Self-rated health and employment status in chronic haemodialysis patients.
Along with survival and other types of clinical outcome, physical, mental and social well-being are important indicators of the effectiveness of the medical care that haemodialysis (HD) patients receive. The present cross-sectional study was designed to assess self-rated health in HD patients from a large Danish HD centre compared to a Danish general population sample with similar sex and age distributions. Furthermore, employment status and associations between self-rated health and clinical, social and demographic factors were investigated. A total of 150 patients were included. They were asked to complete the Short Form 36 (SF-36) questionnaire and additional questions concerning education and employment status. The SF-36 consists of eight scales representing physical, social, mental and general health. Clinical, biochemical and dialysis adequacy data were obtained from hospital records. A total of 112 patients completed the questionnaire, giving a response rate of 75%. Compared to the general population sample, HD patients scored significantly lower on all eight SF-36 scales (p < 0.01), with the greatest difference being observed for items concerning physical functioning. No correlation was found between any of the eight scales and estimates of dialysis adequacy. Of patients aged 18-60 years, 22% were in employment. In a large group of Danish HD patients, self-rated health (and especially physical function) was found to be substantially impaired compared to the general population and only a small proportion of patients were employed. We believe that results obtained using the SF-36 questionnaire represent an independent marker of health status in HD patients and should be considered, together with common clinical outcome measures, when monitoring patients. Furthermore, we believe that self-rated health questionnaires are a useful tool for evaluating the need for and the effects of physical activity programmes in a dialysis unit.


Administer and collect medical questionnaires with Google documents: a simple, safe, and free system.
Questionnaires are an invaluable resource for clinical trials. They serve to estimate disease burden and clinical parameters associated with a particular study. However, current researchers are tackling budget constraints, loss of funding opportunities, and rise of research associated fees. We aimed at exploring alternative avenues taking advantage of the free Google docs software for questionnaire administration. This presents an opportunity to reduce costs while simultaneously increasing efficiency and data fidelity. Google documents were used as a platform to create online questionnaires that were automatically hosted via a unique URL. Password protected access to the URL link and a unique study ID gave patients around the clock access from anywhere in the world. Unique study ID ensured confidentially of all self-reported data. Patient responses were secured using a "Cloud" database where the data was automatically sorted, scaled and scored by custom Excel formulas. Researchers downloaded real-time questionnaire responses in multiple formats (e.g. excel) which was then analyzed with a statistical software of choice. This simple workflow provided instant questionnaire scores that eliminated the use for paper-based responses and subsequent manual entry of data. Ease of access to online questionnaires provided convenience to patients leading to better response rates and increase in data fidelity. The system also allowed for real time monitoring of patient's progress on completing questionnaires. Online questionnaires had 100% completion rate compared to paper-based questionnaires. Google docs can serve as an efficient and free platform to administer questionnaires to a clinical population without sacrificing quality, security, and fidelity of data.


Protective behavioral strategies and future drinking behaviors: Effect of drinking intentions.
Alcohol use is common among United States and Swedish high school students and is related to negative consequences. Whereas drinking intentions are associated with future drinking behaviors, the use of protective behavioral strategies (PBS) is associated with decreased alcohol-related harm among young adults. The interactive effect of PBS and drinking intentions in predicting alcohol outcomes has not been examined. Further, because most PBS studies have been conducted among U.S. college students, PBS research among other populations is needed. The aims of this study were to evaluate longitudinally (a) the relationships between drinking intentions, PBS and alcohol outcomes, and (b) the moderating roles of drinking intentions and country in these relationships among United States and Swedish high school drinkers. Data were collected at baseline, 6- and 12-month follow-ups on 901 Swedish and 288 U.S. high school drinkers. Drinking intentions were associated with more alcohol use and consequences, and use of certain PBS was related to fewer alcohol-related consequences over time. Additionally, the negative prospective relationship between use of PBS and alcohol use, but not alcohol-related consequences, was moderated by intentions, such that the relationship was stronger among participants endorsing high drinking intentions. Country did not moderate these relationships. These results provide initial support for the generalizability of PBS college research to United States and Swedish high school students and suggest that interventions targeting the use of PBS may be most effective among high school drinkers endorsing high drinking intentions. (PsycINFO Database Record


The role of developmental rate, body size, and positional behavior in the evolution of covariation and evolvability in the cranium of strepsirrhines and catarrhines.
Recent studies on hominin craniofacial evolution have focused on phenotypic integration or covariation among traits. Covariation is thought to significantly affect evolutionary trajectories, shaping the ways in which hominins and other primates could have evolved. However, the ways in which covariation itself evolves are not well understood. This study aims to investigate the role of phylogeny, development, body size, and positional behavior in shaping the strength of covariation in strepsirrhine and catarrhine primate crania (n = 1009, representing 11 genera). These factors may have been catalysts for change in the magnitude of covariation, and they have changed significantly during primate evolution and particularly hominin evolution. Modern humans in particular have slow developmental trajectories, large bodies, and a unique form of locomotion in the form of orthograde bipedalism. Variance of eigenvalues, mean integration, mean evolvability, and mean conditional evolvability was estimated and their relationship to the various factors described earlier was assessed using phylogenetic and nonphylogenetic analyses. Results indicate that some phylogenetic signal is present, but it is not equivalent across integration statistics or cranial regions. In particular, these results suggest that closely related species are more similar than more distantly related species in evolvability of the cranial base and integration of the face. Two divergent patterns were also identified, in which covariation and evolvability of the cranial base are linked to developmental rate, but those of the face are linked to body size. Neither locomotion nor posture appears related to covariation or evolvability of the primate cranium. These results suggest that overall low covariation observed in the hominin cranium may be a result of separate trends in different cranial regions.


Immunomodulation by hyperimmunoglobulins after solid organ transplantation: Beyond prevention of viral infection.
Hyperimmunoglobulins are pharmaceutical formulations of human IgG which contain high titers of antibodies against specific viruses. They have been successfully used in solid organ transplantation (SOT) to prevent Cytomegalovirus (CMV) and Hepatitis B Virus (HBV) infection. The introduction of effective and cheaper antiviral drugs has resulted in decreasing usage of hyperimmunoglobulins in SOT. However, it may still be attractive to combine antiviral drug therapy with hyperimmunoglobulins after SOT, as there is some evidence that hyperimmunoglobulins, similar to high doses of intravenous immunoglobulins (IVIgs), might exert anti-inflammatory activity and thereby prevent immunological graft damage and improve graft and patient survival. In this review we discuss the existing clinical evidence for beneficial anti-inflammatory effects of hyperimmunoglobulins after cardiac, lung, kidney, and liver transplantation. Only a limited number of studies have addressed this issue, and these studies often included small patient cohorts and showed considerable variations in the type, intensity and duration of treatment regimens. Due to these limitations, it is difficult to draw firm conclusions. Retrospective studies consistently demonstrated that addition of CMV hyperimmunoglobulin (CMV-Ig) to antiviral drug prophylaxis after lung transplantation is associated with reduced rates of CMV disease and bronchiolitis obliterans syndrome (BOS), and improved patient survival. The doses of CMV-Ig administered after SOT are much lower than the minimal effective dose of IVIg used for anti-inflammatory therapy in auto-immune diseases. Therefore, it is questionable whether the reduced incidence of BOS is the result of 'direct' anti-inflammatory effects of CMV-Ig or is caused by a reduction of CMV infection, which is a risk factor for BOS. No or very limited evidence for better prevention of immunological graft damage by anti-CMV combination therapy is available for heart, kidney and liver transplant patients. In liver transplantation published evidence suggests that the high-doses of Hepatitis B virus hyperimmunoglobulin (HBIg) administered to prevent HBV-infection may reduce the risk of acute rejection, while combination therapy of HBIg and antiviral drugs in HBV-infected patients is consistently associated with better graft and patient survival compared to antiviral monotherapy. Well-designed prospective randomized studies with larger patient cohorts are needed to substantiate the current limited evidence for anti-inflammatory benefits of hyperimmunoglobulins besides prevention of CMV and HBV infection after SOT.


Polyamine delivery as a tool to modulate stem cell differentiation in skeletal tissue engineering.
The first step in skeleton development is the condensation of mesenchymal precursors followed by any of two different types of ossification, depending on the type of bone segment: in intramembranous ossification, the bone is deposed directly in the mesenchymal anlagen, whereas in endochondral ossification, the bone is deposed onto a template of cartilage that is subsequently substituted by bone. Polyamines and polyamine-related enzymes have been implicated in bone development as global regulators of the transcriptional and translational activity of stem cells and pivotal transcription factors. Therefore, it is tempting to investigate their use as a tool to improve regenerative medicine strategies in orthopedics. Growing evidence in vitro suggests a role for polyamines in enhancing differentiation in both adult stem cells and differentiated chondrocytes. Adipose-derived stem cells have recently proved to be a convenient alternative to bone marrow stromal cells, due to their easy accessibility and the high frequency of stem cell precursors per volume unit. State-of-the-art "prolotherapy" approaches for skeleton regeneration include the use of adipose-derived stem cells and platelet concentrates, such as platelet-rich plasma (PRP). Besides several growth factors, PRP also contains polyamines in the micromolar range, which may also exert an anti-apoptotic effect, thus helping to explain the efficacy of PRP in enhancing osteogenesis in vitro and in vivo. On the other hand, spermidine and spermine are both able to enhance hypertrophy and terminal differentiation of chondrocytes and therefore appear to be inducers of endochondral ossification. Finally, the peculiar activity of spermidine as an inducer of autophagy suggests the possibility of exploiting its use to enhance this cytoprotective mechanism to counteract the degenerative changes underlying either the aging or degenerative diseases that affect bone or cartilage.


Intensity-based image registration using robust correlation coefficients.
The ordinary sample correlation coefficient is a popular similarity measure for aligning images from the same or similar modalities. However, this measure can be sensitive to the presence of "outlier" objects that appear in one image but not the other, such as surgical instruments, the patient table, etc., which can lead to biased registrations. This paper describes an intensity-based image registration technique that uses a robust correlation coefficient as a similarity measure. Relative to the ordinary sample correlation coefficient, the proposed similarity measure reduces the influence of outliers. We also compared the performance of the proposed method with the mutual information-based method. The robust correlation-based method should be useful for image registration in radiotherapy (KeV to MeV X-ray images) and image-guided surgery applications. We have investigated the properties of the proposed method by theoretical analysis, computer simulations, a phantom experiment, and with functional magnetic resonance imaging data.


