Although their clinical findings were compatible with the revised El Escorial Criteria for ALS, their progression appeared to be more rapid than that of ALS. Both the edrophonium and repetitive nerve stimulation tests yielded negative results, and diurnal fluctuation was not confirmed. The patients were ultimately diagnosed with anti-MuSK antibody-positive MG. We therefore recommend the measurement of anti-MuSK antibodies when encountering such cases.


Chromatin remodeling of the Kaposi's sarcoma-associated herpesvirus ORF50 promoter correlates with reactivation from latency.
The switch from latent to lytic infection of Kaposi's sarcoma-associated herpesvirus is initiated by the immediate early transcriptional activator protein Rta/open reading frame 50 (ORF50). We examined the transcriptional regulation of the ORF50 core promoter in response to lytic cycle stimulation. We show that the ORF50 promoter is highly responsive to sodium butyrate (NaB) and trichostatin A (TSA), two chemicals known to inhibit histone deacetylases. The NaB and TSA responsive element was mapped to a 70-bp minimal promoter containing an essential GC box that binds Sp1/Sp3 in vitro and in vivo. Micrococcal nuclease mapping studies revealed that a nucleosome is positioned over the transcriptional initiation and the Sp1/3 binding sites. Stimulation with NaB or TSA increased histone acetylation and restriction enzyme accessibility of the ORF50 promoter transcription initiation site. Chromatin immunoprecipitation assay was used to demonstrate that the ORF50 promoter is associated with several different histone deacetylase proteins (including HDAC1, 5, and 7) in latently infected cells. NaB treatment led to the rapid association of Ini1/Snf5, a component of the Swi/Snf family of chromatin remodeling proteins, with the ORF50 promoter. Ectopic expression of the CREB-binding protein (CBP) histone acetyltransferase (HAT) stimulated plasmid-based ORF50 transcription in a HAT-dependent manner, suggesting that CBP recruitment to the ORF50 promoter can be an initiating event for transcription and viral reactivation. Together, these results suggest that remodeling of a stably positioned nucleosome at the transcriptional initiation site of ORF50 is a regulatory step in the transition from latent to lytic infection.


From therapeutic drug monitoring to total drug monitoring and drug-omics.
In view of the role of pharmacotherapy in medicine, on the one hand, and the powerful technical possibilities that are now available on the other hand, therapeutic drug monitoring is a surprisingly neglected area of laboratory medicine. In this viewpoint article, an "omics approach" to pharmacovigilance and drug monitoring is proposed and discussed. A realistic goal for laboratory medicine in the 21st century should indeed be to enable clinicians to check whether the right drug is present in the right patient with an appropriate blood concentration for each compound.


Application of chromogenic media for preliminary identification of acid-resistant bacteria.
The variety of morphological and cultural characteristics of acid-resistant bacteria (ARB) makes it possible to use microscopy and estimate the growth rate and pigment formation when cultivating on solid egg media for preliminary identification only as additional indicative methods. It is necessary to develop new approaches for the cultivation and primary identification of ARB isolated from the biological material. It will allow to obtain data on the prevalence, structure, epidemiological, and clinical features of infectious processes caused by opportunistic ARB. Three hundred and sixty strains of ARB were isolated from the various biological materials obtained from the patients during the examination for tuberculosis. All biological material samples were negative on Mycobacteria tuberculosis complex. Species identification of all bacteria was performed by matrix-assisted lazer desorption/ion-ization time-of-flight mass spectrometry. The cultural characteristics of ARB were evaluated on a universal chromogenic media. As a selective additive, a mixture of bacitracin and polymyxin sulfate which had no effect on ARB was tested to suppress concomitant Gram-positive and Gram-negative microflora. Cultural characteristics were identified and described for all tested representatives of fast-growing nontuberculous mycobacteria (NTM), as well as for all types of nocardia, gordonia, and streptomycetes. Representatives of other genera of ARB on a universal chromogenic media gave meager growth or did not show it at all. When inoculated on a universal chromogenic media with a selective addition, 100% of the strains from the ARB group showed abundant or moderate growth. Incubation time for fast-growing species was up to 7 days; for slow-growing species, it was up to 28 days. Concomitant control strains of Gram-positive and Gram-negative bacteria on universal chromogenic media with selective growth additive did not show the growth. The use of a universal chromogenic media allows to preliminarily identify NTM and other ARB by cultural characteristics. The addition of bacitracin and polymyxin sulfate does not reduce the growth properties of ARB, which can be used when working with both biological materials and for the isolation of pure ARB cultures from mixtures with other bacteria.


Conformational Analysis of Abscisic Acid Analogs Produced by Cercospora cruenta.
The conformation of hydroxy-γ-ionylideneacetic acids produced by Cercospora cruenta was examined by 'H-NMR analysis. (1)H-(1)H COSY and NOE data indicated that (2Z,4E,1'R,4'#)-4'-hydroxy-(γ)- ionylideneacetic acid has a cyclohexane ring of chair form furnishing a hydroxyl group and a 2,4-pentadienoic acid moiety, each with equatorial orientation, while (2Z,4E,1'S,3'S)-3'-hydroxy-γ-ionylideneacetic acid has a flexible twisted-boat form of cyclohexane ring. It is suggested that the structure of another (2Z,4E,1'S,4'R)-isomer of 4'-hydroxy-γ-ionylideneacetic acid with an equatorial hydrogen at the l'-position is the key for further oxygenation to abscisic acid.


