Structural basis for the extended CAP-Gly domains of p150(glued) binding to microtubules and the implication for tubulin dynamics.
p150(glued) belongs to a group of proteins accumulating at microtubule plus ends (+TIPs). It plays a key role in initiating retrograde transport by recruiting and tethering endosomes and dynein to microtubules. p150(glued) contains an N-terminal microtubule-binding cytoskeleton-associated protein glycine-rich (CAP-Gly) domain that accelerates tubulin polymerization. Although this copolymerization is well-studied using light microscopic techniques, structural consequences of this interaction are elusive. Here, using electron-microscopic and spectroscopic approaches, we provide a detailed structural view of p150(glued) CAP-Gly binding to microtubules and tubulin. Cryo-EM 3D reconstructions of p150(glued)-CAP-Gly complexed with microtubules revealed the recognition of the microtubule surface, including tubulin C-terminal tails by CAP-Gly. These binding surfaces differ from other retrograde initiation proteins like EB1 or dynein, which could facilitate the simultaneous attachment of all accessory components. Furthermore, the CAP-Gly domain, with its basic extensions, facilitates lateral and longitudinal interactions of tubulin molecules by covering the tubulin acidic tails. This shielding effect of CAP-Gly and its basic extensions may provide a molecular basis of the roles of p150(glued) in microtubule dynamics.


Overcoming barriers to colorectal cancer screening tests.
The frequency of colorectal cancer screening tests in Israel is poor, and is much lower than in the United States. This low rate has been attributed to health system failures as well as to barriers on the part of both physicians and patients. To further identify particular health system failures, physician and patient-based barriers, and the effectiveness of public lectures in improving the frequency of performance of CRC screening tests. Public lectures on colorectal cancer prevention were held. A gastroenterologist presented the lectures, which were followed immediately by a questionnaire and 4 months later by a telephone call. Of the 80% of attendees who had never undergone any CRC screening test, only 18% reported family physician recommendations for such tests. Eighty-four percent reported willingness to undergo fecal occult blood testing and 52% to undergo colonoscopy; 62% replied that they should undergo some CRC screening test and 90% believed that these tests save lives. Of the women, 47% expressed preference for a female gastroenterologist. Follow-up showed that 34% proceeded to undergo some CRC screening test: 60% chose colonoscopy and 40% FOBT. Public lectures are effective in improving compliance with the CRC screening test. Physicians should recommend these tests to appropriate individuals. Same-gender gastroenterologists should be considered for individuals uneasy about someone from the opposite gender performing the test. Assessing the various health-promotion efforts can direct us in implementing finite resources to greatest effect. Local cancer institutes and societies may be supportive in disseminating screening information in this way.


Reconstruction of the Amazon Basin effective moisture availability over the past 14,000 years.
Quantifying the moisture history of the Amazon Basin is essential for understanding the cause of rain forest diversity and its potential as a methane source. We reconstructed the Amazon River outflow history for the past 14,000 years to provide a moisture budget for the river drainage basin. The oxygen isotopic composition of planktonic foraminifera recovered from a marine sediment core in a region of Amazon River discharge shows that the Amazon Basin was extremely dry during the Younger Dryas, with the discharge reduced by at least 40% as compared with that of today. After the Younger Dryas, a meltwater-driven discharge event was followed by a steady increase in the Amazon Basin effective moisture throughout the Holocene.


Calcium/vitamin D supplementation and coronary artery calcification in the Women's Health Initiative.
Coronary artery calcified plaque is a marker for atheromatous plaque burden and predicts future risk of cardiovascular events. The relationship between calcium plus vitamin D (calcium/D) supplementation and coronary artery calcium (CAC) has not been previously assessed in a randomized trial setting. We compared CAC scores after trial completion between women randomized to calcium/vitamin D supplementation and women randomized to placebo. In an ancillary substudy of women randomized to calcium carbonate (1,000 mg of elemental calcium daily) plus vitamin D3 (400 IU daily) or placebo, nested within the Women's Health Initiative trial of estrogen among women who underwent hysterectomy, we measured CAC with cardiac CT in 754 women aged 50 to 59 years at randomization. Imaging for CAC was performed at 28 of 40 centers after a mean of 7 years of treatment, and scans were read centrally. CAC scores were measured by a central reading center with masking to randomization assignments. Posttrial CAC measurements were similar in women randomized to calcium/D supplementation and those receiving placebo. The mean CAC score was 91.6 for women receiving calcium/D and 100.5 for women receiving placebo (rank test P value = 0.74). After adjustment for coronary risk factors, multivariate odds ratios for increasing CAC score cutpoints (CAC >0, > or =10, and > or =100) for calcium/D versus placebo were 0.92 (95% CI, 0.64-1.34), 1.29 (0.88-1.87), and 0.90 (0.56-1.44), respectively. Corresponding odds ratios among women with a 50% or higher adherence to study pills and for higher levels of CAC (>300) were similar. Treatment with moderate doses of calcium plus vitamin D3 did not seem to alter coronary artery calcified plaque burden among postmenopausal women. Whether higher or lower doses would affect this outcome remains uncertain.


Epizootiology of viral hemorrhagic septicemia virus in Pacific herring from the spawn-on-kelp fishery in Prince William Sound, Alaska, USA.
Both the prevalence and tissue titer of viral hemorrhagic septicemia virus (VHSV) increased in Pacific herring Clupea pallasi following their introduction into net pens (pounds) used in the closed pound spawn-on-kelp (SOK) fishery in Prince William Sound, Alaska. VHSV was also found in water samples from inside and outside the SOK pounds after herring had been confined for several days; however, water samples taken near wild free-ranging, spawning herring either failed to test positive or tested weakly positive for virus. Little or no virus was found in tissue samples from free-ranging, spawning herring captured from the vicinity of the pounds, nor did the prevalence of VHSV increase following spawning as it did in impounded herring. The data indicated that increased prevalences of VHSV were correlated with confinement of herring for the closed pound SOK fishery and that infection was spread within the pounds through waterborne exposure to virus particles originating from impounded fish. In addition, pounds containing predominantly young fish had higher prevalences of VHSV, suggesting that older fish may be partially immune, perhaps as a result of previous infection with the virus. Operation of SOK pounds during spawning seasons in which young herring predominate may amplify the disease and possibly exacerbate the population fluctuations observed in wild herring stocks.


Bayesian sample sizes for exploratory clinical trials comparing multiple experimental treatments with a control.
In this paper, a Bayesian approach is developed for simultaneously comparing multiple experimental treatments with a common control treatment in an exploratory clinical trial. The sample size is set to ensure that, at the end of the study, there will be at least one treatment for which the investigators have a strong belief that it is better than control, or else they have a strong belief that none of the experimental treatments are substantially better than control. This criterion bears a direct relationship with conventional frequentist power requirements, while allowing prior opinion to feature in the analysis with a consequent reduction in sample size. If it is concluded that at least one of the experimental treatments shows promise, then it is envisaged that one or more of these promising treatments will be developed further in a definitive phase III trial. The approach is developed in the context of normally distributed responses sharing a common standard deviation regardless of treatment. To begin with, the standard deviation will be assumed known when the sample size is calculated. The final analysis will not rely upon this assumption, although the intended properties of the design may not be achieved if the anticipated standard deviation turns out to be inappropriate. Methods that formally allow for uncertainty about the standard deviation, expressed in the form of a Bayesian prior, are then explored. Illustrations of the sample sizes computed from the new method are presented, and comparisons are made with frequentist methods devised for the same situation.