Running more than three kilometers during the first week of a running regimen may be associated with increased risk of injury in obese novice runners.
Training guidelines for novice runners are needed to reduce the risk of injury. The purpose of this study was to investigate whether the risk of injury varied in obese and non-obese individuals initiating a running program at different weekly distances. A volunteer sample of 749 of 1532 eligible healthy novice runners was included in a 3-week observational explorative prospective cohort study. Runners were categorized into one of six strata based on their body mass index (BMI) (≤30=low; >30=high) and running distance after 1 week (<3 km = low; 3 to 6 km = medium; >6 km = high). Data was collected for three weeks for the six strata. The main outcome measure was running-related injury. Fifty-six runners sustained a running-related injury during the 3-week data collection. A significantly greater number of individuals with BMI>30 sustained injuries if they ran between 3 to 6 km (cumulative risk difference (CRD) = 14.3% [95%CI: 3.3% to 25.3%], p<0.01) or more than 6 km (CRD = 16.2% [95%CI: 4.4% to 28.0%], p<0.01) the first week than individuals in the reference group (low distance and low BMI). The effect-measure modification between high running distance and BMI on additive scale was positive (11.7% [-3.6% to 27.0%], p=0.13). The number of obese individuals needed to change their running distance from high to low to avoid one injury was 8.5 [95%CI: 4.6 to 52]. Obese individuals were at greater risk of injury if they exceeded 3 km during the first week of their running program. Because of a considerable injury risk compared with their non-obese peers, individuals with a BMI>30 may be well advised to begin running training with an initial running distance of less than 3 km (1.9 miles) the first week of their running regime. Large-scale trials are needed to further describe and document this relationship. Level 2b.


Establishment of a mouse thymic epithelial cell line, IT-76MHC and a brief review on cultured thymic epithelial cells.
Interactions between thymocytes and thymic stromal cells are essential for thymocyte differentiation, but little evidence has been presented to directly show in vivo functions or interactions of the stromal cells. Among the stromal cells, the thymic epithelial cell has been considered to have profound effect on thymocyte differentiation and maturation. The calcium-depleted medium, originally developed for the culture of mouse epidermal cells, was applied for the culture of the mouse thymic epithelial cells, and successfully, an epithelial cell line, IT-76MHC was obtained from the mouse thymus. IT-76MHC cells were identified as distinct mouse thymic epithelial cells by 1/ mosaic-like arrangement, 2/ presence of well-developed desmosome and 3/ tonofilaments, 4/ positivity for cytokeratin, and 5/ induced expression of MHC class I and II by IFN-gamma treatment. IGF-1, IGF-2, oxytocin and vasopressin were also detected immunohistochemically in IT-76MHC cells. Furthermore, the IT-76MHC thymic epithelial cells, when injected intrathymically in the allogeneic mouse, prolonged the survival of skin graft from the same donor strain that IT-76MHC cells were derived. These results demonstrate that the thymic epithelial cell line IT-76MHC produces modest thymocyte survival factors as well as a growth suppressor, and that IT-76MHC cells have the ability to induce transplantation tolerance probably through their expression of MHC class I and II molecules. Taken altogether, the IT-76MHC thymic epithelial cells have been proved to be useful tools to better understand the in vivo functions of thymic epithelial cells, and to gain a deep insight into their involvement in the critical selection process of thymocytes which still remains obscure. Finally and additionally, literatures so far reported on thymic epithelial cells in culture, especially lines and clones, are reviewed and their identity as well as their functions are discussed.


GULP1 regulates the NRF2-KEAP1 signaling axis in urothelial carcinoma.
Disruption of the KEAP1-NRF2 pathway results in the transactivation of NRF2 target genes, consequently inducing cell proliferation and other phenotypic changes in cancer cells. Here, we demonstrated that GULP1 was a KEAP1-binding protein that maintained actin cytoskeleton architecture and helped KEAP1 to sequester NRF2 in the cytoplasm. In urothelial carcinoma of the bladder (UCB), silencing of GULP1 facilitated the nuclear accumulation of NRF2, led to constitutive activation of NRF2 signaling, and conferred resistance to the platinum drug cisplatin. Knockdown of GULP1 in UCB cells promoted tumor cell proliferation in vitro and enhanced tumor growth in vivo. In primary UCB, GULP1 silencing was more prevalent in muscle-invasive UCB compared to nonmuscle-invasive UCB. GULP1 knockdown cells showed resistance to cisplatin treatment. In parallel with decreased GULP1 expression, we observed increased expression of NRF2, HMOX1, and other candidate antioxidant genes in cisplatin-resistant cells. Furthermore, low or no expression of GULP1 was observed in most cisplatin nonresponder cases. Silencing of GULP1 was associated with GULP1 promoter hypermethylation in cell lines and primary tumors, and a high frequency of GULP1 promoter methylation was observed in multiple sets of primary clinical UCB samples. Together, our findings demonstrate that GULP1 is a KEAP1-binding protein that regulates KEAP1-NRF2 signaling in UCB and that promoter hypermethylation of GULP1 is a potential mechanism of GULP1 silencing.


Long-Term Quantitatively Imaging Intracellular Chloride Concentration Using a Core-/Shell-Structured Nanosensor and Time-Domain Dual-Lifetime Referencing Method.
Luminescence lifetime-based nanosensors for chloride ions were designed by incorporating a luminescent ruthenium dye [Ru(1,10-phenanthroline)3] inside silica nanoparticles and chemically labelling their outer surface with chloride ion-sensitive fluorescent dyes (N,N'-bis(carboxypropyl)-9,9'-biacridine). The nanosensor surface was further functionalized with positively charged amino groups to facilitate intracellular uptake via endocytosis and target lysosomes. The nanosensors have an average diameter of 52 nm and are monodispersed in aqueous solutions. Because of the long lifetime of the reference ruthenium dye, the sensor response can be analyzed using the time-domain dual-lifetime referencing (td-DLR) approach. The use of pulsed excitation in td-DLR rather than intense continuous illumination in ratiometric measurements greatly prevents the dye from photobleaching which significantly improves its measurement stability and reproducibility for long-term monitoring. At optimum conditions, the sensor can measure chloride concentration in the range of 0-200 mM with a large ratiometric signal change from 140.9 to 40.2. Combined with our custom-built microscopic td-DLR system, variations of intracellular chloride concentration in lysosomes were imaged quantitatively with a high spatial resolution and accuracy.


Peripheral nerve complications following burn injury.
The involvement of peripheral nerves in burn injury is not common, but when nerves are involved, prompt therapeutic intervention is necessary to avoid increased morbidity. Aside from the direct effects of the trauma, the burn team must anticipate dangerously excessive edema from circumferential burns, and avoid secondary nerve damage from inappropriate splinting, exercises or traction.


A comparative study of protein expression in primary colorectal cancer and synchronous hepatic metastases: the significance of matrix metalloproteinase-1 expression as a predictor of liver metastasis.
This study was undertaken to determine the ability of protein expression in primary colorectal cancer and metastatic liver tumour tissues to predict hepatic metastasis and intrahepatic recurrence. Sixty patients with colorectal cancer were enrolled in this study. The expression of the following five proteins was assessed by immunohistochemical (IHC) staining: carcinoembryonic antigen (CEA); vascular endothelial growth factor (VEGF); matrix metalloproteinase (MMP)-1; MMP-7; and tissue inhibitor of metalloproteinases (TIMP)-1. Protein expression was measured in patients with primary colorectal cancer without liver metastasis (Group A), in patients with primary colorectal cancer with liver metastasis (primary tumour; Group B), and in patients with resected metastatic liver tumour tissues (liver metastasis; Group C). IHC staining revealed more protease activity (MMP-1 and -7) in Group B than in Group A. Angiogenic activity (positive VEGF expression) was significantly greater in Group C than in Group B. Multivariate analysis showed that positive MMP-1 expression, the presence of lymphovascular invasion, and an elevated pre-operative serum CEA level (> 5 ng/ml) were significantly related to synchronous liver metastasis. However, intrahepatic recurrence was not related to protein expression, the presence of lymphovascular invasion, or the pre-operative CEA level. Our findings suggest that protease activity is important for metastasis, and that angiogenic activity is essential for metastatic tumour growth. Furthermore, positive MMP-1 expression in primary colorectal tumour tissues was a significant predictor of liver metastasis. However, the prognostic impact of protein marker expression in terms of intrahepatic recurrence appears to be minimal.


Transparent conducting oxide induced by liquid electrolyte gating.
Optically transparent conducting materials are essential in modern technology. These materials are used as electrodes in displays, photovoltaic cells, and touchscreens; they are also used in energy-conserving windows to reflect the infrared spectrum. The most ubiquitous transparent conducting material is tin-doped indium oxide (ITO), a wide-gap oxide whose conductivity is ascribed to n-type chemical doping. Recently, it has been shown that ionic liquid gating can induce a reversible, nonvolatile metallic phase in initially insulating films of WO3 Here, we use hard X-ray photoelectron spectroscopy and spectroscopic ellipsometry to show that the metallic phase produced by the electrolyte gating does not result from a significant change in the bandgap but rather originates from new in-gap states. These states produce strong absorption below ∼1 eV, outside the visible spectrum, consistent with the formation of a narrow electronic conduction band. Thus WO3 is metallic but remains colorless, unlike other methods to realize tunable electrical conductivity in this material. Core-level photoemission spectra show that the gating reversibly modifies the atomic coordination of W and O atoms without a substantial change of the stoichiometry; we propose a simple model relating these structural changes to the modifications in the electronic structure. Thus we show that ionic liquid gating can tune the conductivity over orders of magnitude while maintaining transparency in the visible range, suggesting the use of ionic liquid gating for many applications.