Linking cognitive and visual perceptual decline in healthy aging: The information degradation hypothesis.
Several hypotheses attempt to explain the relation between cognitive and perceptual decline in aging (e.g., common-cause, sensory deprivation, cognitive load on perception, information degradation). Unfortunately, the majority of past studies examining this association have used correlational analyses, not allowing for these hypotheses to be tested sufficiently. This correlational issue is especially relevant for the information degradation hypothesis, which states that degraded perceptual signal inputs, resulting from either age-related neurobiological processes (e.g., retinal degeneration) or experimental manipulations (e.g., reduced visual contrast), lead to errors in perceptual processing, which in turn may affect non-perceptual, higher-order cognitive processes. Even though the majority of studies examining the relation between age-related cognitive and perceptual decline have been correlational, we reviewed several studies demonstrating that visual manipulations affect both younger and older adults' cognitive performance, supporting the information degradation hypothesis and contradicting implications of other hypotheses (e.g., common-cause, sensory deprivation, cognitive load on perception). The reviewed evidence indicates the necessity to further examine the information degradation hypothesis in order to identify mechanisms underlying age-related cognitive decline.


[Nutritional epigenetics and epigenetic effects of human breast milk].
The article provides an overview of the current literature on nutritional epigenetics. There are currently actively studied hypothesis that nutrition especially in early life or in critical periods of the development, may have a role in modulating gene expression, and, therefore, have later effects on health in adults. Nutritional epigenetics concerns knowledge about the possible effects of nutrients on gene expression. Human breast milk is well-known for its ability in preventing necrotizing enterocolitis, infectious diseases, and also non-communicable diseases, such as obesity and related disorders. This paper discusses about presumed epigenetic effects of human breast milk and some its components. While evidence suggests that a direct relationship may exist of some components of human breast milk with epigenetic changes, the mechanisms involved are stillunclear.


Masquerade without a mass: an unusual cause of severe acute pancreatitis.
After excluding the typical causes, the underlying etiology of severe acute pancreatitis is often elusive; tumors are on the differential but may be difficult to prove in the absence of a discrete mass on imaging. In this report, we describe the case of an elderly woman with diffuse large B-cell lymphoma masquerading as acute pancreatitis. To our knowledge, only twelve other cases of pancreatic B-cell lymphoma presenting as acute pancreatitis have been described. However, while other cases involved well-circumscribed tumors of the pancreas, this is the first known case of pancreatic lymphoma of a diffusely infiltrating pattern presenting as acute pancreatitis.


[Betaxolol for prevention of steroid induced intraocular pressure elevations in patients after radial keratotomy].
To investigate the effect of 0.25% betaxolol (Betoptic S) in the normal myopia eye, on steroid-induced intraocular pressure (IOP) elevations in patients undergoing radial keratotomy. Radial keratotomy was performed on 27 patients (43 eyes). All these patients during the period of 3 months after surgery were treated with 0.1% dexamethasone drops in decreasing doses and 0.25% betaxolol (Betoptic S) drops twice a day. Ophthalmic examination and IOP measurements were made on 1, 2, 3, 14, 30, 60 day after operation. During 3 months of postoperative period 27.9% of eyes had IOP exceeding 25 mm Hg, or had an increase of IOP of 10 mm Hg or more. The results of the current study and the study published by the author previously lead to conclusion, that 0.25% betaxolol (Betoptic S) in the normal myopia eye, decreases the risk of steroid-induced IOP elevation in patients after radial keratotomy, but does not prevent it.


DNA strand breaks induced in cultured human and rodent cells by chlorohydroxyfuranones--mutagens isolated from drinking water.
Chlorohydroxyfuranones, by-products of chlorine disinfection and drinking water contaminants, are shown to produce DNA strand breaks in human and rodent cells. One chlorohydroxyfuranone, 3-chloro-4-dichloromethyl-5-hydroxy-2[5H]-furanone (MX), a potent bacterial mutagen, induces 232 +/- 89 DNA strand breaks.(cell-microM)-1 in human CCRF-CEM cells over a concentration range of 4.4 to 220 microM. This constitutes a DNA damage potency comparable to dimethylsulfate (DMS). By comparison, 3,4-dichloro-5-hydroxy-2[5H]-furanone (MA), another chlorohydroxyfuranone which is approximately four orders of magnitude less mutagenic than MX in Salmonella typhimurium strain TA100, is only about tenfold less potent as an inducer of DNA strand breaks in these cells, i.e., 18.2 +/- 3.1 strand breaks.(cell-microM)-1. The DNA strand-breaking potential of MX is inactivated by prior incubation with a rat liver S9 homogenate. In addition, both chlorohydroxyfuranones are ineffective at producing DNA strand breaks in primary rate hepatocytes (PRH) at concentrations below those which produce cytotoxicity as assessed by release of the cellular enzyme lactate dehydrogenase (LDH). Prior treatment of the PRH with 750 microM diethyl maleate, a glutathione-depleting agent, did not enhance the cytotoxicity nor the DNA strand-breaking potential of either chlorohydroxyfuranone. This could indicate that glutathione-glutathione-S-transferase is not an important mechanism for the detoxification of these compounds in PRH.