BREMSO: a simple score to predict early the natural course of multiple sclerosis.
Early prediction of long-term disease evolution is a major challenge in the management of multiple sclerosis (MS). Our aim was to predict the natural course of MS using the Bayesian Risk Estimate for MS at Onset (BREMSO), which gives an individual risk score calculated from demographic and clinical variables collected at disease onset. An observational study was carried out collecting data from MS patients included in MSBase, an international registry. Disease impact was studied using the Multiple Sclerosis Severity Score (MSSS) and time to secondary progression (SP). To evaluate the natural history of the disease, patients were analysed only if they did not receive immune therapies or only up to the time of starting these therapies. Data from 14 211 patients were analysed. The median BREMSO score was significantly higher in the subgroups of patients whose disease had a major clinical impact (MSSS≥ third quartile vs. ≤ first quartile, P < 0.00001) and who reached SP (P < 0.00001). The BREMSO showed good specificity (79%) as a tool for predicting the clinical impact of MS. BREMSO is a simple tool which can be used in the early stages of MS to predict its evolution, supporting therapeutic decisions in an observational setting.


Association of Variants Near the Bradykinin Receptor B2 Gene With Angioedema in Patients Taking ACE Inhibitors.
Angioedema is a rare but potentially life-threatening adverse reaction associated with angiotensin-converting enzyme (ACE) inhibitors. Identification of potential genetic factors related to this adverse event may help identify at-risk patients. The aim of this study was to identify genetic factors associated with ACE inhibitor-associated angioedema. A genomewide association study involving patients of European descent, all taking ACE inhibitors, was conducted in a discovery cohort (Copenhagen Hospital Biobank), and associations were confirmed in a replication cohort (Swedegene). Cases were defined as subjects with angioedema events and filled prescriptions for ACE inhibitors ≤180 days before the events. Control subjects were defined as those with continuous treatment with ACE inhibitors without any history of angioedema. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed for angioedema risk using logistic mixed model regression analysis. Summary statistics from the discovery and replication cohorts were analyzed using a fixed-effects meta-analysis model. The discovery cohort consisted of 462 cases and 53,391 ACE inhibitor-treated control subjects. The replication cohort consisted of 142 cases and 1,345 ACE inhibitor-treated control subjects. In the discovery cohort, 1 locus, residing at chromosome 14q32.2, was identified that associated with angioedema at the genomewide significance level of P <5 × 10-8. The lead variant at this locus, rs34485356, is an intergenic variant located 60 kb upstream of BDKRB2 (OR: 1.62; 95% CI: 1.38 to 1.90; P = 4.3 × 10-9). This variant was validated in our replication cohort with a similar direction and effect size (OR: 1.60; 95% CI: 1.13 to 2.25; P = 7.2 × 10-3). We found that carriers of the risk allele had significantly lower systolic (-0.46 mm Hg per T allele; 95% CI: -0.83 to -0.10; P = 0.013) and diastolic (-0.26 mm Hg per T allele; 95% CI: -0.46 to -0.05; P = 0.013) blood pressure. In this genomewide association study involving individuals treated with ACE inhibitors, we found that common variants located in close proximity to the bradykinin receptor B2 gene were associated with increased risk for ACE inhibitor-related angioedema.


Trends in Stroke Incidence in High-Income Countries in the 21st Century: Population-Based Study and Systematic Review.
Background and Purpose- Population-based studies provide the most reliable data on stroke incidence. A previous systematic review of population-based studies suggested that stroke incidence in high-income countries decreased by 42% between the 1970s and early 2000s. However, it is uncertain whether this trend of steady decline has been maintained in more recent periods. Methods- Data from OCSP (Oxfordshire Community Stroke Project; 1981-1986) and OXVASC (Oxford Vascular Study; 2002-2017) along with other published population-based stroke incidence studies that reported temporal trends of stroke incidence since 1990 in high-income countries were included. Age-standardized relative incidence rate ratios were calculated for each study and then pooled with inverse-variance weighted random-effects meta-analysis. Projection estimates were calculated for the number of incident stroke patients in the United Kingdom from year 2015 to 2045. Results- In Oxfordshire, stroke incidence fell by 32% from OCSP to OXVASC, with a similar trend before or after year 2000. With the projected aging population, if the age-specific stroke incidence continued to decrease at its current rate (6% every 5 years), there would still be a 13% increase of the number of first-ever strokes in the United Kingdom up to year 2045. Incorporating the Oxfordshire data with other 12 population-based studies, stroke incidence declined steadily between the 1990s and 2010s within each study, resulting in a 28% decline over an average period of 16.5 years (pooled incidence rate ratio, 0.72 [95% CI, 0.66-0.79]; P<0.0001). The trend was the same for men (0.69 [95% CI, 0.61-0.77]; P<0.0001) and women (0.66 [95% CI, 0.59-0.74]; P<0.0001) and remained consistent after year 2010 in OXVASC. Proportion of disabling or fatal stroke also decreased over time (early versus later period, 53.6% versus 46.1%; P=0.02). Conclusions- Stroke incidence is continuing to decline with steady rate in Oxfordshire and in other high-income settings. However, the absolute number of strokes occurring is not falling.


'I am not only beneficial to the community but to the entire country, I am trained as a researcher now': Developing health research skills in low-income countries.
ABSTRACTPartnerships between Higher Education Institutions in the global South and North have potential for building capacity in public health research in low-resource countries. We present experiences of partners involved in a North-South-South partnership between universities in Norway, the Democratic Republic of Congo (DRC) and South Africa. The partnership aimed to establish a postgraduate programme in nutritional epidemiology at the University of Kinshasa, DRC, and develop a cadre of researchers and academic leaders to provide locally generated health research to inform policy. In-depth interviews were conducted with 31 purposively selected stakeholders, facilitators, and students from partner institutions. All participants expressed positive experiences, indicating that the partnership provided excellent opportunities to network, enriched participants' learning and enhanced academic growth, with benefits at individual, institutional, and country levels. Participants suggested that maintaining a common vision was important for success, facilitated by joint planning of project activities, focussing strongly on building research and academic capacity at Kinshasa School of Public Health and addressing local nutrition problems. Important challenges highlighted for future partnerships included failures of co-facilitation and co-supervision, poor research dissemination and policy impact, and concerns about sustainability. Notwithstanding, North-South-South partnerships can address skills shortages in public health research with significant benefits to all partner institutions.


Imaging Retinal Vascular Changes in the Mouse Model of Oxygen-Induced Retinopathy.
Oxygen-induced retinopathy in the mouse is the standard experimental model of retinopathy of prematurity. Assessment of the pathology involves in vitro analysis of retinal vaso-obliteration and retinal neovascularization. The authors studied the clinical features of oxygen-induced retinopathy in vivo using topical endoscopy fundus imaging (TEFI), in comparison to standard investigations, and evaluated a system for grading these features. Postnatal day (P)7 mice were exposed to 75% oxygen for five days to induce retinopathy or maintained in room air as controls. Retinal vascular competence was graded against standard photographs by three masked graders. Retinal photographs were obtained at predetermined ages using TEFI. Postmortem, retinal vaso-obliteration was measured in whole mounts with labeled vasculature, and retinal neovascularization was quantified in hematoxylin- and eosin-stained ocular cross sections. Fundus photography by TEFI was possible from P15, when retinal vascular incompetence, including dilatation and tortuosity, was significant in mice with oxygen-induced retinopathy in comparison to controls. Vascular incompetence peaked in severity at P17 and persisted through P25. Comparison with in vitro analyses indicated that vascular changes were most severe after retinal avascularity had begun to decrease in area, and coincident with the maximum of retinal neovascularization. A weighted Fleiss-Cohen kappa indicated good intra- and interobserver agreement for a 5-point grading system. Topical endoscopy fundus imaging demonstrates retinal vascular incompetence in mice with oxygen-induced retinopathy. The technique complements standard postmortem analysis for following the course of the model. Topical endoscopy fundus imaging has application in the evaluation of novel biologic drugs for retinopathy of prematurity.


Electromagnetic analysis for optical coherence tomography based through silicon vias metrology.
This paper reports on progress in the analysis of time-domain optical coherence tomography (OCT) applied to the dimensional metrology of through-silicon vias (TSVs), which are vertical interconnect accesses in silicon, enabling three-dimensional (3D) integration in microelectronics, and estimates the deviations from earlier, simpler models. The considered TSV structures are 1D trenches and circular holes etched into silicon with a large aspect ratio. As a prerequisite for a realistic modeling, we work with spectra obtained from reference interferograms measured at a planar substrate, which fully includes the dispersion of the OCT apparatus. Applying a rigorous modal approach, we estimate the differences to a pure ray tracing technique. Accelerating our computations, we focus on the relevant fundamental modes and apply a Fabry-Perot model as an efficient approximation. Exploiting our results, we construct and present an iterative procedure based on the minimization of a merit function, which concludes TSV heights reliably, accurately, and rapidly from measured interferograms.