Effect of saccharin on antibacterial activity of chlorhexidine gel.
Although chlorhexidine is the most effective agent against dental plaque it is extremely bitter. To prepare formulations, it is necessary to use flavoring and sweetening, which can inhibit the antibacterial effect of chlorhexidine. Saccharin has been considered a compatible substance to use in chlorhexidine rinse or gel preparations; however, the effect of a range of concentrations has not been studied. To evaluate the effect of different concentrations of saccharin on the antibacterial activity of chlorhexidine gel, hydroxy-ethyl-cellulose gels containing 1.0% chlorhexidine digluconate and 0.0 to 1.0% sodium saccharin were prepared. Activity against Streptococcus mutans was evaluated using the agar diffusion method and determination of MIC values. The inhibitory zones of growth were 7.83 +/- 0.54 mm when no saccharin was added to the chlorhexidine gel and 7.75 +/- 0.50, 7.63 +/- 0.48, 6.21 +/- 0.40, 4.13 +/- 0.38, when the concentrations of saccharin in the gels were 0.02, 0.10, 0.5, and 1.0%, respectively. The range of MIC values was 1-2 micrograms/ml, with saccharin concentrations of 0%, 0.02, and 0.1%. In contrast, the MIC values were 4-8 and 8-16 micrograms/ml with saccharin concentrations of 0.5% and 1.0%, respectively. The paired "t" test showed that 0.5 and 1.0% sodium saccharin inhibit the antibacterial activity of 1% digluconate chlorhexidine gel. These in vitro results suggest that saccharin may inhibit the efficacy of chlorhexidine against mutans streptococci, depending on the concentration.


[Background activity of neurons of the tracheal plexus in the rat].
Morphological structure of the nerve plexus of the rat tracheal dorsal muscle wall is described and electrophysiological data on neuronal activity of this plexus are presented. Extracellular recording revealed two types of spontaneous activity including a single-spike type and a serial-spike type. The presence of excitatory and inhibitory interaction between neurons of a single ganglion is shown. Characteristic features of the tracheal part are discussed in comparison with other parts of the metasympathetic system.


Sustainable Design Approach for Modeling Bioprocesses from Laboratory toward Commercialization: Optimizing Chitosan Production.
Enhancing the biochemical supply chain towards sustainable development requires more efforts to boost technology innovation at early design phases and avoid delays in industrial biotechnology growth. Such a transformation requires a comprehensive step-wise procedure to guide bioprocess development from laboratory protocols to commercialization. This study introduces a process design framework to guide research and development (R&D) through this journey, bearing in mind the particular challenges of bioprocess modeling. The method combines sustainability assessment and process optimization based on process efficiency indicators, technical indicators, Life Cycle Assessment (LCA), and process optimization via Water Regeneration Networks (WRN). Since many bioprocesses remain at low Technology Readiness Levels (TRLs), the process simulation module was examined in detail to account for uncertainties, providing strategies for successful guidance. The sustainability assessment was performed using the geometric mean-based sustainability footprint metric. A case study based on Chitosan production from shrimp exoskeletons was evaluated to demonstrate the method's applicability and its advantages in product optimization. An optimized scenario was generated through a WRN to improve water management, then compared with the case study. The results confirm the existence of a possible configuration with better sustainability performance for the optimized case with a sustainability footprint of 0.33, compared with the performance of the base case (1.00).


Impact of metabolic syndrome on progression of aortic stenosis: influence of age and statin therapy.
The aims of this study were to examine prospectively the relationship between metabolic syndrome (MetS) and aortic stenosis (AS) progression and to evaluate the effect of age and statin therapy on AS progression in patients with or without MetS. Despite the clear benefits of statin therapy in primary and secondary coronary heart disease prevention, several recent randomized trials have failed to demonstrate any significant effect of this class of drugs on the progression of AS. Previous retrospective studies have reported an association between MetS and faster AS progression. This predefined substudy included 243 of the 269 patients enrolled in the ASTRONOMER (AS Progression Observation: Measuring Effects of Rosuvastatin) trial. Follow-up was 3.4 ± 1.3 years. AS progression rate was measured by calculating the annualized increase in peak aortic jet velocity measured by Doppler echocardiography. Patients with MetS (27%) had faster stenosis progression (+0.25 ± 0.21 m/s/year vs. +0.19 ± 0.19 m/s/year, p = 0.03). Predictors of faster AS progression in multivariate analysis were older age (p = 0.01), higher degree of valve calcification (p = 0.01), higher peak aortic jet velocity at baseline (p = 0.007), and MetS (p = 0.005). Impact of MetS on AS progression was most significant in younger (< 57 years) patients (MetS: +0.24 ± 0.19 m/s/year vs. no MetS: +0.13 ± 0.18 m/s/year, p = 0.008) and among patients receiving statin therapy (+0.27 ± 0.23 m/s/year vs. +0.19 ± 0.18 m/s/year, p = 0.045). In multivariate analysis, the MetS-age interaction was significant (p = 0.01), but the MetS-statin use interaction was not. MetS was found to be a powerful and independent predictor of faster AS progression, with more pronounced impact in younger patients. These findings emphasize the importance of routinely identifying and treating MetS in AS patients. The apparent faster stenosis progression in the subset of normocholesterolemic patients with MetS receiving the statin will need to be confirmed by future studies.


Mobilization of the Proteus mirabilis chromosome by R plasmid R772.
The P-1 incompatibility group plasmid R772 can mobilize the chromosome of Proteus mirabilis strain PM5006. The decreasing gradient of recombinant recovery frequencies found for markers which were increasingly distal to 0 min with plasmid D donors was not found with R772. Instead, it produced recombinants for all markers at frequencies of about 5 X 10(-5) per donor. This is about 10-fold lower than the plasmid transfer frequency. Recombinants were stable and recombination was only detected over short segments of the chromosome which corresponded to about 10 min on the D plasmid map of the chromosome. All recombinants had inherited R772 and expressed all properties of the plasmid. Attempts to isolate variant plasmids with increased frequencies of recombinant formation were unsuccessful.


Oxidative stress assessment in intestine of newborn rats submitted to hypoxia and reoxygenation with tadalafil.
To evaluate the functional and structural response of tadalafil effects in the intestinal mucosa, using an experimental model of hypoxia and reoxygenation injury in rats. The animals were divided into 4 groups: CTL, H/R, H/R+Td and M+Td. The newborn rats allocated in groups H/R, H/R+Td and M+Td were submitted twice a day, to a gas chamber with CO2 at 100% for 10 minutes and afterward reoxygenation with O2 at 98% for 10 minutes, in the three first days of life. Tadalafil dose was given to newborn of group H/R+Td and to the pregnant rat of group M+Td. Histological analysis was made with hematoxylin-eosin technique and oxidative stress through nitrite and nitrate levels and lipid peroxidation. The histological analysis showed a reduction of mucosa alterations in the groups that received tadalafil. In the oxidative stress evaluation, occurred an increase of NO levels and less lipidic peroxidation in the ileum segments that received tadalafil. Tadalafil provides tissue protection when administered independently to both, pregnant or newborns.


Mental disorders and earnings: results from the Nigerian National Survey of Mental Health and Well-Being (NSMHW).
Mental disorders are associated with a loss in earnings both at the individual and societal level. Very few studies have addressed the issue of the cost of mental illness in Sub-saharan Africa. These studies have been largely hospital based, localized, and have addressed only a few mental disorders using very small sample sizes. To examine the impact of mental disorders on earnings of affected persons. Mental disorders on and personal earnings were assessed in a representative sample of 1,889 Nigerians aged 18-64 years in an epidemiological survey. Version 3.0 of the World Health Organization Composite International Diagnostic Interview (WHO-CIDI) was used to assess mental disorders. Respondents were also asked to report their personal earnings before tax in the past 12 months, while authors predicted personal earnings in the same period from information about 12 month and life time DSM IV mental disorders among respondents. A 12 month prevalence of Serious Mental Illness (SMI) was found in 0.5% of the sample while other 12 month disorders had a prevalence of 4.83%. The prevalence of other lifetime disorders was 4.14%. The mean annual impact of serious mental illness was 60,126 Naira (US$ 463). At the level of the society the annual impact was 21.6 billion Naira (US$ 166.2 million). Mental disorders have an enormous individual and societal financial burden. This impact appears more severe in males. Mental disorders have enormous negative impacts on earnings both at the individual and societal level. This analysis highlights the financial value of lost earnings in the absence of such disorders. An increase in spending on mental health based on proportionate economic burden of mental disorders may substantially reduce financial losses due to mental disorders. In the present study, only the indirect health care costs have been assessed. Future research should consider direct costs.


Predicting miRNA-disease associations based on multi-view information fusion.
MicroRNAs (miRNAs) play an important role in various biological processes and their abnormal expression could lead to the occurrence of diseases. Exploring the potential relationships between miRNAs and diseases can contribute to the diagnosis and treatment of complex diseases. The increasing databases storing miRNA and disease information provide opportunities to develop computational methods for discovering unobserved disease-related miRNAs, but there are still some challenges in how to effectively learn and fuse information from multi-source data. In this study, we propose a multi-view information fusion based method for miRNA-disease association (MDA)prediction, named MVIFMDA. Firstly, multiple heterogeneous networks are constructed by combining the known MDAs and different similarities of miRNAs and diseases based on multi-source information. Secondly, the topology features of miRNAs and diseases are obtained by using the graph convolutional network to each heterogeneous network view, respectively. Moreover, we design the attention strategy at the topology representation level to adaptively fuse representations including different structural information. Meanwhile, we learn the attribute representations of miRNAs and diseases from their similarity attribute views with convolutional neural networks, respectively. Finally, the complicated associations between miRNAs and diseases are reconstructed by applying a bilinear decoder to the combined features, which combine topology and attribute representations. Experimental results on the public dataset demonstrate that our proposed model consistently outperforms baseline methods. The case studies further show the ability of the MVIFMDA model for inferring underlying associations between miRNAs and diseases.


[Enterosorbents in the treatment of atherosclerosis].
The article lists, characterizes, and discusses the mechanism of the action of endosorbents possessing hypocholesteremic and hypolipidemic effects. Among them are natural endosorbents--food fibers (cellulose, hemicellulose, pectins, gum, mucus, lignin and chitin compounds, etc.); artificial specific affinin and nonspecific carbonic enterosorbents (carbonitrate family, granulated, fibrous), as well as silica (aerosil, polysorb). The effectiveness and pathogenetic expediency of correcting disorders of lipid metabolism in atherosclerosis with enterosorbents is substantiated.