Modeling mode choice behavior incorporating household and individual sociodemographics and travel attributes based on rough sets theory.
Most traditional mode choice models are based on the principle of random utility maximization derived from econometric theory. Alternatively, mode choice modeling can be regarded as a pattern recognition problem reflected from the explanatory variables of determining the choices between alternatives. The paper applies the knowledge discovery technique of rough sets theory to model travel mode choices incorporating household and individual sociodemographics and travel information, and to identify the significance of each attribute. The study uses the detailed travel diary survey data of Changxing county which contains information on both household and individual travel behaviors for model estimation and evaluation. The knowledge is presented in the form of easily understood IF-THEN statements or rules which reveal how each attribute influences mode choice behavior. These rules are then used to predict travel mode choices from information held about previously unseen individuals and the classification performance is assessed. The rough sets model shows high robustness and good predictive ability. The most significant condition attributes identified to determine travel mode choices are gender, distance, household annual income, and occupation. Comparative evaluation with the MNL model also proves that the rough sets model gives superior prediction accuracy and coverage on travel mode choice modeling.


Synthesis and reactivity of titanium 'POCOP' pincer complexes.
The 'POCOP' pincer ligand, [2,6-(OPR2)2C6H3], has been attached to titanium in both Ti(III) and Ti(IV) complexes for the first time. Using a lithium-halogen exchange route [2,6-(OPR2)2C6H3]Li ([RPOCOP]Li) can be synthesised. Both the iso-propyl and tert-butyl derivatives can be made, but only the latter isolated. These can be reacted with the Ti(III) and Ti(IV) synthons to make a range of [POCOP]TiClx species. In the presence of Ti(IV), THF and [RPOCOP]Li, an unprecedented ligand rearrangement occurs. (tBuPOCOP)TiCl2, 1, can be derivatised with alkylating agents to make bis-methyl, phenyl and neopentyl complexes. The last of these can activate H2 to make a rare example of a titanium chlorohydride, with the metal pincer fragment staying attached. EPR has been used to characterise the paramagnetic complexes and locate their electron spins, which is further validated with DFT calculations. This opens the door for this archetypical pincer ligand to be used with early transition metals.


Occurrence of hydroxylated jasmonic acids in leaflets of Solanum demissum plants grown under long- and short-day conditions.
Under short-day (SD) conditions both 11-OH-jasmonic acid (11-OH-JA) and a smaller quantity of 12-OH-JA occurred in leaflets of Solanum demissum Lindl. Plants which had formed tubers. This is the first time that 11-OH-JA has been detected as a native substance in higher plants. Under long-day (LD) conditions no tubers were formed and none of these compounds were detectable. A positive correlation was found between the occurrence of 11-OH-JA and 12-OH-JA in leaflets of S. demissum and tuber formation, but a causal relation has yet to be proved. The (-)-JA content in leaflets was not significantly different under short and long days. Mild stress applied to detached SD and LD leaflets caused a rapid accumulation of JA in these leaflets. Upon this treatment an increase in the levels of hydroxylated JAs was detected in SD leaflets only. JA was a potent promotor of tuber formation in vitro in S. demissum explants. Lipoxygenase (LOX: EC 126.96.36.199) is involved in the biosynthesis of JA. Under SD conditions, application of salicylhydroxamic acid (SHAM), an inhibitor of LOX activity, to the roots did not prevent tuber formation in vivo. It is suggested that daylength controls the hydroxylation of JA. The enzyme(s), responsible for the hydroxylation of JA, would only be effective under SD conditions.


Enhanced topical penetration, system exposure and anti-psoriasis activity of two particle-sized, curcumin-loaded PLGA nanoparticles in hydrogel.
Psoriasis is an immune-mediated skin disorder, which is triggered by the aberrant activation of dendritic cells in skin. This activation is followed by the complex interaction between the immune cells in the skin and keratinocyte in the epidermis. To improve the conditions of poor aqueous solubility and chemical stability, overcome skin barriers, and enhance in vivo anti-psoriatic activity, curcumin (Cur) loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were fabricated and administered by topical route to treat imiquimod (IMQ)-induced psoriasis-like mouse model. Spherical Cur-NPs with the mean particle sizes of 50nm and 150nm, respectively, were fabricated using a multi-inlet vortex mixer system, with both exhibiting significantly stronger anti-proliferation effect than Cur solution on HaCaT cells in vitro. Psoriatic skin was utilized in the in vitro skin penetration studies, and the results demonstrated that more drugs penetrated through or accumulated in the skin when administered as the Cur-NPs-loaded hydrogel compared to the drug suspension loaded hydrogel. To compare the nanosizing effect of these Cur-NPs, the mice with IMQ-induced psoriasis-like skin disease were treated with blank gel, Cur gel, 50nm sized NPs gel, 150nm sized NPs gel or tracrolimus cream (positive control), respectively. The results indicated that Cur-NPs hydrogel has a superior performance to Cur hydrogel on the IMQ-induced psoriasis-like mouse model in terms of morphological evaluation, biomarkers at mRNA, and protein levels. In conclusion, encapsulation of Cur into PLGA NPs, particularly for NPs of 50nm, could facilitate lipophilic Cur's dispersion, sustained-release, accumulation, and penetration across the skin and into the blood circulation, which significantly improves anti-psoriasis activity in mice.


Effects of beta-amyloid peptides on the fluidity of membranes from frontal and parietal lobes of human brain. High potencies of A beta 1-42 and A beta 1-43.
beta-amyloid peptide (A beta) and several A beta-fragments decrease the fluidity of human cortex membranes in a concentration dependent fashion. The effect of A beta on membrane fluidity increases with peptide length, is most pronounced for A beta 1-43 and can be seen at concentrations as low as 100 nmol/l. While the fragment A beta 25-35 is active, scrambled peptide (A beta 35-25) when investigated under similar conditions shows no effects on membrane fluidity. The effect of A beta peptides on fluidity of the phospholipid bilayer is more pronounced in the hydrocarbon core (labeled with the fluorescence probe 1,6-diphenylhexa-1,3,5-triene) than in the region of the hydrophilic heads (labeled with the fluorescence probe 1-[4'-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene). It is suggested that the effect of A beta on neuronal membranes is probably a major initial mechanism in a cascade of events finally leading to neurotoxicity and cell death in Alzheimer's disease.