Prophylaxis of radiation-induced nausea and vomiting using 5-hydroxytryptamine-3 serotonin receptor antagonists: a systematic review of randomized trials.
To systematically review the effectiveness and safety of 5-hydroxytryptamine-3 receptor antagonists (5-HT3 RAs) compared with other antiemetic medication or placebo for prophylaxis of radiation-induced nausea and vomiting. We searched the following electronic databases: MEDLINE, Embase, the Cochrane Central Register of Controlled Clinical Trials, and Web of Science. We also hand-searched reference lists of included studies. Randomized, controlled trials that compared a 5-HT3 RA with another antiemetic medication or placebo for preventing radiation-induced nausea and vomiting were included. We excluded studies recruiting patients receiving concomitant chemotherapy. When appropriate, meta-analysis was conducted using Review Manager (v5) software. Relative risks were calculated using inverse variance as the statistical method under a random-effects model. We assessed the quality of evidence by outcome using the Grading of Recommendations Assessment, Development, and Evaluation approach. Eligibility screening of 47 articles resulted in 9 included in the review. The overall methodologic quality was moderate. Meta-analysis of 5-HT3 RAs vs. placebo showed significant benefit for 5-HT3 RAs (relative risk [RR] 0.70; 95% confidence interval [CI] 0.57-0.86 for emesis; RR 0.84, 95% CI 0.73-0.96 for nausea). Meta-analysis comparing 5-HT3 RAs vs. metoclopramide showed a significant benefit of the 5-HT3 RAs for emetic control (RR 0.27, 95% CI 0.15-0.47). 5-Hydroxytryptamine-3 RAs are superior to placebo and other antiemetics for prevention of emesis, but little benefit was identified for nausea prevention. 5-Hydroxytryptamine-3 RAs are suggested for prevention of emesis. Limited evidence was found regarding delayed emesis, adverse events, quality of life, or need for rescue medication. Future randomized, controlled trials should evaluate different 5-HT3 antiemetics and new agents with novel mechanisms of action such at the NK(1) receptor antagonists to determine the most effective drug. Delayed nausea and vomiting should be a focus of future study, perhaps concentrating on the palliative cancer population.


Molecular mechanisms of erythrophagocytosis. Characterization of the senescent erythrocytes that are phagocytized by macrophages.
We have recently developed a flow cytometric assay for the quantitation of erythrophagocytosis, using PKH 26-labeled erythrocytes as the target cells. Using this assay we have shown that there is extensive phagocytosis of desialylated erythrocytes. Furthermore, we have demonstrated that it is the densest population of erythrocytes obtained on a self-forming gradient of Percoll that shows the greatest susceptibility to phagocytosis. We designate this population of erythrocytes as fraction X; it is even denser than the fraction 5 found previously. This population of erythrocytes corresponds to zone X previously seen in the dot-plot of the flow cytometric analyses of human erythrocytes. Further scrutiny of this fraction indicates that a) it shows the greatest reactivity with annexin V, which is specific for the detection of phosphatidylserine (PS) exposed on the outer leaflet of the erythrocyte membrane, b) it is the most susceptible to erythrophagocytosis by resident murine peritoneal macrophages, and c) this erythrophagocytosis of PKH 26-labeled erythrocytes can be inhibited by annexin V and by liposomes containing PS. Scanning electron microscopy of fraction X shows two populations of erythrocytes: (A) spheroechinocytes with filipodes and (B) echinocytes without filipods. After a 2-h period of phagocytosis, the cells remaining in fraction X show a decrease in population A, commensurate with a decrease in reactivity with FITC-labeled annexin V from 65.5 to 24%.


High expression of the chemokine receptor CCR3 in human blood basophils. Role in activation by eotaxin, MCP-4, and other chemokines.
Eosinophil leukocytes express high numbers of the chemokine receptor CCR3 which binds eotaxin, monocyte chemotactic protein (MCP)-4, and some other CC chemokines. In this paper we show that CCR3 is also highly expressed on human blood basophils, as indicated by Northern blotting and flow cytometry, and mediates mainly chemotaxis. Eotaxin and MCP-4 elicited basophil migration in vitro with similar efficacy as regulated upon activation normal T cells expressed and secreted (RANTES) and MCP-3. They also induced the release of histamine and leukotrienes in IL-3-primed basophils, but their efficacy was lower than that of MCP-1 and MCP-3, which were the most potent stimuli of exocytosis. Pretreatment of the basophils with a CCR3-blocking antibody abrogated the migration induced by eotaxin, RANTES, and by low to optimal concentrations of MCP-4, but decreased only minimally the response to MCP-3. The CCR3-blocking antibody also affected exocytosis: it abrogated histamine and leukotriene release induced by eotaxin, and partially inhibited the response to RANTES and MCP-4. In contrast, the antibody did not affect the responses induced by MCP-1, MCP-3, and macrophage inflammatory protein-1alpha, which may depend on CCR1 and CCR2, two additional receptors detected by Northern blotting with basophil RNA. This study demonstrates that CCR3 is the major receptor for eotaxin, RANTES, and MCP-4 in human basophils, and suggests that basophils and eosinophils, which are the characteristic effector cells of allergic inflammation, depend largely on CCR3 for migration towards different chemokines into inflamed tissues.


[The distribution of azidothymidine palmitate galactosylated liposomes in mice].
Hepatocytes act as a reservoir for the human immunodeficiency viruses (HIV) and are responsible for its continual dissemination in the peripheral circulation. For this reason, galactosylated liposomes (GalLs) containing home-made [(2-lactoylamido) ethylamino] formic acid cholesterol ester (CH-ED-LA ) as a homing device were prepared to study the biodistribution of the liposomal azidothymidine palmitate (AZTP) in mice. Four liposomes of the present study, soybean phosphatidylcholine (SPC)/cholesterol(CH)/CH-ED-LA (80 : 10: 10, 10% GalLs), SPC/CH/CH-ED-LA (80 : 15:5, 5% GalLs), SPC/CH/CH-ED-LA (80 : 17 : 3, 3% GallLs) and SPC/CH (80 : 20, CL) incorporated AZTP were prepared by ethanol-injection method followed by ultrasonic-dispersion and characterized by entrapped efficiency which was more than 95% and their mean diameter was less than 100 nm, respectively. The effects of the addition upon the liposomal membrane potential and AZTP content were also unseen. The distributions of AZT in various organs were determinated by reversed phase HPLC after intravenous administration via tail vein in mice, at a dose of 15.85 mg x kg(-1) AZT solution and 30 mg x kg(-1) AZTP (at equimolar doses) in CL or GalLs, respectively. Compared to AZT control solution, the half-life of AZT in each group of AZTP liposomes increased significantly (P < 0.05). In addition, the concentration-averaged overall drug targeting efficiency (r(e)) of the liver presented by AZTP CL and GalLs containing 3% , 5% , 10% (mol/mol) CH-ED-LA increased 1.32 and 1.48, 2.13, 1.50 times as that of AZT solution, respectively. These results indicate that liposomes containing such novel galactosylated lipid, CH-ED-LA, had remarkably improved the targetability of AZTP to liver, and are anticipated to be a potential candidate for liver targeting delivery carriers.


The effect of health information technology on quality in U.S. hospitals.
Health information technology (IT), such as computerized physician order entry and electronic health records, has potential to improve the quality of health care. But the returns from widespread adoption of such technologies remain uncertain. We measured changes in the quality of care following adoption of electronic health records among a national sample of U.S. hospitals from 2004 to 2007. The use of computerized physician order entry and electronic health records resulted in significant improvements in two quality measures, with larger effects in academic than nonacademic hospitals. We conclude that achieving substantive benefits from national implementation of health IT may be a lengthy process. Policies to improve health IT's efficacy in nonacademic hospitals might be more beneficial than adoption subsidies.