The crystal structure of a tetrameric hemoglobin in a partial hemichrome state.
Tetrameric hemoglobins are the most widely used systems in studying protein cooperativity. Allosteric effects in hemoglobins arise from the switch between a relaxed (R) state and a tense (T) state occurring upon oxygen release. Here we report the 2.0-A crystal structure of the main hemoglobin component of the Antarctic fish Trematomus newnesi, in a partial hemichrome form. The two alpha-subunit iron atoms are bound to a CO molecule, whereas in the beta subunits the distal histidine residue is the sixth ligand of the heme iron. This structure, a tetrameric hemoglobin in the hemichrome state, demonstrates that the iron coordination by the distal histidine, usually associated with denaturing states, may be tolerated in a native-like hemoglobin structure. In addition, several features of the tertiary and quaternary organization of this structure are intermediate between the R and T states and agree well with the R --> T transition state properties obtained by spectroscopic and kinetic techniques. The analysis of this structure provides a detailed pathway of heme-heme communication and it indicates that the plasticity of the beta heme pocket plays a role in the R --> T transition of tetrameric hemoglobins.


Immunosuppressive activity of Phaseolus coccineus and Phaseolus vulgaris extracts in mice.
Lectin mixtures from 10 samples of Phaseolus coccineus and Phaseolus vulgaris beans were used as immunosuppressive agents in the sheep red blood cell (SRBC) antibody response of the mouse. Some bean samples contain lectins capable of inducing several times better suppression of humoral immunity than concanavalin A and phytohemagglutinin tested before in the same immune system. High dilutions of the 10 bean extracts were shown to agglutinate mouse, rabbit and sheep erythrocytes in vitro but the titers and "specificities" did not correlate with the immunosuppressive potency and selectivity displayed by the same extracts in mice. Two immunosuppressive bean extracts, assayed in lymphocyte cultures, were found to stimulate DNA synthesis of murine spleen T cells. This interaction appears to be a necessary step for the reduction of antibody synthesis to SRBC in the whole animal.


Interest of active posturography to detect age-related and early Parkinson's disease-related impairments in mediolateral postural control.
Patients with Parkinson's disease display impairments of postural control most particularly in active, challenging conditions. The objective of the present study was to analyze early signs of disease-related and also age-related impairments in mediolateral body extension and postural control. Fifty-five participants (18 Hoehn and Yahr stage 2 patients in the off-drug condition, 18 healthy elderly control subjects, and 19 young adults) were included in the study. The participants performed a quiet stance task and two active tasks that analyzed the performance in mediolateral body motion: a limit of stability and a rhythmic weight shift task. As expected, the patients displayed significantly lower and slower body displacement (head, neck, lower back, center of pressure) than elderly control subjects when performing the two body excursion tasks. However, the behavioral variability in both tasks was similar between the groups. Under these active conditions, the patients showed significantly lower contribution of the hip postural control mechanisms compared with the elderly control subjects. Overall, the patients seemed to lower their performance in order to prevent a mediolateral postural instability. However, these patients, at an early stage of their disease, were not unstable in quiet stance. Complementarily, elderly control subjects displayed slower body performance than young adults, which therefore showed an additional age-related impairment in mediolateral postural control. Overall, the study illustrated markers of age-related and Parkinson's disease impairments in mediolateral postural control that may constrain everyday activities in elderly adults and even more in patients with Parkinson's disease.


Do I need to have my hands free to understand hand-related language? Investigating the functional relevance of experiential simulations.
Theories of embodiment state that people mentally simulate the described situations and events during language comprehension. While several studies have provided evidence that these simulations exist, it is still unclear whether they are functionally relevant for comprehension. To investigate this question, we studied the effects of a secondary task on the processing of hand- and foot-related nouns. The secondary task occupied either the hand or the foot system, thereby impeding hand- or foot-related simulations, respectively. Participants performed a lexical decision task by responding to the presented nouns with their left hand or foot, depending on the color of the words, while withholding their response to pseudowords. In half of the experimental blocks, participants performed a simultaneous tapping task with their right hand (Experiment 1) or foot (Experiment 2). If simulations are functionally relevant for comprehension, the secondary task should affect the processing of hand words to a larger degree than the processing foot words in Experiment 1 and vice versa in Experiment 2. In both experiments, hand responses were faster for hand words than foot words, whereas the opposite was true for foot responses. This finding indicates that participants indeed simulated the words' meanings. Importantly, there was no difference between the influence of the hand tapping and the foot tapping task on lexical decision times to hand and foot words, indicating that experiential simulation might just be an optional by-product of language processing.


The Papua New Guinea medical supply system - documenting opportunities and challenges to meet the Millennium Development Goals.
Limited human resources are widely recognised as an impediment to achieving the health-related Millennium Development Goals in Pacific Island Countries, with the availability of medical supplies and suitably trained health personnel crucial to ensuring a well-functioning medical supply chain. This paper presents our findings as we seek to answer the research question 'What factors influence the availability of medical supplies within the health facilities of Papua New Guinea?' We used a qualitative, triangulated strategy using semi-structured interviews, workplace observation and semi-structured focus groups. The parallel use of the interview tool and workplace observation tool allowed identification of 'know-do' gaps between what the interviewee said they did in their work practices, and the actual evidence of these practices. Focus groups provided further opportunities for raising and elaborating issues. During 2 weeks of data collection we conducted 17 interviews and 15 observational workplace surveys in 15 facilities. Sixteen health personnel participated in 3 focus groups across 2 provinces and one district. An array of medical supply issues across all levels of the medical supply chain were revealed, including standard operating procedures, facilities, transport, emergency medical kits, the cold chain and record keeping. The influence of health worker training and competency was found to be common across all of these issues. The factors influencing the availability of medical supplies in PNG consist of a range of interrelating issues, consisting of both simple and complex problems involving the different levels and cadres of workers within the medical supply chain. Health systems sustainability theory suggests that a coordinated approach which addresses the inter-related nature of these issues, led by the PNG government and supported by suitable development partners, will be required for sustainable health systems change to occur. These changes are necessary for PNG to meet the health-related Millennium Development Goals.


Implementation of promotion and prevention activities in decentralized health systems: comparative case studies from Chile and Brazil.
The policies for restructuring health systems in Latin America during the 1990s have included an emphasis on changing in the model of health care delivery to one that incorporates prevention and promotion activities. At the same time, health systems have been decentralized in their management, allowing room for greater variation in local interpretation and implementation of policy directives. Despite rhetoric and policy debate, there is no documentation or evaluation of actual experiences of prevention and promotion within decentralized health systems in Latin America. This paper explores the ways in which the national structure of a health system influences the implementation of activities for prevention and promotion through a comparison of the experiences in four local health systems in each of Brazil and Chile. These experiences in Brazil and Chile are presented by key themes of national health system structure, local health system structure, partnership and intersectorality, human resources and introducing a family health approach. Five clear factors emerge as operating at the national level that influence prevention and promotion activities in local health systems: vertical (Chile) versus horizontal (Brazil) structure of health system; greater awareness of prevention and promotion issues in Chile; greater urban bias in Chile compared with Brazil; strategies to attract human resources to primary care and rural areas; importance of local capacity building especially in rural areas. This account of case study experiences in Brazil and Chile provides a series of examples of arrangements and strategies that can facilitate implementation and usefully highlights a number of issues that policy-makers and health system managers need explicitly to consider. As such, the paper hopes to provoke debate about the structures and strategies for supporting the implementation of prevention and promotion programmes in Latin America and further health systems research in this field.


Online tailored weight management in the worksite: does it make a difference in biennial health risk assessment data?
Overweight and obesity are directly associated with heart disease, cancer, and diabetes and pose a serious cost-related challenge to employers. As most of the rise in health care spending is traced to the rise in population risk factors, maintaining or reducing the prevalence of disease represents a strategy with large potential payoffs. Tailored communication is a promising communication strategy for influencing health behavior change, including behaviors for weight management. Much of the tailored communication research is based on communication developed for research purposes, yet access to commercially available tailored health programs for worksites is growing. As health risk assessments are increasingly used for setting health programming and insurance priorities in U.S. workplaces and worksites have opportunities to purchase tailored programs, it is important to understand the effect of tailored communication on health risk assessment data. The purpose of this study was to evaluate the long-term effects of a commercially available web-based tailored weight management program on employee weight, body mass index, blood pressure, cholesterol, and blood glucose. The authors compared health risk assessment data at baseline and 2 years later from 101 overweight and obese employees who participated in the tailored weight management program and 137 overweight and obese employees who did not participate in the program. Results show that there were significant mean differences in systolic blood pressure, HDL cholesterol, and blood sugar levels, but each in a clinically undesirable direction. More research is needed to understand the effect of tailored programs used in worksite health promotion.


Early effects of reward anticipation are modulated by dopaminergic stimulation.
The abilities to predict future rewards and assess the value of reward delivery are crucial aspects of adaptive behavior. While the mesolimbic system, including dopaminergic midbrain, ventral striatum and prefrontal cortex have long been associated with reward processing, recent studies also indicate a prominent role of early visual brain regions. However, the precise underlying neural mechanisms still remain unclear. To address this issue, we presented participants with visual cues predicting rewards of high and low magnitudes and probability (2 × 2 factorial design), while neural activity was scanned using magnetoencephalography. Importantly, one group of participants received 150 mg of the dopamine precursor levodopa prior to the experiment, while another group received a placebo. For the placebo group, neural signals of reward probability (but not magnitude) emerged at ∼ 100 ms after cue presentation at occipital sensors in the event-related magnetic fields. Importantly, these probability signals were absent in the levodopa group indicating a close link. Moreover, levodopa administration reduced oscillatory power in the high (20-30 Hz) and low (13-20 Hz) beta band during both reward anticipation and delivery. Taken together, our findings indicate that visual brain regions are involved in coding prospective reward probability but not magnitude and that these effects are modulated by dopamine.