A pan-cancer analysis of the frequency of DNA alterations across cell cycle activity levels.
Pan-cancer genomic analyses based on the magnitude of pathway activity are currently lacking. Focusing on the cell cycle, we examined the DNA mutations and chromosome arm-level aneuploidy within tumours with low, intermediate and high cell-cycle activity in 9515 pan-cancer patients with 32 different tumour types. Boxplots showed that cell-cycle activity varied broadly across and within all cancers. TP53 and PIK3CA mutations were common in all cell cycle score (CCS) tertiles but with increasing frequency as cell-cycle activity levels increased (P < 0.001). Mutations in BRAF and gains in 16p were less frequent in CCS High tumours (P < 0.001). In Kaplan-Meier analysis, patients whose tumours were CCS Low had a longer Progression Free Interval (PFI) relative to Intermediate or High (P < 0.001) and this significance remained in multivariable analysis (CCS Intermediate: HR = 1.37; 95% CI 1.17-1.60, CCS High: 1.54; 1.29-1.84, CCS Low = Ref). These results demonstrate that whilst similar DNA alterations can be found at all cell-cycle activity levels, some notable exceptions exist. Moreover, independent prognostic information can be derived on a pan-cancer level from a simple measure of cell-cycle activity.


Decreased expression of orexin 1 receptor in adult mice testes during alloxan-induced diabetes mellitus perturbs testicular steroidogenesis and glucose homeostasis.
Diabetes mellitus (DM) affects male reproductive system and causes infertility. The male reproductive health is largely dependent upon uptake and proper utilization of glucose by testicular cells. Results show involvement of orexin A (OXA) and its receptor (OX1R) in regulation of steroidogenesis and glucose homeostasis in adult mice testis. However, the role of OX1R in regulation of testicular functions during hyperglycemia has not been investigated so far. The present study, therefore, examined the role of OX1R in regulation of steroidogenesis and glucose homeostasis in testis of adult mice during alloxan-induced type 1 DM. A significant decrease was noted in body weight and testis weight in alloxan-treated mice compared to controls. The blood glucose level, however, was markedly increased in treated animals than in controls. Further, serum and intratesticular level of testosterone, activities of testicular steroidogenic enzymes, and expressions of various steroidogenic markers, OX1R, glucose transporter 3 (GLUT3) and Wilms' tumor gene (WT1) were downregulated in treated mice. The level of glucose, activity of lactate dehydrogenase (LDH) and lactate concentration in the testes of diabetic mice were also decreased; a significant increase in the number of testicular apoptotic cells with concomitant increase in the expression of caspase-3 was noted in these mice. Furthermore, DM affected germ cell proliferation with decreased expression of proliferating cell nuclear antigen (PCNA). Results thus suggest that type 1 DM impairs testicular steroidogenesis and glucose homeostasis through inhibition of OXA/OX1R signaling cascade due to decreased OX1R expression in adult mice, thereby affecting germ cell survival and their proliferation in the testis.


[Rapid method of obtaining ultrathin sections in monolayer embedding].
It is proposed to employ a simple optical method for a correct relative adjustment of the knife and the roof of the piramid for obtaining ultrathin sections of monolayer embedding. For the material embedding, plastic cuvets and a lavsan film are employed, this technique facilitating the process of embedding.


[Psychometric properties of Q-DIO, an instrument to measure the quality of documented nursing diagnoses, interventions and outcomes].
The instrument Q-DIO was developed in the years 2005 till 2006 to measure the quality of documented nursing diagnoses, interventions, and nursing sensitive patient outcomes. Testing psychometric properties of the Q-DIO (Quality of nursing Diagnoses, Interventions and Outcomes.) was the study aim. Instrument testing included internal consistency, test-retest reliability, interrater reliability, item analyses, and an assessment of the objectivity. To render variation in scores, a random strata sample of 60 nursing documentations was drawn. The strata represented 30 nursing documentations with and 30 without application of theory based, standardised nursing language. Internal consistency of the subscale nursing diagnoses as process showed Cronbach's Alpha 0.83 [0.78, 0.88]; nursing diagnoses as product 0.98 [0.94, 0.99]; nursing interventions 0.90 [0.85, 0.94]; and nursing-sensitive patient outcomes 0.99 [0.95, 0.99]. With Cohen's Kappa of 0.95, the intrarater reliability was good. The interrater reliability showed a Kappa of 0.94 [0.90, 0.96]. Item analyses confirmed the fulfilment of criteria for degree of difficulty and discriminative validity of the items. In this study, Q-DIO has shown to be a reliable instrument. It allows measuring the documented quality of nursing diagnoses, interventions and outcomes with and without implementation of theory based, standardised nursing languages. Studies for further testing of Q-DIO in other settings are recommended. The results implicitly support the use of nursing classifications such as NANDA, NIC and NOC.