Orientation-dependent biases in length judgments of isolated stimuli.
Vertical line segments tend to be perceived as longer than horizontal ones of the same length, but this may in part be due to configuration effects. To minimize such effects, we used isolated line segments in a two-interval, forced choice paradigm, not limiting ourselves to horizontal and vertical. We fitted psychometric curves using a Bayesian method that assumes that, for a given subject, the lapse rate is the same across all conditions. The closer a line segment's orientation was to vertical, the longer it was perceived to be. Moreover, subjects tended to report the standard line (in the second interval) as longer. The data were well described by a model that contains both an orientation-dependent and an interval-dependent multiplicative bias. Using this model, we estimated that a vertical line was on average perceived as 9.2% ± 2.1% longer than a horizontal line, and a second-interval line was on average perceived as 2.4% ± 0.9% longer than a first-interval line. Moving from a descriptive to an explanatory model, we hypothesized that anisotropy in the polar angle of lines in three dimensions underlies the horizontal-vertical illusion, specifically, that line segments more often have a polar angle of 90° (corresponding to the ground plane) than any other polar angle. This model qualitatively accounts not only for the empirical relationship between projected length and projected orientation that predicts the horizontal-vertical illusion, but also for the empirical distribution of projected orientation in photographs of natural scenes and for paradoxical results reported earlier for slanted surfaces.


Improved axonal regeneration of transected spinal cord mediated by multichannel collagen conduits functionalized with neurotrophin-3 gene.
Functionalized biomaterial scaffolds targeted at improving axonal regeneration by enhancing guided axonal growth provide a promising approach for the repair of spinal cord injury. Collagen neural conduits provide structural guidance for neural tissue regeneration, and in this study it is shown that these conduits can also act as a reservoir for sustained gene delivery. Either a G-luciferase marker gene or a neurotrophin-3-encoding gene, complexed to a non-viral, cyclized, PEGylated transfection vector, was loaded within a multichannel collagen conduit. The complexed genes were then released in a controlled fashion using a dual release system both in vitro and in vivo. For evaluation of their biological performance, the loaded conduits were implanted into the completely transected rat thoracic spinal cord (T8-T10). Aligned axon regeneration through the channels of conduits was observed one month post-surgery. The conduits delivering neurotrophin-3 polyplexes resulted in significantly increased neurotrophin-3 levels in the surrounding tissue and a statistically higher number of regenerated axons versus the control conduits (P<0.05). This study suggests that collagen neural conduits delivering a highly effective non-viral therapeutic gene may hold promise for repair of the injured spinal cord.


A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone.
Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide (NO) have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which may reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways, (ii) the concentrations in the tracheo-bronchial lining fluid, (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, the model illuminates the discrepancies between observed and theoretically predicted blood-breath ratios of acetone during resting conditions, i.e., in steady state. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases and thus is expected to have general relevance for a wider range of blood-borne inert gases. The chief intention of the present modeling study is to provide mechanistic relationships for further investigating the exhalation kinetics of acetone and other water-soluble species. This quantitative approach is a first step towards new guidelines for breath gas analyses of volatile organic compounds, similar to those for nitric oxide.


Paradoxical role of DNA methylation in activation of FoxA2 gene expression during endoderm development.
The transcription factor FoxA2 is a master regulator of endoderm development and pancreatic beta cell gene expression. To elucidate the mechanisms underlying the activation of the FoxA2 gene during differentiation, we have compared the epigenetic status of undifferentiated human embryonic stem cells (hESCs), hESC-derived early endoderm stage cells (CXCR4+ cells), and pancreatic islet cells. Unexpectedly, a CpG island in the promoter region of the FoxA2 gene displayed paradoxically high levels of DNA methylation in expressing tissues (CXCR4+, islets) and low levels in nonexpressing tissues. This CpG island region was found to repress reporter gene expression and bind the Polycomb group protein SUZ12 and the DNA methyltransferase (DNMT)3b preferentially in undifferentiated hESCs as compared with CXCR4+ or islets cells. Consistent with this, activation of FoxA2 gene expression, but not CXCR4 or SOX17, was strongly inhibited by 5-aza-2'-deoxycytidine and by knockdown of DNMT3b. We hypothesize that in nonexpressing tissues, the lack of DNA methylation allows the binding of DNA methyltransferases and repressing proteins, such as Polycomb group proteins; upon differentiation, DNMT activation leads to CpG island methylation, causing loss of repressor protein binding. These results suggest a novel and unexpected role for DNA methylation in the activation of FoxA2 gene expression during differentiation.


The immunobiology and pathophysiology of primary biliary cirrhosis.
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony-stimulating factor-stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.


Prognostic factors for long-term outcome of chronic slipped capital femoral epiphysis treated with fixation in situ.
Predictive factors for long-term outcome after in situ fixation for chronic slipped capital femoral epiphysis (SCFE) have so far not been systematically analysed. The aims of this study were to define predictors for long-term outcome and to assess the association between initial grade of slipping and post-slip deformities. We studied 51 patients (60 hips) with chronic SCFE treated with in situ fixation. There were 31 males and 20 females with a mean age of 12.9 years. The mean follow-up was 39.0 years (21.1 to 56.8). Post-slip deformity was defined as abnormal alpha (a) angles in anteroposterior (AP) and lateral radiographs; AP angle of 74° and lateral angle of 63° were used as cutoffs between normal and abnormal α-angles. Harris hip score (HHS) less than 85 points was classified as a poor clinical outcome and osteoarthritis was a poor radiographic outcome. The mean slip angle was 31.7° (12° to 77°). The mean AP α-angle was 67.4° (36° to 111°) and the mean lateral α-angle was 57.1° (22° to 104°). Post-slip deformities developed in almost one-third of hips with a mild degree of slipping and in about half the hips with more pronounced degrees of slipping. The long-term outcome was good in 40 hips (67%) and poor in 20 hips. A small AP α-angle was the only independent prognostic factor for a good combined clinical and radiographic outcome. Post-slip deformity, defined as an abnormally high AP α-angle, is the most important prognostic factor for poor long-term clinical and radiographic outcome in chronic SCFE treated with in situ fixation.


Comorbid type 2 diabetes mellitus and hypertension exacerbates cognitive decline: evidence from a longitudinal study.
diabetes and hypertension are two highly prevalent diseases in the old population. They are highly related such that comorbidity is common. to examine (i) the independent impact of the respective diseases on cognitive decline in very old age and (ii) the interactive impact of the two diseases on cognitive decline. 258 individuals (mean age = 83 years), all non-demented at baseline. Of these, 128 individuals (non-cases) were free from diabetes and hypertension, 92 individuals had a diagnosis of hypertension, 16 had a type 2 diabetes mellitus diagnosis without hypertension, and 22 had comorbid diabetes and hypertension. a population-based longitudinal study of ageing (The OCTO-Twin Study), including four measurement occasions 2 years apart. The Mini-Mental State Examination was used to measure general cognitive function. Data were analysed using SAS Proc Mixed multilevel modelling. longitudinal trajectories indicated a steeper decline in cognitive function related to diabetes but not related to hypertension. However, the results indicated greatest cognitive decline among persons with comorbid diabetes and hypertension. it is concluded that comorbidity of diabetes and hypertension produce a pronounced cognitive decline. This finding emphasises the importance of prevention and treatment of those highly prevalent diseases in the old population.