Effects of trimethylsilylation of copper(II)-phthalocyanine sulfonyl-aminopropyl silica gels on the separation of pi-electron-rich compounds by high-performance liquid chromatography.
As an attempt to elucidate the factor(s) responsible for the poor performance of a copper(II)-phthalocyanine aminopropylsilica gels (CU-PCSD) column for HPLC, the silanol and/or amino groups remaining on Cu-PCSD were endcapped with trimethylchlorosilane (TMCS) or N-trimethylsilylimidazole (TMSI). The trimethylsilylated Cu-PCS(D)S (Cu-PCSD-TMCS and -TMSI) were investigated concerning their performance as an HPLC-stationary phase in the separation of pi-electron-rich polyaromatic hydrocarbons (PAHs), such as mutagenic anthracene and pyrene. As a result, trimethylsilylation with TMSI, which reacts only with silanol-groups, was not effective to improve the column efficiency. In contrast, trimethylsilylation by TMCS, which reacts with both the silanol- and amino-groups, improved the theoretical plate numbers (N) for PAHs separation with the Cu-PCS(D) column, indicating that the low N values on the Cu-PCSD column were caused by electrostatic interactions between PAHs and the remaining amino-groups on Cu-PCS(D). Furthermore, the retention data of mutagenic heterocyclic amines (HCAs) indicated that the remaining amino groups interact with the polar groups of HCAs.


Successful suppression of the early rejection of pig islets in monkeys.
Primary nonfunction (PNF) is seen very frequently after xenogeneic transplantation of islets of Langerhans. In a pig-to-rat model we recently observed that no PNF occurs when the islets are kept in culture at 37 degrees C for 1-2 weeks prior to transplantation. In order to investigate the rejection mechanisms in a preclinical model, we transplanted cultured porcine islets under the capsule of both kidneys in four cynomolgous monkeys. Islets were isolated from adult sows by means of digestion with Liberase in University of Wisconsin solution (UWS). The digest was purified by a density gradient of OptiPrep in UWS. Highly purified (>95%) islets were cultured 1-2 weeks in RPMI. All monkeys showed significant titers of preformed anti-pig antibodies. The immunosuppression of the monkeys consisted of cyclophosphamide (Cy) (2 days), cyclosporin A (CsA), and prednisolone. Anticipating a fast rejection we carried out nephrectomies at different time points within 2 weeks after transplantation. Following unilateral nephrectomy, well-preserved islets with no signs of rejection were observed between 3 and 7 days posttransplant. Later, between days 11 and 15 posttransplant, histology in the first three animals demonstrated no islets. In the fourth monkey histology on day 11 showed islets with excellent morphology and some small focal infiltrates. The highest CsA blood levels (around 1000 ng/ml) were found in animals with the best graft survival. We conclude that cultured porcine islets can be grafted without hyperacute rejection in monkeys with preformed anti-pig antibodies. In the presence of high levels of CsA only marginal signs of a cellular immune response were observed 11 days after transplantation.


IRAK3 modulates downstream innate immune signalling through its guanylate cyclase activity.
Interleukin-1 receptor associated kinase 3 (IRAK3) is a cytoplasmic homeostatic mediator of inflammatory responses and is potentially useful as a prognostic marker in inflammation. IRAK3 inhibits signalling cascades downstream of myddosome complexes associated with toll like receptors. IRAK3 contains a death domain that interacts with other IRAK family members, a pseudokinase domain and a C-terminus domain involved with tumour necrosis factor receptor associated factor 6 (TRAF6). Previous bioinformatic studies revealed that IRAK3 contained a guanylate cyclase centre in its pseudokinase domain but its role in IRAK3 action is unresolved. We demonstrate that wildtype IRAK3 is capable of producing cGMP. Furthermore, we show that a specific point mutation in the guanylate cyclase centre reduced cGMP production. Cells containing toll like receptor 4 and a nuclear factor kappa-light-chain-enhancer of activated B cells (NFĸB) reporter system were transfected with IRAK3 or mutant IRAK3 proteins. Cell-permeable cGMP treatment of untransfected control cells suppresses downstream signalling through modulation of the NFĸB in the presence of lipopolysaccharides. Cells transfected with wildtype IRAK3 also suppress lipopolysaccharide induced NFĸB activity in the absence of exogenous cGMP. Lipopolysaccharide induced NFĸB activity was not suppressed in cells transfected with the IRAK3 mutant with reduced cGMP-generating capacity. Whereas in the presence of exogenously applied cell-permeable cGMP the IRAK3 mutant was able to retain its function by suppressing lipopolysaccharide induced NFĸB activity. Furthermore, increasing the amount of membrane permeable cGMP did not affect IRAK3's ability to reduce NFĸB activity. These results suggest that cGMP generated by IRAK3 may be involved in regulatory function of the protein where the presence of cGMP may selectively affect downstream signalling pathway(s) by modulating binding and/or activity of nearby proteins that interact in the inflammatory signalling cascade.


Parallel selection on TRPV6 in human populations.
We identified and examined a candidate gene for local directional selection in Europeans, TRPV6, and conclude that selection has acted on standing genetic variation at this locus, creating parallel soft sweep events in humans. A novel modification of the extended haplotype homozygosity (EHH) test was utilized, which compares EHH for a single allele across populations, to investigate the signature of selection at TRPV6 and neighboring linked loci in published data sets for Europeans, Asians and African-Americans, as well as in newly-obtained sequence data for additional populations. We find that all non-African populations carry a signature of selection on the same haplotype at the TRPV6 locus. The selective footprints, however, are significantly differentiated between non-African populations and estimated to be younger than an ancestral population of non-Africans. The possibility of a single selection event occurring in an ancestral population of non-Africans was tested by simulations and rejected. The putatively-selected TRPV6 haplotype contains three candidate sites for functional differences, namely derived non-synonymous substitutions C157R, M378V and M681T. Potential functional differences between the ancestral and derived TRPV6 proteins were investigated by cloning the ancestral and derived forms, transfecting cell lines, and carrying out electrophysiology experiments via patch clamp analysis. No statistically-significant differences in biophysical channel function were found, although one property of the protein, namely Ca(2+) dependent inactivation, may show functionally relevant differences between the ancestral and derived forms. Although the reason for selection on this locus remains elusive, this is the first demonstration of a widespread parallel selection event acting on standing genetic variation in humans, and highlights the utility of between population EHH statistics.


Pri smORF Peptides Are Wide Mediators of Ecdysone Signaling, Contributing to Shape Spatiotemporal Responses.
There is growing evidence that peptides encoded by small open-reading frames (sORF or smORF) can fulfill various cellular functions and define a novel class regulatory molecules. To which extend transcripts encoding only smORF peptides compare with canonical protein-coding genes, yet remain poorly understood. In particular, little is known on whether and how smORF-encoding RNAs might need tightly regulated expression within a given tissue, at a given time during development. We addressed these questions through the analysis of Drosophila polished rice (pri, a.k.a. tarsal less or mille pattes), which encodes four smORF peptides (11-32 amino acids in length) required at several stages of development. Previous work has shown that the expression of pri during epidermal development is regulated in the response to ecdysone, the major steroid hormone in insects. Here, we show that pri transcription is strongly upregulated by ecdysone across a large panel of cell types, suggesting that pri is a core component of ecdysone response. Although pri is produced as an intron-less short transcript (1.5 kb), genetic assays reveal that the developmental functions of pri require an unexpectedly large array of enhancers (spanning over 50 kb), driving a variety of spatiotemporal patterns of pri expression across developing tissues. Furthermore, we found that separate pri enhancers are directly activated by the ecdysone nuclear receptor (EcR) and display distinct regulatory modes between developmental tissues and/or stages. Alike major developmental genes, the expression of pri in a given tissue often involves several enhancers driving apparently redundant (or shadow) expression, while individual pri enhancers can harbor pleiotropic functions across tissues. Taken together, these data reveal the broad role of Pri smORF peptides in ecdysone signaling and show that the cis-regulatory architecture of the pri gene contributes to shape distinct spatial and temporal patterns of ecdysone response throughout development.


The evolution of resistance and tolerance as cancer defences.
Although there is a plethora of cancer associated-factors that can ultimately culminate in death (cachexia, organ impairment, metastases, opportunistic infections, etc.), the focal element of every terminal malignancy is the failure of our natural defences to control unlimited cell proliferation. The reasons why our defences apparently lack efficiency is a complex question, potentially indicating that, under Darwinian terms, solutions other than preventing cancer progression are also important contributors. In analogy with host-parasite systems, we propose to call this latter option 'tolerance' to cancer. Here, we argue that the ubiquity of oncogenic processes among metazoans is at least partially attributable to both the limitations of resistance mechanisms and to the evolution of tolerance to cancer. Deciphering the ecological contexts of alternative responses to the cancer burden is not a semantic question, but rather a focal point in understanding the evolutionary ecology of host-tumour relationships, the evolution of our defences, as well as why and when certain cancers are likely to be detrimental for survival.


High Variability in Implementation of Selective-Prevention Services for Cardiometabolic Diseases in Five European Primary Care Settings.
(1) Background: Cardiometabolic diseases are the most common cause of death worldwide. As part of a collaborative European study, this paper aims to explore the implementation of primary care selective-prevention services in five European countries. We assessed the implementation process of the selective-prevention services, participants' cardiometabolic profile and risk and participants' evaluation of the services, in terms of feasibility and impact in promoting a healthy lifestyle. (2) Methods: Eligible participants were primary care patients, 40-65 years of age, without any diagnosis of cardiometabolic disease. Two hundred patients were invited to participate per country. The extent to which participants adopted and completed the implementation of selective-prevention services was recorded. Patient demographics, lifestyle-related cardiometabolic risk factors and opinions on the implementation's feasibility were also collected. (3) Results: Acceptance rates varied from 19.5% (n = 39/200) in Sweden to 100% (n = 200/200) in the Czech Republic. Risk assessment completion rates ranged from 65.4% (n = 70/107) in Greece to 100% (n = 39/39) in Sweden. On a ten-point scale, the median (25-75% quartile) of participant-reported implementation feasibility ranged from 7.4 (6.9-7.8) in Greece to 9.2 (8.2-9.9) in Sweden. Willingness to change lifestyle exceeded 80% in all countries. (4) Conclusions: A substantial variation in the implementation of selective-prevention receptiveness and patient risk profile was observed among countries. Our findings suggest that the design and implementation of behavior change cardiometabolic programmes in each country should be informed by the local context and provide some background evidence towards this direction, which can be even more relevant during the current pandemic period.