Oteseconazole: a long-awaited diversification of the antifungal arsenal to manage recurrent vulvovaginal candidiasis (RVVC).
Recurrent vulvovaginal candidiasis (RVVC) affects women worldwide and has far-reaching implications for a patient's quality of life. For decades, maintenance treatment using the azole antifungal fluconazole was the preferred treatment. Although efficient in controlling the symptoms, the development of azole resistance and high rates of recurrence after therapy cessation have emerged as significant limitations. Nevertheless, persistent efforts have delivered novel treatment options. Oteseconazole (VT-1161), marketed as VIVJOA, is an oral, tetrazole antifungal with unprecedented specificity toward the fungal lanosterol 14α-demethylase. We reviewed literature data on oteseconazole with a focus on the management of RVVC. Therapeutic options for RVVC are limited, and novel, innovative approaches are needed to treat this debilitating condition. These therapies need to be well-tolerated and prevent RVVC recurrence. The available clinical data show excellent safety and efficacy, with an unprecedentedly low recurrence rate. However, we believe health-care providers should be mindful to monitor for the development of resistance, as this may result in treatment failure. Further, the availability and cost may, like for most novel drugs, affect the widespread clinical implementation of VIVJOA. Altogether, we are convinced that VIVJOA is a significant advance in RVVC management.


Birthweight and Lipids in Adult Life: Population-Based Cross Sectional Study.
The purpose of this study was to examine the association of birthweight with lipid profile in the general adult population. Participants in the second-wave of a nationally representative cross sectional AusDiab-study were asked to complete a birthweight questionnaire. Fasting total cholesterol (TC), LDL-C, HDL-C, and triacylglycerol levels were modeled against birthweight. Four thousand five hundred and two people reported their birthweights, mean (SD) of 3.4(0.7) kg. Females with low birthweight-LBW had higher levels of TC, LDL-C, and triacylglycerols, but no difference in HDL-C, than those with normal-birthweight-NBW;≥2.5 kg. People with LBW showed a trend toward increased risk for high TC (≥5.5 mmol/L) compared to NBW. Among females with LBW, the risk for high LDL-C (≥3.5 mmol/L) was increased compared to those of NBW. The risk for low HDL-C (<0.9 mmol/L) was increased among males with LBW compared to those with NBW. Examination of the relationship on the continuum showed no differences except for high triacylglycerol levels among females with the lowest birthweight quintile compared to the higher birthweight quintile. However, the risk for various abnormalities by birthweight quintiles was similar to that when we used the traditional definition of LBW vs. NBW. Females and males with low birthweight differ in their risk for lipids abnormalities. Females had higher risk for high LDL-C, whereas males had high risk for low HDL-C (<0.9 mmol/L). In addition, females with low birthweight had the highest triacylglycerol levels. High LDL-C, low HDL-C, and high triacylglycerols are well-recognized risk factors for cardiovascular disease.


The Use of Therapeutic Drug Monitoring in Complex Antituberculous and Antiretroviral Drug Dosing in HIV/Tuberculosis-Coinfected Patients.
We report 2 cases coinfected with HIV and tuberculosis (HIV/TB), requiring drug dose adjustments guided by therapeutic drug monitoring (TDM) and/or serum drug concentrations. Over the course of the 9-months of TB treatment, drugs that required increased doses due to low concentrations included efavirenz (800 mg), rifampin (900 mg), and isoniazid (450 mg). Higher drug doses were well tolerated until the end of treatment. Over the 12-month course of TB therapy, drugs that required increased doses due to incomplete and/or delayed absorption were rifampin (1500 mg), moxifloxacin (800 mg), and ethambutol (1600 mg). Higher drug doses were well tolerated until the end of treatment. Due to delayed/incomplete drug absorption and weight gain during therapy, higher antituberculous doses may be required in patients coinfected with HIV/TB. A daily dose of efavirenz 800 mg was well tolerated in both patients (weight over 70 kg). Managing patients coinfected with HIV/TB is complex, and, therefore, TDM of drug concentrations can help guide clinical decision making.


Age differences in strain and emotional reactivity to stressors in professional careers.
While age differences of workers gain increasing importance because of demographic changes in most industrialized countries, age differences in stress experience and resistance have been rarely addressed. In this initial empirical study, we explore the general relationship of age and strain as a function of three processes: (1) older workers might experience less strain because of better coping strategies; (2) older workers might experience more strain because of higher vulnerability; or (3) age and strain might be curvilinearly related with highest strain reported by middle-age workers. Using both general and experience-based measures, strain and emotional reactivity to stressful job events were reported by 274 workers aged between 18 and 65 years. Results showed an inverted U-shaped relationship between age and strain experience.


Effects of feeding blends of grains naturally contaminated with Fusarium mycotoxins on performance and metabolism of laying hens.
An experiment was conducted to evaluate the effects of feeding laying hens grains naturally contaminated with a combination of Fusarium mycotoxins. Parameters measured included performance, organ weights, and plasma chemistry. One hundred and forty-four, 45-wk-old laying hens were fed diets including: (1) control, (2) contaminated grains, and (3) contaminated grains + 0.2% polymeric glucomannan mycotoxin adsorbent (GMA) for a 12-wk period. The feeding of contaminated grains decreased feed consumption compared with controls in the first 4 wk. Feed consumption increased, however, from 4 to 8 wk and from 8 to 12 wk. The efficiency of feed utilization (feed consumption/egg mass) decreased compared with controls in the periods from 4 to 8 and from 8 to 12 wk when birds were fed contaminated grains. Supplementation with GMA decreased feed consumption and increased the efficiency of feed utilization in the period from 8 to 12 wk. Egg production and egg mass decreased in wk 4 and 8 compared with controls when contaminated grains were fed, whereas egg and eggshell weights decreased in the fourth wk. Plasma uric acid concentrations increased throughout the experiment and relative kidney weights increased at the end of the experiment compared with controls when birds were fed contaminated grains. The feeding of GMA prevented the elevation in uric acid concentrations and relative kidney weights. It was concluded that layer performance and metabolism were adversely affected by chronic feeding of a combination of Fusarium mycotoxins, and that GMA prevented many of these effects.