Maternal near-miss and death and their association with caesarean section complications: a cross-sectional study at a university hospital and a regional hospital in Tanzania.
The maternal near-miss (MNM) concept has been developed to assess life-threatening conditions during pregnancy, childhood, and puerperium. In recent years, caesarean section (CS) rates have increased rapidly in many low- and middle-income countries, a trend which might have serious effects on maternal health. Our aim was to describe the occurrence and panorama of maternal near-miss and death in two low-resource settings, and explore their association with CS complications. We performed a cross-sectional study, including all women who fulfilled the WHO criteria for MNM or death between February and June 2012 at a university hospital and a regional hospital in Dar es Salaam, Tanzania. Cases were assessed individually to determine their association with CS. Main outcome measures included MNM ratio; maternal mortality ratio; proportion of MNM and death associated with CS complications; and the risk for such outcomes per 1,000 operations. The risk ratio of life-threatening CS complications at the university hospital compared to the regional hospital was calculated. We identified 467 MNM events and 77 maternal deaths. The MNM ratio was 36 per 1,000 live births (95% CI 33-39) and the maternal mortality ratio was 587 per 100,000 live births (95% CI 460-730). Major causes were eclampsia and postpartum haemorrhage, but we also detected nine MNM events and five deaths from iatrogenic complications. CS complications accounted for 7.9% (95% CI 5.6-11) of the MNM events and 13% (95% CI 6.4-23) of the maternal deaths. The risk of experiencing a life-threatening CS complication was three times higher at the regional hospital (22/1,000 operations, 95% CI 12-37) compared to the university hospital (7.0/1,000 operations, 95% CI 3.8-12) (risk ratio 3.2, 95% CI 1.5-6.6). The occurrence of MNM and death at the two hospitals was high, and many cases were associated with CS complications. The maternal risks of CS in low-resource settings must not be overlooked, and measures should be taken to avoid unnecessary CSs. More comprehensive training of staff, improved postoperative surveillance, and a more even distribution of resources within the health care system might reduce the risks of CS.


Coalescence driven self-organization of growing nanodroplets around a microcap.
The coalescence between growing droplets is important for the surface coverage and spatial arrangements of droplets on surfaces. In this work, total internal reflection fluorescence (TIRF) microscopy is utilized to in situ investigate the formation of nanodroplets around the rim of a polymer microcap, with sub-micron spatial and millisecond temporal resolution. We observe that the coalescence among droplets occurs frequently during their growth by solvent exchange. Our experimental results show that the position of the droplet from two merged droplets is related to the size of the parent droplets. The position of the coalesced droplet and the ratio of parent droplet sizes obey a scaling law, reflecting a coalescence preference based on the size inequality. As a result of droplet coalescence, the angles between the centroids of two neighbouring droplets increase with time, obeying a nearly symmetrical arrangement of droplets at various time intervals. The evolution of the position and number from coalescence of growing droplets is modelled. The mechanism for coalescence driven self-organization of growing droplets is general, applicable to microcaps of different sizes and droplets of different liquids. The understanding from this work may be valuable for positioning nanodroplets by nucleation and growth without using templates.


Complex regional pain syndrome: a vitamin K dependent entity?
Complex regional pain syndrome (CRPS) is the complication of some injuries, such as a fracture, which affects the distal end of the injured extremity characterized by pain, allodynia, hyperalgesia, edema, abnormal vasomotor and sudomotor activity, movement disorders, joint stiffness, regional osteoporosis, and dystrophic changes in soft tissue. Exact pathogenic mechanism of CRPS is still unclear. Suggested pathogenic mechanisms of CRPS are evaluated in four major groups consist of classic inflammation, hypoxic changes and chronic ischemia, neurogenic inflammation and sympathetic dysregulation. All of these suggested pathogenic mechanisms produced by inflammatory cytokines mediated by nuclear factor kappaB. Vitamin K is a family of structurally similar, fat-soluble, 2-methyl-1,4-naphthoquinones. Vitamin K exerts a powerful influence on bone formation, especially in osteoporosis. Fat in bone stores some vitamin K. Gamma-carboxylation of the glutamic acid in osteocalcin is vitamin K dependent. Osteocalcin plays a role in calcium uptake and bone mineralization. Osteocalcin, the most abundant non-collagenous protein in bone, is produced by osteoblasts during bone matrix formation. Because osteocalcin is not carboxylated in case of vitamin K deficiency at the distal site of fracture or injury, it cannot bind to hydroxyapatite causing osteoporosis. Fracture starts a local inflammatory process in the fracture site and adjacent tissues as seen in CRPS. Vitamin K was shown to suppress the inflammatory cytokines and NF-kappaB and prevent oxidative, hypoxic, ischemic injury (which have key role in both initiation and progression of CRPS) to oligodendrocytes and neurons. We hypothesized that vitamin K has a key role and modulatory effect in CRPS pathogenesis. Vitamin K deficiency at the distal site of fracture occurs because of diminished and slowed circulation, local immobilization after extremity fracture or injury and use of vitamin K store at the distal site of the injured extremity and in the circulation for fracture healing and bone remodelling. In case of vitamin K deficiency at the distal site of fracture, classic inflammation starts with fracture at the distal tissues could not be restricted and classic inflammation, hypoxic changes, chronic ischemia, neurogenic inflammation, sympathetic dysregulation, which are the pathogenic mechanisms of CRPS, and patchy osteoporosis which occur due to high level of under-carboxylated osteocalcin could not be prevented. Briefly vitamin K level decreases in the distal site of the injured extremity consequently resulting in patchy osteoporosis due to high level of under-carboxylated osteocalcin and unrestricted inflammation which are the cause for both initiation and progression of CRPS.


Making sense of a new transport system: an ethnographic study of the Cambridgeshire Guided Busway.
An increase in public transport use has the potential to contribute to improving population health, and there is growing interest in innovative public transport systems. Yet how new public transport infrastructure is experienced and integrated (or not) into daily practice is little understood. We investigated how the Cambridgeshire Guided Busway, UK, was used and experienced in the weeks following its opening, using the method of participant observation (travelling on the busway and observing and talking to passengers) and drawing on Normalization Process Theory to interpret our data. Using excerpts of field notes to support our interpretations, we describe how the ease with which the new transport system could be integrated into existing daily routines was important in determining whether individuals would continue to use it. It emerged that there were two groups of passengers with different experiences and attitudes. Passengers who had previously travelled frequently on regular bus services did not perceive the new system to be an improvement; consequently, they were frustrated that it was differentiated from and not coherent with the regular system. In contrast, passengers who had previously travelled almost exclusively by car appraised the busway positively and perceived it to be a novel and superior form of travel. Our rich qualitative account highlights the varied and creative ways in which people learn to use new public transport and integrate it into their everyday lives. This has consequences for the introduction and promotion of future transport innovations. It is important to emphasise the novelty of new public transport, but also the ways in which its use can become ordinary and routine. Addressing these issues could help to promote uptake of other public transport interventions, which may contribute to increasing physical activity and improving population health.


Split Point Analysis and Uncertainty Quantification of Thermal-Optical Organic/Elemental Carbon Measurements.
Researchers from myriad fields frequently seek to quantify and classify concentrations of carbonaceous aerosols as organic carbon (OC) or elemental carbon (EC). This is commonly accomplished using thermal-optical OC/EC analyzers (TOAs), which enable measurement via controlled thermal pyrolysis and oxidation under specific temperature protocols and within constrained atmospheres. Several commercial TOAs exist, including a semi-continuous instrument that enables on-line analyses in the field. This instrument employs an in-test calibration procedure that requires relatively frequent calibration. This article details a calibration protocol for this semi-continuous TOA and presents an open-source software tool for data analysis and rigorous Monte Carlo quantification of uncertainties. Notably, the software tool includes novel means to correct for instrument drift and identify and quantify the uncertainty in the OC/EC split point. This is a significant improvement on the uncertainty estimation in the manufacturer's software, which ignores split point uncertainty and otherwise uses fixed equations for relative and absolute errors (generally leading to under-estimated uncertainties and often yielding non-physical results as demonstrated in several example data sets). The demonstrated calibration protocol and new software tool enabling accurate quantification of combined uncertainties from calibration, repeatability, and OC/EC split point are shared with the intent of assisting other researchers in achieving better measurements of OC, EC, and total carbon mass in aerosol samples.