Three-dimensional reconstruction of magnetic resonance images of the anal sphincter and correlation between sphincter volume and pressure.
The purpose of this study was to assess the correlation between internal and external anal sphincter volumes and manometric anal pressures. Ten healthy nulliparous women underwent anal sphincter magnetic resonance imaging and anal manometry measurement. A 3-dimensional reconstruction of magnetic resonance images was accomplished with the use of 3-dimensional slicer. Sphincter volumes were measured 3 times by the same observer for each of 10 patients. The intrarater reliability was measured with the use of the intraclass correlation coefficient (ICC = sigma (2)(patients)/(sigma (2)(patients) + sigma (2)(error))) from a 2-way analysis of variance model with terms for patient and measurement trial. Measurements that were recorded on anal manometry included squeeze length, length of the high-pressure zone, and maximal resting and squeeze pressures. The mean volumes (+/- SD) were 18.77 +/- 4.64 cm(3), 13.82 +/- 3.8 cm(3), and 32.36 +/- 8.37 cm(3) for internal, external, and combined sphincters, respectively. Intrarater reliability was 98% for external sphincter volume (95% CI, 94%-99%), 98% for internal sphincter volume (95% CI, 94%-99%), and 99% for total volume (95% CI, 97%-100%). On the 3-dimensional images, the internal sphincter was found to be cylindric in shape, with an ellipse as a base. It is elongated in the anterior and posterior direction and flattened on the sides. The external sphincter was found to be funnel-shaped, being narrower caudad and widening in the cephalad direction. Similar to the internal sphincter, the external sphincter is elongated in the anteroposterior diameter. Volumes of the internal, external, and combined sphincters did not correlate with the maximum pressures at rest and squeeze. Correlations higher than r = 0.5 were observed for all 3 sphincter volume measurements versus high pressure zone at squeeze. The highest correlation, r = 0.66, was for internal sphincter volume versus high pressure zone at squeeze Three-dimensional reconstruction of the rectal sphincter musculature can be performed easily with 3-dimensional software. Measurements of the sphincter volumes have excellent intrarater reliability. Sphincter volumes do not correlate with pressures at rest or squeeze, but the internal sphincter volume correlates with the length of the high pressure zone at squeeze. Contrary to current generalized concepts, it is possible that the internal sphincter may play some role in generating the squeeze pressure. More research is necessary in applying 3-dimensional magnetic resonance image reconstruction in patients with different parity and continence status. Reconstruction of magnetic resonance images of the rectal sphincter musculature may prove to be beneficial in planning the treatment of patients with fecal incontinence.


Fatal sepsis after intravesical instillation of BCG: case report.
Intravesical instillation of bacillus Calmette-Guérin (BCG) is the treatment of choice for carcinoma in situ and non-invasive high-grade superficial tumors of the urinary bladder. This treatment is well tolerated overall, but serious complications can occur. An elderly man with coronary disease and recurrent high-grade superficial carcinoma of the bladder underwent intravesical instillation of BCG and developed septic shock. He received wide range antibiotics, tuberculostatic and vasoactive drugs, corticosteroids, mechanical ventilation and renal replacement therapy without improvement. He died nine days after the intravesical instillation of BCG because of multiple organ failure.


In silico prediction and automatic LC-MS(n) annotation of green tea metabolites in urine.
The colonic breakdown and human biotransformation of small molecules present in food can give rise to a large variety of potentially bioactive metabolites in the human body. However, the absence of reference data for many of these components limits their identification in complex biological samples, such as plasma and urine. We present an in silico workflow for automatic chemical annotation of metabolite profiling data from liquid chromatography coupled with multistage accurate mass spectrometry (LC-MS(n)), which we used to systematically screen for the presence of tea-derived metabolites in human urine samples after green tea consumption. Reaction rules for intestinal degradation and human biotransformation were systematically applied to chemical structures of 75 green tea components, resulting in a virtual library of 27,245 potential metabolites. All matching precursor ions in the urine LC-MS(n) data sets, as well as the corresponding fragment ions, were automatically annotated by in silico generated (sub)structures. The results were evaluated based on 74 previously identified urinary metabolites and lead to the putative identification of 26 additional green tea-derived metabolites. A total of 77% of all annotated metabolites were not present in the Pubchem database, demonstrating the benefit of in silico metabolite prediction for the automatic annotation of yet unknown metabolites in LC-MS(n) data from nutritional metabolite profiling experiments.


The role of hepatic veins in liver operations.
In this report we review the role of the hepatic veins in resective operations of the liver. Emphasis is placed on the distribution of the hepatic veins, their relationship to hepatic arterial and portal venous inflow tracts, and the drainage patterns of hepatic lobules. An extensive review of the older literature has emphasized the necessity to preserve hepatic venous drainage for the various hepatic segments to prevent postoperative liver congestion and injury. Recent experimental and clinical reports have identified the mechanisms through which hepatic vein obstruction can be well tolerated. These mechanisms include interlobar and interlobular collateral development, reversal of blood flow in the portal vein with conversion of the portal vein to an outflow tract, development of extrahepatic collaterals, drainage through the caudate lobe, and increased lymphatic draining to relieve hepatic congestion.


Isolation and analysis of a novel gene, HXC-26, adjacent to the rab GDP dissociation inhibitor gene located at human chromosome Xq28 region.
We screened potential promoter regions from NotI-linking cosmid clones mapped on human chromosome Xq28 region with our constructed trapping vector and isolated six fragments containing transcription activity. Using one of the obtained fragments as a probe, a novel gene was isolated by screening a human skeletal muscle cDNA library. The isolated cDNA, termed HXC-26, contained an open reading frame of 975 nucleotides encoding 325 amino acids (38,848 Da). The HXC-26 gene was composed of 13 exons that span approximately 8 kb. Several potential GC boxes were found in the putative promoter region, but no typical TATA box. The HXC-26 gene associated with a CpG island was located adjacent to the rab GDP dissociation inhibitor (GDI) gene.


A 5' differentially methylated sequence and the 3'-flanking region are necessary for H19 transgene imprinting.
The mouse H19 gene is expressed exclusively from the maternal allele. The imprinted expression of the endogenous gene can be recapitulated in mice by using a 14-kb transgene encompassing 4 kb of 5'-flanking sequence, 8 kb of 3'-flanking sequence, which includes the two endoderm-specific enhancers, and an internally deleted structural gene. We have generated multiple transgenic lines with this 14-kb transgene and found that high-copy-number transgenes most closely follow the imprinted expression of the endogenous gene. To determine which sequences are important for imprinted expression, deletions were introduced into the transgene. Deletion of the 5' region, where a differentially methylated sequence proposed to be important in determining parental-specific expression is located, resulted in transgenes that were expressed and hypomethylated, regardless of parental origin. A 6-kb transgene, which contains most of the differentially methylated sequence but lacks the 8-kb 3' region, was not expressed and also not methylated. These results indicate that expression of either the H19 transgene or a 3' DNA sequence is key to establishing the differential methylation pattern observed at the endogenous locus. Finally, methylation analysis of transgenic sperm DNA from the lines that are not imprinted reveals that the transgenes are not capable of establishing and maintaining the paternal methylation pattern observed for imprinted transgenes and the endogenous paternal allele. Thus, the imprinting of the H19 gene requires a complex set of elements including the region of differential methylation and the 3'-flanking sequence.


Cyclooxygenases in the central nervous system: implications for treatment of neurological disorders.
Recognition of two isoforms of cyclooxygenase and reports that nonsteroidal anti-inflammatory drugs may be beneficial in devastating neurological conditions such as Alzheimer's disease have led to increased interest in cyclooxygenase function in the nervous system. In the present paper we review current data on the multiplicity of cyclooxygenase and prostaglandin mediated effects in the central nervous system (CNS). We discuss CNS cells types, including neurons, glia, and cerebrovascular elements, where cyclooxygenases-1 and -2 are expressed under normal conditions or can be induced by physiological or pathological stimuli. We also address physiological processes such as pain sensitization, CNS inflammation and fever induction that are regulated or modified by cyclooxygenase activity. Finally, we describe potential roles of cyclooxygenase in neurological diseases and rationales for nonsteroidal anti-inflammatory drug use in the treatment of neurodegenerative disorders, stroke and CNS injury.


Fecal Short-Chain Fatty Acid Variations by Breastfeeding Status in Infants at 4 Months: Differences in Relative versus Absolute Concentrations.
Our gut microbiota provide a number of important functions, one of which is the metabolism of dietary fiber and other macronutrients that are undigested by the host. The main products of this fermentation process are short-chain fatty acids (SCFAs) and other intermediate metabolites including lactate and succinate. Production of these metabolites is dependent on diet and gut microbiota composition. There is increasing evidence for the role of SCFAs in host physiology and metabolic processes as well as chronic inflammatory conditions such as allergic disease and obesity. We aimed to investigate differences in fecal SCFAs and intermediate metabolites in 163 infants at 3-5 months of age according to breastfeeding status. Compared to no exposure to human milk at time of fecal sample collection, exclusive breastfeeding was associated with lower absolute concentrations of total SCFAs, acetate, butyrate, propionate, valerate, isobutyrate, and isovalerate, yet higher concentrations of lactate. Further, the relative proportion of acetate was higher with exclusive breastfeeding. Compared to non-breastfed infants, those exclusively breastfed were four times more likely (aOR 4.50, 95% CI 1.58-12.82) to have a higher proportion of acetate relative to other SCFAs in their gut. This association was independent of birth mode, intrapartum antibiotics, infant sex, age, recruitment site, and maternal BMI or socioeconomic status. Our study confirms that breastfeeding strongly influences the composition of fecal microbial metabolites in infancy.