Risk of recurrent stroke in patients with atrial fibrillation treated with oral anticoagulants alone or in combination with anti-platelet therapy.
Ischaemic stroke patients with atrial fibrillation (AF) are at high risk of stroke recurrence despite oral anticoagulation therapy. Patients with cardiovascular comorbidities may take both antiplatelet and oral anticoagulation therapy (OAC/AP). Our study aims to evaluate the safety and efficacy of OAC/AP therapy as secondary prevention in people with AF and ischaemic stroke. We performed a post-hoc analysis of pooled individual data from multicenter prospective cohort studies and compared outcomes in the OAC/AP cohort and patients on DOAC/VKA anticoagulation alone (OAC cohort). Primary outcome was a composite of ischaemic stroke, systemic embolism, intracranial bleeding, and major extracranial bleeding, while secondary outcomes were ischaemic and haemorrhagic events considered separately. A multivariable logistic regression analysis was performed to identify independent predictors for outcome events. To compare the risk of outcome events between the two cohorts, the relation between the survival function and the set of explanatory variables were calculated by Cox proportional hazard models and the results were reported as adjusted hazard ratios (HR). Finally another analysis was performed to compare the overall risk of outcome events in both OAC/AP and OAC cohorts after propensity score matching (PSM). During a mean follow-up time of 7.5 ± 9.1 months (median follow-up time 3.5 months, interquartile range ±3), 2284 stroke patients were on oral anticoagulants and 215 were on combined therapy. The multivariable model demonstrated that the composite outcome is associated with age (OR: 1.03, 95% CI: 1.01-1.04 for each year increase) and concomitant antiplatelet therapy (OR: 2.2, 95% CI: 1.48-3.27), the ischaemic outcome with congestive heart failure (OR: 1.55, 95% CI: 1.02-2.36) and concomitant antiplatelet therapy (OR: 1.93, 95% CI: 1.19-3.13) and the haemorrhagic outcome with age (OR: 1.03, 95% CI: 1.01-1.06 for each year increase), alcoholism (OR: 2.15, 95% CI: 1.06-4.39) and concomitant antiplatelet therapy (OR: 2.22, 95% CI: 1.23-4.02). Cox regression demonstrated a higher rate of the composite outcome (hazard ratio of 1.93 [95% CI, 1.35-2.76]), ischaemic events (HR: 2.05 [95% CI: 1.45-2.87]) and bleeding outcomes (HR: 1.90 [95% CI, 1.06-3.40]) in OAC/AP cohort. After PSM analysis, the composite outcome remained more frequent in people treated with OAC + AP (RR: 1.70 [95% CI, 1.05-2.74]). Secondary prevention with combination of oral anticoagulant and antiplatelet therapy after ischaemic stroke was associated with worse outcomes in our cohort. Further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischaemic stroke in patients with atrial fibrillation.


Experimental respiratory Marburg virus haemorrhagic fever infection in the common marmoset (Callithrix jacchus).
Marburg virus causes a highly infectious and lethal haemorrhagic fever in primates and may be exploited as a potential biothreat pathogen. To combat the infection and threat of Marburg haemorrhagic fever, there is a need to develop and license appropriate medical countermeasures. To determine whether the common marmoset (Callithrix jacchus) would be an appropriate model to assess therapies against Marburg haemorrhagic fever, initial susceptibility, lethality and pathogenesis studies were performed. Low doses of virus, between 4 and 28 TCID50 , were sufficient to cause a lethal, reproducible infection. Animals became febrile between days 5 and 6, maintaining a high fever before succumbing to disease between 8 and 11 days postchallenge. Typical signs of Marburg virus infection were observed including haemorrhaging and a transient rash. In pathogenesis studies, virus was isolated from the animals' lungs from day 3 postchallenge and from the liver, spleen and blood from day 5 postchallenge. Early signs of histopathology were apparent in the kidney and liver from day 3. The most striking features were observed in animals exhibiting severe clinical signs, which included high viral titres in all organs, with the highest levels in the blood, increased levels in liver function enzymes and blood clotting times, decreased levels in platelets, multifocal moderate-to-severe hepatitis and perivascular oedema.


Survey of statistical methods used in the veterinary medical literature.
Articles published in 1992 in 6 veterinary journals were reviewed. In 51% of the articles, statistical analyses were not performed or only descriptive statistics (eg, mean, median, standard deviation) were used. The most commonly used statistical tests were ANOVA and t-tests. Knowledge of 5 categories of statistical methods (ANOVA, t-tests, contingency tables, nonparametric tests, and simple linear regression) permitted access to 90% of the veterinary literature surveyed. These data may be useful when modifying the veterinary curriculum to reflect current statistical usage.


Impact of Body Composition and Physical Function on Quality of Life After Gastrectomy for Gastric Cancer.
Patients with gastric cancer after gastrectomy often suffer from a decline in their quality of life (QoL), but the relationship between body composition (BC) and physical function on QoL has rarely been studied. This study aims to evaluate and determine the changes in QoL after gastrectomy and the impact of BC and physical function on QoL. A total of 311 gastric cancer patients completed EORTC QLQ-C30 and EORTC QLQ-STO22 questionnaires before and 1, 3, 6 months post-surgery. Data including BC, handgrip strength (HGS) and 6-m gait speed (GS) were collected prospectively. Multiple linear regression analysis was used to determine the correlation between QoL and BC, HGS and GS. Patients had significantly worse scores after surgery on most function and symptom scales (p < 0.001), but most of these scales recovered within 6 months after surgery. A higher subcutaneous fat area (SFA)was associated with increased symptom scores 1 month after surgery. A higher GS is associated with a better global health status symptom. Patients suffer from a decline in their QoL after gastrectomy for gastric cancer. Intervention strategies aiming at reducing SFA and improving GS may improve the QoL in patients underwent gastrectomy for gastric cancer.