Structural consequences of a carcinogenic alkylation lesion on DNA: effect of O6-ethylguanine on the molecular structure of the d(CGC[e6G]AATTCGCG)-netropsin complex.
Exposure of cells to alkylating agents produces DNA lesions, most of which are repaired. However some alkyl lesions persist and play a role in inducing point mutations and the subsequent carcinogenic conversion. O6-Ethylguanine (e6G) is a relatively persistent alkylation lesion caused by the exposure of DNA to N-ethyl-N-nitrosourea. We study the consequence of the e6G incorporation in DNA by X-ray crystallography. We have obtained crystals of the modified DNA dodecamer d(CGC[e6G]AATTCGCG) and the unmodified d(CGCGAATTCGCG), complexed to the minor groove binding drug netropsin. The space group of both crystals is P2(1)2(1)2(1), isomorphous to other related dodecamer DNA crystals. The structures have been solved by the molecular replacement method and refined by the constrained least-squares procedure to R-factors of approximately 16% at resolution of approximately 2.5 A. The two independent e6G-C base pairs in the DNA duplex adopt different base-pairing schemes. The e6G4-C21 base pair has a configuration similar to a normal Watson-Crick base pair, except with one three-centered hydrogen bond pair and one direct hydrogen bond between e6G4 and C21. In contrast, the e6G16-C9 base pair adopts a wobble configuration. The ethyl group is in the proximal orientation (to N7) in both base pairs. These observations enrich and support those found in the crystal structure of d(CGC[e6G]AATTCGCG), complexed to minor groove binding drugs Hoechst 33258 and Hoechst 33342 [Sriram et al. (1992) EMBO J. 11, 225-232]. We suggest that a dynamic equilibrium between these two configurations for the e6G-C base pair is likely and would present an ambiguous signal to the cellular transcription, replication, or repair mechanisms. In contrast, thymine can pair with e6G in only one way, albeit imperfect, mimicking a Watson-Crick base pair. This may be a plausible explanation of why thymine is found preferentially incorporated across the e6G during replication. In addition, we analyze the influence of the alkylation lesion on DNA and the molecular details of netropsin-DNA interaction. In the present two new netropsin complexes, the netropsin spans across five base pairs (starting halfway between C3-G22 and e6G4-C21 base pairs and ending at T8-A17 base pair) in the narrow minor groove. This is in contrast to the earlier crystal structure of netropsin complexed with another DNA dodecamer having the same AATT central core sequence, d(CGCGAATT[br5C]GCG) [Kopka et al. (1985) J. Mol. Biol. 272, 390-395]. In the latter structure, the netropsin lies between G4-br5C21 and br5C9-G16 base pairs.(ABSTRACT TRUNCATED AT 400 WORDS)


Multimodality treatment of malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is a rare disease of the pleura and is largely related to asbestos exposure. Despite recent advancements in technologies and a greater understanding of the disease, the prognosis of MPM remains poor; the median overall survival rate is about 6 to 9 months in untreated patients. The main therapeutic strategies for MPM are surgery, chemotherapy, and radiation therapy (RT). The two main surgical approaches for MPM are extrapleural pneumonectomy (EPP), in which the lung is removed en bloc, and pleurectomy/decortication, in which the lung stays in situ. Chemotherapy usually consists of a platinum-based chemotherapy, such as cisplatin, often combined with a folate antimetabolite, such as pemetrexed. More recently, immunotherapy has emerged as a possible therapeutic strategy for MPM. Evidence suggests that single-modality treatments are not an effective therapeutic approach for MPM. Therefore, researchers have started to explore different multimodality treatment approaches, in which often combinations of surgery, chemotherapy, immunotherapy, and RT are investigated. There is still no definitive answer to the question of which multimodality treatment combinations are most effective in improving the poor prognosis of MPM. Research into the effects of trimodality treatment approaches have found that radical approaches such as EPP and hemithoracic RT post-EPP are less effective than was previously assumed. In general, there are still a great number of unanswered questions and unknown factors regarding the ideal treatment approach for MPM. Hopefully, more research into multimodality therapy will provide insight into which combination of treatment modalities is most effective.


Neural differentiation of lexico-syntactic categories or semantic features? event-related potential evidence for both.
Event-related potentials (ERPs) were used to investigate whether processing differences between nouns and verbs can be accounted for by the differential salience of visual-perceptual and motor attributes in their semantic specifications. Three subclasses of nouns and verbs were selected, which differed in their semantic attribute composition (abstract, high visual, high visual and motor). Single visual word presentation with a recognition memory task was used. While multiple robust and parallel ERP effects were observed for both grammatical class and attribute type, there were no interactions between these. This pattern of effects provides support for lexical-semantic knowledge being organized in a manner that takes account both of category-based (grammatical class) and attribute-based distinctions.


Mechanical and biochemical changes in the superficial zone of articular cartilage in canine experimental osteoarthritis.
The changes in the tensile mechanical properties and biochemical composition of the superficial zone of articular cartilage were examined in a canine model of early osteoarthritis generated by transection of the anterior cruciate ligament. Sixteen weeks following ligament transection, the tensile stiffness of the articular cartilage was decreased by 44% and the ion-induced stress relaxation of the tissue was increased by 57% compared with the contralateral control. Biochemical analyses indicated that the water content of the experimental tissue was increased by 13%, which was reflected as an apparent 37% decrease in the proteoglycan content and a 36% decrease in the collagen content (expressed per wet weight). The hydroxypyridinium crosslink density was decreased in the experimental tissue by 11%. A significant negative correlation was found between the ion-induced stress relaxation and the hydroxypyridinium crosslink density in both control tissue (R = -0.56) and experimental tissue (R = -0.70). No correlation was noted between the tensile stiffness and the biochemical composition of the tissue. These results suggest that, in the superficial zone of articular cartilage, the structure of the tissue may play a more important role than the composition in the determination of its mechanical properties. A major event observed in the model of early osteoarthritis appears to be the disruption and remodeling of the collagen network in the superficial zone of the articular cartilage.


Recruitment of subjects into clinical trials for Alzheimer disease.
Alzheimer disease is a devastating neurodegenerative disorder affecting millions of Americans. It reduces the ability of the individual to remain independent, places a burden on caregivers, and substantially increases healthcare costs. New treatments are being tested in numerous clinical trials with the goal of preventing or delaying the onset of Alzheimer disease, slowing or modifying the disease's course, or finding a cure for patients with the disease. Alzheimer disease research can successfully proceed only if individuals who have this illness are willing to participate in clinical trials. However, recruitment and retention of subjects in clinical trials for Alzheimer disease is a challenging task. Furthermore, because of reductions in decision-making capacities of individuals with Alzheimer disease, clinical trials also need to involve caregivers. The present article delineates unique hurdles encountered in the recruitment process for Alzheimer disease clinical trials. The article also identifies strategies for effective recruitment of subjects in Alzheimer disease clinical trials, including guidelines to help principal investigators and clinical research coordinators reach recruitment goals.


Safe in the city: effective prevention interventions for human immunodeficiency virus and sexually transmitted infections.
The public health literature documents the efficacy-effectiveness gap between research and practice resulting from the research priority of demonstrating efficacy at the expense of testing for effectiveness. The Safe in the City video-based HIV/sexually transmitted infection (STI) prevention intervention designed for sexually transmitted disease (STD) clinic waiting rooms is presented as a case study to demonstrate the application of a new framework to bridge efficacy and effectiveness. The goal of the study is to determine the extent to which clinics are implementing the intervention. As part of the case study, data were collected from a convenience sample of 81 publicly funded STD clinics during program implementation to determine whether clinics were showing the video. A baseline telephone survey was administered to clinic directors from November to December 2008, and a follow-up was conducted from March to May 2009. Data analysis was completed in 2009. At baseline, 41% of STD clinics were showing Safe in the City, which increased to 58% at follow-up. None reported previous implementation of behavioral interventions delivered in waiting rooms. Almost one fourth of clinics adapted the intervention by showing the video on laptop computers in examination rooms or in other venues with different audiences. The Safe in the City intervention was implemented by the majority of STD clinics and adapted for implementation. The framework for HIV/STI prevention intervention illustrates how measures of effectiveness were increased in the development, evaluation, dissemination, implementation and sustainability phases of research and program.