How adolescent patients use ward space.
This paper is a report of a study of the use of ward space in a purpose-built adolescent ward and the influence of that space on both adolescent patients and nurses. A separate ward environment gives adolescent patients opportunities to be with peers, have privacy and independence and be nursed away from younger children. The aim of adolescent wards is to cater for these differences and to set routines around this age group. Data were collected between 2002 and 2003 by participant observation and interview. In total 35 observations were undertaken of both adolescents and nursing staff, with associated interviews. A further 17 semi-structured individual nurse and 11 adolescent interviews were conducted, aimed at exploring the use of ward space. Patient demographics, ward policies and patient information sheets were also used. Adolescent patients created their own spaces on the ward from personal effects that were of interest to them. These spaces show nurses who they are. Adolescent patients want to be identified as more than 'just' a patient when they are in hospital. What the creation of these spaces does is assist the adolescent patient in escaping the homogeneity of the ward by cutting across its activities. By understanding patients through their self-created spaces, nurses can improve the capacity of adolescents to contribute to their own care, whilst enhancing their care experiences through understanding and collaboration.


Small heat-shock protein structures reveal a continuum from symmetric to variable assemblies.
The small heat-shock proteins (sHSPs) form a diverse family of proteins that are produced in all organisms. They function as chaperone-like proteins in that they bind unfolded polypeptides and prevent uncontrolled protein aggregation. Here, we present parallel cryo-electron microscopy studies of five different sHSP assemblies: Methanococcus jannaschii HSP16.5, human alphaB-crystallin, human HSP27, bovine native alpha-crystallin, and the complex of alphaB-crystallin and unfolded alpha-lactalbumin. Gel-filtration chromatography indicated that HSP16.5 is the most monodisperse, while HSP27 and the alpha-crystallin assemblies are more polydisperse. Particle images revealed a similar trend showing mostly regular and symmetric assemblies for HSP16.5 particles and the most irregular assemblies with a wide range of diameters for HSP27. A symmetry test on the particle images indicated stronger octahedral symmetry for HSP16.5 than for HSP27 or the alpha-crystallin assemblies. A single particle reconstruction of HSP16.5, based on 5772 particle images with imposed octahedral symmetry, resulted in a structure that closely matched the crystal structure. In addition, the cryo-EM reconstruction revealed internal density presumably corresponding to the flexible 32 N-terminal residues that were not observed in the crystal structure. The N termini were found to partially fill the central cavity making it unlikely that HSP16.5 sequesters denatured proteins in the cavity. A reconstruction calculated without imposed symmetry confirmed the presence of at least loose octahedral symmetry for HSP16.5 in contrast to the other sHSPs examined, which displayed no clear overall symmetry. Asymmetric reconstructions for the alpha-crystallin assemblies, with an additional mass selection step during image processing, resulted in lower resolution structures. We interpret the alpha-crystallin reconstructions to be average representations of variable assemblies and suggest that the resolutions achieved indicate the degree of variability. Quaternary structural information derived from cryo-electron microscopy is related to recent EPR studies of the alpha-crystallin domain fold and dimer interface of alphaA-crystallin.


The Feasibility of At-Home iPad Cognitive Testing For Use in Clinical Trials.
Technological advances now make it feasible to administer cognitive assessments at-home on mobile and touch-screen devices such as an iPad or tablet computer. Validation of these techniques is necessary to assess their utility in clinical trials. We used a Computerized Cognitive Composite for Preclinical Alzheimer's Disease (C3-PAD) developed for iPad 1) to determine the feasibility of performing the C3-PAD at home by older individuals without the presence of a trained psychometrician; 2) to explore the reliability of in-clinic compared to at-home C3-PAD performance and 3) to examine the comparability of C3-PAD performance to standardized neuropsychological tests. Forty-nine cognitively normal older individuals (mean age, 71.467.7 years; 20% non-Caucasian) were recruited from research centers at the Massachusetts General Hospital and Brigham and Women's Hospital. Participants made two in-clinic visits one-week apart and took five 30-minute alternate versions of the C3-PAD at-home measuring episodic memory, reaction time and working memory. A reliability analysis explored equivalence of the six alternate C3-PAD test versions. A feasibility assessment calculated the percentage of individuals who completed all at-home tests correctly, in contrast to incomplete assessments. Correlational analyses examined the association between C3-PAD-clinic compared to C3-PAD-home assessments and between C3-PAD performance and standardized paper and pencil tests. Excellent reliability was observed among the 6 C3-PAD alternate versions (Cronbach alpha coefficient=0.93). A total of 28 of 49 participants completed all at-home sessions correctly and 48 of 49 completed four out of five correctly. There were no significant differences in participant age, sex or education between complete and incomplete at-home assessments. A single in-clinic C3-PAD assessment and the at-home C3-PAD assessments were highly associated with each other (r2=0.508, p<0.0001), suggesting that at-home tests provide reliable data as in-clinic assessments. There was also a moderate association between the at-home C3-PAD assessments and the in-clinic standardized paper and pencil tests covering similar cognitive domains (r2= 0.168, p< 0.003). Reliable and valid cognitive data can be obtained from the C3-PAD assessments in the home environment. With initial in-clinic training, a high percentage of older individuals completed at-home assessments correctly. At-home cognitive testing shows promise for inclusion into clinical trial designs.


The effects of in ovo administration of encapsulated Toll-like receptor 21 ligand as an adjuvant with Marek's disease vaccine.
Marek's Disease Virus (MDV) is the causative agent of a lymphoproliferative disease, Marek's disease (MD) in chickens. MD is only controlled by mass vaccination; however, immunity induced by MD vaccines is unable to prevent MDV replication and transmission. The herpesvirus of turkey (HVT) vaccine is one of the most widely used MD vaccines in poultry industry. Vaccines can be adjuvanted with Toll-like receptor ligands (TLR-Ls) to enhance their efficacy. In this study, we examined whether combining TLR-Ls with HVT can boost host immunity against MD and improve its efficacy. Results demonstrated that HVT alone or HVT combined with encapsulated CpG-ODN partially protected chickens from tumor incidence and reduced virus replication compared to the control group. However, encapsulated CpG-ODN only moderately, but not significantly, improved HVT efficacy and reduced tumor incidence from 53% to 33%. Further investigation of cytokine gene profiles in spleen and bursa of Fabricius revealed an inverse association between interleukin (IL)-10 and IL-18 expression and protection conferred by different treatments. In addition, the results of this study raise the possibility that interferon (IFN)-β and IFN-γ induced by the treatments may exert anti-viral responses against MDV replication in the bursa of Fabricius at early stage of MDV infection in chickens.


Insulinlike effects of sodium selenate in streptozocin-induced diabetic rats.
Treatment of streptozocin (STZ)-induced diabetic rats with sodium selenate (10-15 mumol.kg-1.day-1) for 7 wk resulted in a decrease in plasma glucose, food intake, and water intake to control or near control levels. Plasma insulin was reduced in control rats given sodium selenate to the level found in the diabetic and treated diabetic group. Treatment did not affect control rats with regard to the other measurements cited. Sodium selenate enhanced weight gain in responding diabetic rats to that seen in controls; sodium selenate's actions thus resembled those of insulin. Thus selenate, like vanadium, appears to have insulinlike effects when administered in vivo.


Influence of heart rate and inhibition of autonomic tone on the QT interval.
To evaluate whether heart-rate-induced changes of the QT interval are dependent on autonomic tone, we studied 13 healthy subjects, mean age 67.5 years. The maximal uncorrected QT from leads I, II, V1 and V6 was determined during atrial pacing at 90 beats/min and 130 beats/min before and after i.v. administration of propranolol, 0.1 mg/kg, and atropine, 0.02 mg/kg. Significant reductions (p less than 0.01) of QT were induced by the paced increases in heart rate before drugs (10%), after propranolol (10%) and after the combination of atropine and propranolol (9%). Propranolol caused no significant change in the QT interval when heart rate was held constant by pacing. In contrast, atropine produced rate-independent reductions of QT interval (5%) in subjects with beta-adrenergic blockade (p less than 0.05). Bazett's formula for heart-rate correction of the QT interval (QTc) was not applicable for atrial overdrive pacing, as it gave proportionately longer QTc values at higher heart rates. These results show that heart rate is a major determinant of the duration of the QT interval and that paced changes in heart rate induce QT-interval responses that are essentially uninfluenced by autonomic tone. The rate-dependent effect of the QT interval produced by elimination of cholinergic tone suggests a direct influence of cholinergic activity on the repolarization of ventricular myocardium.


[Pygopagus Siamese twins. Surgical treatment].
A case is presented wherein a set of black female pygopagus siamese twins were successfully separated by our department in their 45th day of life. Both twins had multiple malformations: cardiopulmonary, vertebral, anorectal, genitourinary, etc. The bilateral renal absence in one of them, originated her death on the 7th postoperative day. Only nine other cases have been referred successful during the last 35 years, in a bibliographic review conducted. The associated malformations and surgical skills for treatment and separation of them, are studied: previous colostomy and effective separation at life ages, comprised between one and thirteen months.


Kinetic and in silico studies of hydroxy-based inhibitors of carbonic anhydrase isoforms I and II.
A series of hydroxy and phenolic compounds have been assayed for the inhibition of two physiologically relevant carbonic anhydrase (CA, EC 126.96.36.199) isozymes, the cytosolic human isozymes I and II. The investigated molecules showed inhibition constants in the range of 1.07-4003 and 0.09-31.5 μM at the hCA I and hCA II enzymes, respectively. In order to investigate the binding mechanisms of these inhibitors, in silico studies were also applied. Molecular docking scores of the studied compounds are compared using three different scoring algorithms, namely Glide/SP, Glide/XP and Glide/IFD. In addition, different ADME (absorption, distribution, metabolism and excretion) analysis was performed. All the examined compounds were found within the acceptable range of pharmacokinetic profiles.


In vitro comparison of the efficacy of Carisolv and conventional rotary instrument in caries removal.
The purpose of this in vitro study was to compare the efficacy of a new chemomechanical caries removal agent, Carisolv (MediTeam AB, Sävedalen, Sweden), with conventional slow-speed rotary instrument (bur). Fourteen extracted human molar teeth with deep dentine caries and no enamel coverage were selected for the study. Their laser fluorescence values were over 30 (DIAGNOdent; KaVo, Biberach, Germany). After the teeth were sectioned through the centre of the carious lesion, one half was removed with conventional drilling (bur); the other half was removed with Carisolv gel. Removal of carious dentine was continued until the lesion was deemed caries-free by visual and tactile criteria. The preparation time for each caries removal technique was also noted. The two halves of each tooth were fixed in 10% buffered-formaldehyde for 1 week. They were then decalcified, dehydrated and embedded in paraffin blocks for histological studies. After taking serial sections of 5 microm thickness, sections were mounted on glass slides, deparaffinized, dehydrated and stained with toluidine blue for observation under a light microscope. Each section was examined for the presence of bacteria. Complete removal of caries was achieved in 13 (93%) of 14 conventionally prepared teeth, and 5 (36%) of 14 chemomechanically prepared teeth (P < 0.05). Mean (+/-SD) time for caries removal was 272 s (+/-53.3) with Carisolv, and 116 s (+/-49.4) with drilling. The results of this study suggest that conventional rotary instrument (bur) was more effective than Carisolv in removal of carious tissue and also takes shorter time.