Misinterpretation of drinking water quality monitoring data with implications for risk management.
A survey of two groups of environmental professionals was conducted to explore the degree of understanding in the interpretation of monitoring results for informing decision-making and responding to data appropriately to manage environmental health risks. Specifically, the understanding of the predictive value of a monitoring result and the appreciation that false positive results will inevitably predominate when monitoring for rare or infrequent hazards was explored. Results indicate evidence of misinterpretation and overconfidence in the meaning of monitoring results, and the ability of laboratory methods to detect reliably an infrequent hazard in environmental samples. A hypothetical monitoring scenario was presented with characteristics sufficient to estimate what level of confidence was warranted in a positive result. The majority of respondents in both groups (most of whom had more than 10 years experience in their field) reported between very likely to almost certain confidence (80-100% likelihood) in a hypothetical monitoring result which was, in fact, less than 5% likely to be correct. Additionally, there was little influence of the beliefs expressed about the validity of the monitoring result on the actions proposed to be taken in response to finding that monitoring result. The independence of respondents' follow-up action to what they believe of a monitoring result implies a level of detachment between the understanding of the monitoring data and the resulting risk management response.


Altered cellular distribution and sub-cellular sorting of doppel (Dpl) protein in human astrocytoma cell lines.
Doppel, a prion-like protein, is a GPI-membrane anchored protein generally not expressed in the Central Nervous System (CNS) of different mammalian species, including human. Nevertheless, in astrocytomas, a particular kind of glial tumors, the doppel encoding gene (PRND) is over-expressed and the corresponding protein product (Dpl) is ectopically localized in the cytoplasm of the tumor cells. In this study we have analysed the sub-cellular localization of Dpl using double-immunofluorescence staining and confocal microscopy examinations in two astrocytoma-derived human cell lines (IPDDC-A2 and D384-MG). Our results confirmed that Dpl is localized in the cytoplasm of the astrocytoma cells and indicated that it is mostly associated with Lamp-1 and Limp-2 positive lysosomal vesicles and, marginally, to the Golgi apparatus and other cellular organelles. Noticeably, none of the examined tumor cells showed a membrane-Dpl localization. The membrane-associated Dpl expression was restored after the transfection of the astrocytoma cells with mutated Dpl-expression vectors in its glycosylation sites. Additionally, Dpl showed altered expression and traffic using the acidotropic agent ammonium chloride, leading to the accumulation of Dpl in nascent exocytic vesicles. Altogether, these results indicated that in the astrocytic tumor cells Dpl has an altered biosynthetic trafficking, likely derived from abnormal post-translational processes: these modifications do not permit the localization of Dpl in correspondence of the plasma membrane and lead to its intracellular accumulation in the lysosomes. In these proteolytic compartments, the astrocytic tumor cells might provide to the degradation of the excess of a potentially cytotoxic Dpl product.


Synthesis, characterization and anti-inflammatory activity of new 5-(3,4-dichlorophenyl)-2-(aroylmethyl) thio-1,3,4-oxadiaxoles.
Several 5-(3,4-dichlorophenyl)-2-(aroylmethyl)thio-1,3,4-oxadiazoles were synthesized and characterized by elemental analyses, IR and nuclear magnetic resonance spectra. All compounds were evaluated for anti-inflammatory activity by determining their ability to provide protection against carregeenan-induced edema in rat paw. In addition, ulcerogenic activity was determined. The anti-inflammatory data scoring showed that compounds 5e, 5f and 5g, at the dose of 100 mg/kg, exhibited anti-inflammatory activity, which for compound 5f was comparable to that of the reference drug indometacin (CAS 53-86-1).


Leukoencephalopathy induced by levamisole alone for the treatment of recurrent aphthous ulcers.
We report imaging and clinical findings of leukoencephalopathy occurring after levamisole. The lesions were hypoattenuating on CT and appeared as multifocal oval or elliptical foci in the white matter or along the subependymal veins on MRI. Most lesions resolve after prompt withdrawal of levamisole. Detailed history taking is important for diagnosing levamisole-induced leukoencephalopathy because multiple sclerosis and acute disseminated encephalomyelitis cannot be differentiated by neuroimaging findings alone.


[Satisfaction with the quality of life in the Russian regions in the context of realizing the resource potential of elderly people.]
A system of indicators is proposed to assess the relationship between quality of life from the point of view of realization of resource potential of elderly people in conditions of demographic aging of the population and to analyze various aspects of socio-economic development of the Russian regions. The statistical evaluation of these indicators and the level of inequality in the context of research topic in context of the regions of Russia is carried out.