Intraspecific Variation in Growth and Reproduction of the Marine Leech, Heptacyclus buthi.
Heptacyclus buthi was harvested from fish hosts in rocky intertidal zones of Sonoma and Marin Counties, California, in October 2008 (n = 162) and October 2010 (n = 51). The size of the leeches was quantified using a method that approximated the sagittal cross-section of each specimen. Size-frequency curves were modeled to estimate the number of size-class cohorts in each year. If H. buthi is an annual species like many of its relatives, the single cohort modeled for in 2010 and the comparable "older" cohort in 2008, both with a broad range of sizes, may represent 1 component of its reproductive life history. A second, younger, more-numerous, less-variable cohort modeled from the 2008 sample may represent a second reproductive bout during that year that was prevented in the subsequent La Niña period of 2010-2011.


Bayesian learning in assisted brain-computer interface tasks.
Successful implementation of a brain-computer interface depends critically on the subject's ability to learn how to modulate the neurons controlling the device. However, the subject's learning process is probably the least understood aspect of the control loop. How should training be adjusted to facilitate dexterous control of a prosthetic device? An effective training schedule should manipulate the difficulty of the task to provide enough information to guide improvement without overwhelming the subject. In this paper, we introduce a bayesian framework for modeling the closed-loop BCI learning process that treats the subject as a bandwidth-limited communication channel. We then develop an adaptive algorithm to find the optimal difficulty-schedule for performance improvement. Simulation results demonstrate that our algorithm yields faster learning rates than several other heuristic training schedules, and provides insight into the factors that might affect the learning process.


Recurrence of uveitis after discontinuation of infliximab.
To evaluate the recurrence of uveitis after discontinuation of infliximab once control of inflammation is achieved. A retrospective cohort study was conducted of patients seen at the Proctor Foundation between 1998 and 2010 who discontinued infliximab after achieving corticosteroid-sparing control by Standardization of Uveitis Nomenclature criteria. The main outcome was the proportion of patients who had a relapse of uveitis. Eighteen patients attempted to discontinue infliximab after achieving control of inflammation, and 11 patients had a relapse. Median time to relapse was 603 days (95% CI: 85-1461 days). Patients with juvenile idiopathic arthritis (JIA)-associated uveitis (n = 4) relapsed faster (median time to relapse: 76 days, p = 0.002) compared with patients who did not have JIA-associated uveitis (median = 1169 days). The majority of patients who achieved control of inflammation on infliximab had a recurrence after discontinuing therapy. Patients with JIA experienced recurrence faster compared to other patients.


Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle.
The ability of muscles from Glut 4-null mice to take up and metabolize glucose has been studied in the isolated white EDL and red soleus muscles. In EDL muscles from male or female Glut 4-null mice, basal deoxyglucose uptake was lower than in control muscles and was not stimulated by insulin. In parallel, glycogen synthesis and content were decreased. Soleus muscles from male Glut 4-null mice took up twice more deoxyglucose in the absence of insulin than control muscles, but did not respond to insulin. In females, soleus deoxyglucose uptake measured in the absence of hormone was similar in Glut 4-null mice and in control mice. This uptake was stimulated twofold in Glut 4-null mice and threefold in control mice. Basal glycogen synthesis was increased by 4- and 2.2-fold in male and female null mice, respectively, compared to controls, and insulin had no or small (20% stimulation over basal) effect. These results indicate that while EDL muscles behaved as expected, soleus muscles were able to take up a large amount of glucose in the absence (males) or the presence of insulin (females). Whether this is due to a change in Glut 1 intrinsic activity or targeting and/or to the appearance of another glucose transporter remains to be determined.


Cancer in First Nations people in Ontario, Canada: Incidence and mortality, 1991 to 2010.
This study aims to measure cancer incidence and mortality rates of Registered First Nations people in Ontario and compare them with those of other people in Ontario from 1991 to 2010. The federal Indian Register, the Ontario Cancer Registry and the Registered Persons Database were linked to develop a cohort of First Nations people diagnosed with cancer in Ontario. Sex-and site-specific age-standardized cancer incidence and mortality rates, and selected trends over time, were calculated. Rate ratios (RRs) were used to compare rates in First Nations peoples with those of other people in Ontario. The First Nations cohort comprised 194,392 people, with 6,859 cancer diagnoses. First Nations people had higher rates for certain cancers than others in Ontario: lung (males RR 1.19; females RR 1.47), colorectal (males RR 1.36; females RR 1.34) and kidney (males RR1.95; females RR 2.23). While lung cancer rates rose in First Nations females (annual percent change [APC] +2.67), they fell at a similar rate (APC -2.28) in males. Cervical cancer rates fell (APC -9.53) and approached the rate among other females in Ontario. Kidney cancer rates increased in First Nations people. First Nations people in Ontario have higher incidence and mortality for certain cancers compared with other people in Ontario. However, the declines in cervical cancer rates in First Nations females and lung cancer rates in First Nations males illustrate the likely impact of Pap test uptake and smoking cessation programs. Community-led efforts to develop culturally appropriate prevention and screening programs are essential to further reduce cancer rates in First Nations people.


Reinforcement learning of two-joint virtual arm reaching in a computer model of sensorimotor cortex.
Neocortical mechanisms of learning sensorimotor control involve a complex series of interactions at multiple levels, from synaptic mechanisms to cellular dynamics to network connectomics. We developed a model of sensory and motor neocortex consisting of 704 spiking model neurons. Sensory and motor populations included excitatory cells and two types of interneurons. Neurons were interconnected with AMPA/NMDA and GABAA synapses. We trained our model using spike-timing-dependent reinforcement learning to control a two-joint virtual arm to reach to a fixed target. For each of 125 trained networks, we used 200 training sessions, each involving 15 s reaches to the target from 16 starting positions. Learning altered network dynamics, with enhancements to neuronal synchrony and behaviorally relevant information flow between neurons. After learning, networks demonstrated retention of behaviorally relevant memories by using proprioceptive information to perform reach-to-target from multiple starting positions. Networks dynamically controlled which joint rotations to use to reach a target, depending on current arm position. Learning-dependent network reorganization was evident in both sensory and motor populations: learned synaptic weights showed target-specific patterning optimized for particular reach movements. Our model embodies an integrative hypothesis of sensorimotor cortical learning that could be used to interpret future electrophysiological data recorded in vivo from sensorimotor learning experiments. We used our model to make the following predictions: learning enhances synchrony in neuronal populations and behaviorally relevant information flow across neuronal populations, enhanced sensory processing aids task-relevant motor performance and the relative ease of a particular movement in vivo depends on the amount of sensory information required to complete the movement.


Biomechanical factors behind toe clearance during the swing phase in hemiparetic patients.
The toe clearance of a paretic limb in the swing phase of gait is related to tripping, which is considered a major cause of falls. The biomechanical factors for obtaining toe clearance are more complicated in hemiparetic gait than that in normal gait because of the compensatory movements during swing phase. Understanding the biomechanical factors should help in targeting the point for rehabilitative interventions. To clarify the biomechanical factors behind toe clearance during swing phase in hemiparetic gait. Fifty patients with hemiparesis after a stroke participated in this study. Three-dimensional motion analysis was used for the kinematic analysis of the hemiparetic gait. The correlation coefficients between limb shortening and angle changes and between limb shortening and hip elevation and foot lateral shift were calculated. Limb shortening was defined as the shortening of the hip-toe distance. The significant factors that determine toe clearance were examined by multiple regression analysis. Independent variables were limb shortening, hip elevation, and foot lateral shift. Limb shortening was negatively correlated with hip elevation (r = -0.75) and foot lateral shift (r = -0.41). Multiple regression analysis showed a significant contribution of limb shortening and hip elevation to toe clearance. The coefficient of determination was 0.95. Toe clearance was mainly determined by limb shortening and hip elevation, which were found to be in a trade-off relationship. These results warrant further investigation into the use of three-dimensional motion analysis in the rehabilitation clinic to facilitate targeted rehabilitative training to restore gait ability.