Place-Based Strategies Addressing Neighborhood Environments to Improve Perinatal and Preterm Infant Outcomes.
Preterm birth (defined as birth <37 weeks of gestation) is a significant health concern globally, with lasting implications for individuals, families, and society. In the United States, high preterm birth rates among Black and low-income populations likely result from differences in environmental exposures. Structural racism and economic disadvantage have led to unequal distribution of polluting industrial sites and roadways across society as well as differential access to health-promoting resources which contribute to preterm birth risk. Once born, preterm infants remain at risk for numerous environmentally responsive adverse health outcomes that affect growth and development throughout childhood and adulthood. In this commentary, we describe associations of neighborhood environments with pregnancy and preterm infant health outcomes and propose strategies to address harmful exposures that affect families across the lifespan.


Increased interleukin 21 (IL-21) and IL-23 are associated with increased disease activity and with radiographic status in patients with early rheumatoid arthritis.
To investigate the levels of the T helper (Th)17-related cytokines interleukin 17A (IL-17A), IL-21, and IL-23 and their association with disease activity in rheumatoid arthritis (RA). In a longitudinal sample set from patients with early RA (< 6 months; n = 40), we measured the plasma cytokine levels of IL-17A, IL-21, and IL-23 and analyzed for correlation with disease activity in 28 joints (Disease Activity Score 28-joint count; DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and total Sharp score (TSS). In a transverse sample set of patients with chronic RA (> 8 years), using paired peripheral blood mononuclear cells and synovial fluid mononuclear cells, we investigated the cellular expression of IL-17A, IL-21, and IL-23R. Patients with early-stage RA had significantly increased plasma levels of IL-21 and IL-23, but not IL-17A, compared to patients with chronic RA and healthy volunteer controls. Plasma levels of IL-21 and IL-23 after 12 months of treatment correlated with DAS28 and ESR, but not to TSS. Changes in IL-23 plasma levels from time of diagnosis to 12 months correlated with change in DAS28 and with TSS scores at 2 years. The numbers of CD4+ T cells producing IL-21 were significantly increased in the synovial fluid of patients with chronic RA, with only marginal coexpression of IL-21 and IL-17A. Our results show a significant association between plasma levels of IL-21 and IL-23 and disease activity in RA, supporting the hypothesis that IL-21 and IL-23 are important pathogenic factors of this disease.


The molecular basis of monopolin recruitment to the kinetochore.
The monopolin complex is a multifunctional molecular crosslinker, which in S. pombe binds and organises mitotic kinetochores to prevent aberrant kinetochore-microtubule interactions. In the budding yeast S. cerevisiae, whose kinetochores bind a single microtubule, the monopolin complex crosslinks and mono-orients sister kinetochores in meiosis I, enabling the biorientation and segregation of homologs. Here, we show that both the monopolin complex subunit Csm1 and its binding site on the kinetochore protein Dsn1 are broadly distributed throughout eukaryotes, suggesting a conserved role in kinetochore organisation and function. We find that budding yeast Csm1 binds two conserved motifs in Dsn1, one (termed Box 1) representing the ancestral, widely conserved monopolin binding motif and a second (termed Box 2-3) with a likely role in enforcing specificity of sister kinetochore crosslinking. We find that Box 1 and Box 2-3 bind the same conserved hydrophobic cavity on Csm1, suggesting competition or handoff between these motifs. Using structure-based mutants, we also find that both Box 1 and Box 2-3 are critical for monopolin function in meiosis. We identify two conserved serine residues in Box 2-3 that are phosphorylated in meiosis and whose mutation to aspartate stabilises Csm1-Dsn1 binding, suggesting that regulated phosphorylation of these residues may play a role in sister kinetochore crosslinking specificity. Overall, our results reveal the monopolin complex as a broadly conserved kinetochore organiser in eukaryotes, which budding yeast have co-opted to mediate sister kinetochore crosslinking through the addition of a second, regulatable monopolin binding interface.


Effects of ascorbic acid on gingival melanin pigmentation in vitro and in vivo.
Gingival melanin pigmentation may cause esthetic concerns, even if no serious medical problem is present. As an inhibitor of melanin formation, ascorbic acid is often used to treat skin melanin pigmentation. Thus, the present study investigated the effects of ascorbic acid on gingival melanin pigmentation in vitro and in vivo. The effects of ascorbic acid on melanin formation were evaluated in vitro in B16 mouse melanoma cells and three-dimensional human skin models. In addition, a clinical trial was performed to investigate the inhibitory effects of a gel containing ascorbic acid 2-glucoside (AS-G gel) on gingival melanin pigmentation. This study used a double-masked, split-mouth design on 73 subjects with symmetric gingival melanin pigmentation. AS-G gel was applied to one side of the gingiva for 12 weeks, whereas placebo gel was applied to the other side as a control. Luminance (L*)-value, which describes the lightness of gingiva, was determined by spectrophotometry to obtain an objective measure of melanin pigmentation every 4 weeks. Ascorbic acid significantly inhibited tyrosinase activity and melanin formation in B16 mouse melanoma cells (P <0.01 and P <0.05, respectively). The inhibitory effects of ascorbic acid on melanin formation were also significant in three-dimensional human skin models (P <0.01). Moreover, in the clinical trial, a significant relative change in pigmentation was seen after 4 weeks with the application of AS-G gel compared to placebo (L*-value ratio). Ascorbic acid (AS-G) has potential for the treatment of gingival melanin pigmentation.


Accumulation of gene products in the oocytes of the dragonfly Cordulia aenea. II. Induction of annulate lamellae within dense masses during diapause.
During the 3 years of nymphal development of the dragonfly Cordulia aenea, gene products slowly accumulate in the cytoplasm of the previtellogenic oocytes. Nuclear extrusions separate into nematosome and dense-mass components. The dense masses, RNP-containing globules of thightly packed fibrillar material, disperse throughout the oocyte cytoplasm. The last instar nymph experiences an obligatory diapause, after which oocyte development passes from mid to late previtellogenesis, and eventually to vitellogenesis proper in the adult. During diapause, annulate lamellae are induced within the dense masses. This process is continued during late previtellogenesis. The formation of annulate lamellae may be related to activation of some genetic message stored in the dense masses. The possibility of tubulin synthesis is discussed.


Relative and Combined Prognostic Importance of On-Treatment Mean and Visit-to-Visit Blood Pressure Variability in ONTARGET and TRANSCEND Patients.
In 28 790 patients recruited for the ONTARGET (Ongoing Treatment Alone and in Combination With Ramipril Global End Point Trials) and TRANSCEND (Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease) trials, we investigated the prognostic value for cardiovascular events (primary outcome) of (1)on-treatment visit-to-visit systolic blood pressure (SBP) variability versus mean SBP and (2) the 2 measures together. SBP variability was measured by the coefficient of variation (CV) of mean SBP to which it was unrelated. Confounders such as variable time and number of visits from which to calculate SBP-CV were avoided by using the same number of visits at identical times in all patients. The covariate-adjusted risk of the primary outcome (Cox models) increased as SBP-CV or mean on-treatment quintile SBP increased, but only for mean on-treatment SBP, the relationship achieved statistical significance: global test for trend, P=0.12 versus P<0.0001. SBP-CV showed a relationship with fatal events, but it was unrelated to the risk of myocardial infarction and stroke, which were predicted by on-treatment mean SBP. Prediction of the primary outcome improved by the combined use of both measures: global test for trend, P<0.0001; hazard ratio for combined fifth versus first quintile, 1.42 (1.20-1.68) compared with 1.13 (1.01-1.27) for SBP-CV and 1.24 (1.11-1.40) for mean SBP. Thus, in the present study, on-treatment mean SBP provided an overall better prediction of cardiovascular risk than visit-to-visit SBP-CV. Prediction improved by their combined use, which may thus offer a more precise estimate of the protective effect of treatment. URL: http//www.clinicaltrial.gov. Unique identifier: NCT00153101


Newly recognized infectious exanthems.
An exanthem is defined as any rash which is associated with an infectious agent. During the past 6 years, molecular techniques have produced a revolution in clinical dermatology including the exanthems. The infectious agents responsible for many exanthems of previously unknown causes have been uncovered. Included in this review is an update of the rapidly changing spectrum of exanthems, and 10 examples of new viral etiologies of exanthems and two new bacterial exanthems that were recognized during the past 5 years.


Neutrophilic infiltration within the airway smooth muscle in patients with COPD.
COPD is an inflammatory disorder characterised by chronic airflow limitation, but the extent to which airway inflammation is related to functional abnormalities is still uncertain. The interaction between inflammatory cells and airway smooth muscle may have a crucial role. To investigate the microlocalisation of inflammatory cells within the airway smooth muscle in COPD, surgical specimens obtained from 26 subjects undergoing thoracotomy (eight smokers with COPD, 10 smokers with normal lung function, and eight non-smoking controls) were examined. Immunohistochemical analysis was used to quantify the number of neutrophils, macrophages, mast cells, CD4+ and CD8+ cells localised within the smooth muscle of peripheral airways. Smokers with COPD had an increased number of neutrophils and CD8+ cells in the airway smooth muscle compared with non-smokers. Smokers with normal lung function also had a neutrophilic infiltration in the airway smooth muscle, but to a lesser extent. When all the subjects were analysed as one group, neutrophilic infiltration was inversely related to forced expiratory volume in 1 second (% predicted). Microlocalisation of neutrophils and CD8+ cells in the airway smooth muscle in smokers with COPD suggests a possible role for these cells in the pathogenesis of smoking induced airflow limitation.