CTRP6 Regulates Porcine Adipocyte Proliferation and Differentiation by the AdipoR1/MAPK Signaling Pathway.
Intramuscular fat (IMF) and subcutaneous fat (SCF), which are modulated by adipogenesis of intramuscular and subcutaneous adipocytes, play key roles in pork quality. C1q/tumor necrosis factor-related protein 6 (CTRP6), an adipokine, plays an important role in the differentiation of 3T3-L1 cells. However, the effect and regulatory mechanisms of CTRP6 on porcine adipogenesis, and whether CTRP6 has the same effect on intramuscular and subcutaneous adipocytes, are still unknown. Here, we found that CTRP6 significantly inhibited both adipocyte proliferation assessed by proliferative marker expression, but CTRP6 decreased the proliferation rate of intramuscular adipocytes (IM) to a greater extent than subcutaneous adipocytes (SC). Moreover, CTRP6 promoted the activity of the p38 signaling pathway during the proliferation of both cell types. Nevertheless, in subcutaneous adipocytes, CTRP6 also influenced the phosphorylation of extracellular regulated protein kinases1/2 (p-Erk1/2), but not in intramuscular adipocytes. Additionally, during the differentiation of intramuscular and subcutaneous adipocytes, CTRP6 increased adipogenic genes expression and the level of p-p38, while it decreased the activity of p-Erk1/2. Interestingly, the effect of CTRP6 shRNA or CTRP6 recombinant protein was attenuated by U0126 (a special p-Erk inhibitor) or SB203580 (a special p-p38 inhibitor) in adipocytes. By target gene prediction and experimental validation, we demonstrated that CTRP6 may be a target of miR-29a in porcine adipocytes. Moreover, AdipoR1was identified as a receptor of CTRP6 in intramuscular adipocytes, but not in subcutaneous adipocytes. On the basis of the above findings, we suggest that CTRP6 was the target gene of miR-29a, inhibited intramuscular and subcutaneous adipocyte proliferation, but promoted differentiation by the mitogen-activated protein kinase (MAPK) signaling pathway. These findings indicate that CTRP6 played an essentially regulatory role in fat development.


Secondary Immune Thrombocytopenic Purpura in Renal Cell Cancer: A Paraneoplastic Syndrome.
Secondary immune thrombocytopenic purpura (ITP) as a paraneoplastic syndrome has been reported in literature. It is commonly associated with chronic lymphocytic leukemia (CLL) and hodgkins lymphoma. Its association with solid malignancies, especially renal cell cancer is rare, with only a few documented case reports. Treatment usually consisted of targeting the underlying malignancy or utilization of steroid and intravenous immunoglobulin (IVIG) to improve thrombocytopenia. Here, we describe a case of a 75-year-old man with renal cell cancer (RCC), who presented with secondary thrombocytopenia treated with steroid and IVIG. It is important to keep RCC in differential diagnosis for causes for secondary ITP as this impacts treatment.


Lack of localization of 5-HT6 receptors on cholinergic neurons: implication of multiple neurotransmitter systems in 5-HT6 receptor-mediated acetylcholine release.
The involvement of the cholinergic system in learning and memory together with the cognitive enhancing properties of 5-HT6 receptor antagonists led us to study the relationship between 5-HT6 receptors and cholinergic neurotransmission. A selective cholinergic lesion, induced by injection of the immunotoxin 192-IgG-Saporin into the nucleus basalis magnocellularis, failed to alter the density of 5-HT6 receptor mRNA or protein expression in the deafferentated frontal cortex, suggesting that 5-HT6 receptors are not located on cholinergic neurons. The 5-HT6 receptor antagonist SB-357134 (0.001-1 microM) induced a concentration-dependant K+-evoked [3H]acetylcholine (ACh) release in vitro in rat cortical and striatal slices, which was blocked by tetrodotoxin. SB-357134, up to 1 microM, stimulated glutamate release in cortical and striatal slices. In the cortex, riluzole (1 microM) blocked the SB-357134-induced K+-stimulated [3H]ACh release, and simultaneous administration of MK-801 (1 microM) and SB-357134 (0.05 microM) elicited an increase in K+-evoked ACh release. In the striatum, SB-357134, 1 microM, decreased dopamine release, and the increase in K+-evoked [3H]ACh release induced by 5-HT6 receptor blockade was reversed by the D1 receptor antagonist, SCH23390 (1 microM). In both the frontal cortex and striatum, bicuculline, 1 microM, showed no effect on SB-357134-evoked [3H]ACh. These results are discussed in terms of neurochemical mechanisms involved in 5-HT6 receptor functions.


Prevalence of Hypertension and its Risk Factors Among School Going Adolescents of Patna, India.
Hypertension (HT) has its origin in childhood and adolescent period but it goes undetected due to absence of sign and symptoms, unless specifically looked for during this period. It has been seen that one with raised blood pressure level in this period will also have raised Blood Pressure (BP) level in their adulthood and elderly period. The present study was conducted to estimate the prevalence of HT and its risk factor among apparently healthy school going adolescents of Patna district. A cross-sectional study among 2913 school going adolescents of eighth to 10th standard was conducted from April 2014 to August 2015 by adopting a two stage cluster sampling technique. The questions pertaining to risk behavior in relation to cardiovascular diseases from WHO's Global School based Student Health Survey were used for this study. The mean systolic and diastolic blood pressure of study population was 107.4 mm of Hg (95% C.I. 106.93-107.77) and 67.4 mm of Hg (95% C.I. 67.26-67.54), respectively. Prevalence of pre-HT and HT was 10.9% and 4.6% in school going adolescents while prevalence of overweight/obesity was 1.5%. Both systolic and diastolic blood pressures had positive and significant correlation with age, height and body mass index. The proportion of children who had ever taken tobacco was 5.3%, cigarette smoking 4.3%, alcohol consumption 2.1%, and excess salt intake 22.3%. Only 49.1% children were doing physical activity at least one hour a day in past seven days for maintenance of good health. The present study recommends that regular screening of blood pressure level must be initiated in adolescents so that remedial measure can be initiated as early as possible.