[Role of anti-angiogenic factor chondromodulin-I for maintaining cardiac valvular function].
Cardiac valves are recognized as avascular tissue as well as cartilage and eye. We recently identified chondromodulin-I as crucial anti-angiogenic factor for maintaining cardiac valvular function. chondromodulin-I was first detected at developmental stage E9.5 in outflow tract, valvular primordium, and left ventricle, but was restricted to cardiac valves from late embryogenesis to adult. In ApoE(-/-) mice and human valvular heart diseases such as atherosclerosis, rheumatic heart diseases, and infective endocarditis, vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) expression and neovascularization were observed in the area of down-regulation of chondromodulin-I. Conditioned medium from cultured-valvular interstitial cells strongly inhibited tube formation and migration of endothelial cells, and these effects were partially blocked by chondromodulin-I siRNA in vitro. Gene targeting of chondromodulin-I caused VEGF expression, neovascularization, lipid deposition, and calcification in cardiac valves of aged mice. Echocardiography showed aortic valve thickening and turbulent flow suggesting early stage of aortic stenosis. These findings provide evidence that chondromodulin-I is a crucial factor for maintaining normal cardiac valvular function by preventing angiogenesis that may lead to valvular heart diseases.


Escape from adaptive conflict after duplication in an anthocyanin pathway gene.
Gene duplications have been recognized as an important source of evolutionary innovation and adaptation since at least Haldane, and their varying fates may partly explain the vast disparity in observed genome sizes. The expected fates of most gene duplications involve primarily non-adaptive substitutions leading to either non-functionalization of one duplicate copy or subfunctionalization, neither of which yields novel function. A significant evolutionary problem is thus elucidating the mechanisms of adaptive evolutionary change leading to evolutionary novelty. Currently, the most widely recognized adaptive process involving gene duplication is neo-functionalization (NEO-F), in which one copy undergoes directional selection to perform a novel function after duplication. An alternative, but understudied, adaptive fate that has been proposed is escape from adaptive conflict (EAC), in which a single-copy gene is selected to perform a novel function while maintaining its ancestral function. This gene is constrained from improving either novel or ancestral function because of detrimental pleiotropic effects on the other function. After duplication, one copy is free to improve novel function, whereas the other is selected to improve ancestral function. Here we first present two criteria that can be used to distinguish NEO-F from EAC. Using both tests for positive selection and assays of enzyme function, we then demonstrate that adaptive evolutionary change in a duplicated gene of the anthocyanin biosynthetic pathway in morning glories (Ipomoea) is best interpreted as EAC. Finally, we argue that this phenomenon likely occurs more often than has been previously believed and may thus represent an important mechanism in generating evolutionary novelty.


Increased chemotherapeutic activity of camptothecin in cancer cells by siRNA-induced silencing of WRN helicase.
Werner syndrome helicase (WRN) participates in a wide range of DNA activities, including replication, double-strand DNA break repair, telomere and retrovirus long terminal repeat maintenance. Mutations of the WRN gene cause Werner syndrome (WS), an autosomal recessive premature ageing disorder associated with various symptoms related to ageing. In this study, we investigated the siRNA that specifically down-regulates WRN expression. WRN silencing increased markedly the chemotherapeutic activity of camptothecin (CPT) on cancer cells in terms of the extent of efficacy and lowering effective drug dosage, accompanied by suppressing recovery from DNA damage caused by CPT. Here, we propose a potential combination therapy of WRN-siRNA and CPT, looking forward to minimizing the inevitable adverse effects associated with cancer chemotherapy.


Treatment of bleeding from portal hypertensive gastropathy by portacaval shunt.
Portal hypertensive gastropathy is a vascular disorder of the gastric mucosa distinguished by ectasia of the mucosal capillaries and submucosal veins without inflammation. During 1988 to 1993, 12 patients with biopsy-proven cirrhosis (10 alcoholic, 2 posthepatitic) were evaluated and treated prospectively by portacaval shunt for active bleeding from severe portal hypertensive gastropathy. Eleven patients had been hospitalized for bleeding three to nine times previously, and one was bleeding uncontrollably for the first time. Requirement for blood transfusions ranged from 11 to 39 units cumulatively, of which 8 to 30 units were required specifically to replace blood lost from portal hypertensive gastropathy. Admission findings were ascites in 9 patients, jaundice in 8, severe muscle wasting in 10, hyperdynamic state in 9. Child's risk class was C in 7, B in 4, A in 1. Ten of the 12 patients had previously received repetitive endoscopic sclerotherapy for esophageal varices, which has been reported to precipitate portal hypertensive gastropathy. Eight patients had failed propranolol therapy for bleeding. Portacaval shunt was performed emergently in 11 patients and electively in 1, and permanently stopped bleeding in all by reducing the mean portal vein-inferior vena cava pressure gradient from 251 to 16 mm saline. There were no operative deaths, and two unrelated late deaths after 13 and 24 months. During 1 to 6.75 years of follow-up, all shunts remained patent by ultrasonography, the gastric mucosa reverted to normal on serial endoscopy, and there was no gastrointestinal bleeding. Recurrent portal-systemic encephalopathy developed in only 8% of patients. Quality of life was generally good.(ABSTRACT TRUNCATED AT 250 WORDS)


Airway and feeding problems in infants with Fairbairn-Robin triad deformities.
The majority of patients with Pierre Robin sequence in the subdivision Fairbairn- Robin triad (FRT), are born with glossoptosis, retro-/micrognathia and cleft or agenesis of the palate leading to feeding difficulties and airway obstruction. There is limited literature on these problems, and on methods used to address them. Community nurses in the Facial Cleft Deformity Clinic evaluate associated airway obstruction and feeding problems and devise nursing interactions to address these. This retrospective study examined the incidence of airway and feeding difficulties in the neonatal, pre-surgical period, as well as the surgical and nutritional management of these infants. Retrospective records of 215 infants with FRT were examined and data on incidence, airway and feeding difficulties and surgical and nutritional management was collected. Descriptive statistics, including average and percentage values, were compiled. The incidence of FRT amongst the cleft palate patients was 6.0%, with 37.7% of these having feeding difficulties. However, surgical interventions such as glossopexy (5.6%), distraction osteogenesis (0.9%) and tracheotomy (2.3%) for airway management were seldom required. Most of the infants who had upper airway obstruction and feeding problems were handled by means of suction and drinking plates, along with additional specific feeding aids. This reduced airway obstruction in 70.6%, and feeding problems in 62.4% of these infants. Based on this study's finding the introduction of the suction and drinking plate and the use of specific types of feeding devices and surgical management can improve growth and development in infants with FRT.


T cell lines characterize events in the pathogenesis of the Wiskott-Aldrich syndrome.
The Wiskott-Aldrich syndrome (WAS) is a severe immunodeficiency and platelet deficiency disease arising from an X-linked defect. The disease is correctable by transplantation of hematopoietic stem cells, but the product of the defective gene is unidentified and the number of defects in patient blood cells is large. The current hurdle is the need to identify the early pathogenic event(s) that are the cause of other defects. As a step toward this goal, we have generated and examined a panel of interleukin 2-dependent allospecific T cell lines from peripheral lymphocytes of seven WAS patients and five normal individuals. WAS cell lines, like normal lines, undergo vigorous proliferation when challenged with specific allostimulant or with phorbol myristate acetate and ionomycin. Both normal and WAS T cell lines express cell surface molecules CD2, CD3, T cell receptor-alpha/beta, human histocompatibility leukocyte antigen class I, CD45 and CD11a, and varying ratios of CD4 and CD8, and are negative for natural killer cell and monocyte surface molecules. WAS T cell lines express CD43 (sialophorin/leukosialin) with molecular weight and in an amount comparable with normal T cell lines. WAS T cell lines thus do not express defects in CD43 (decreased amount, abnormal molecular weight), previously documented in WAS circulating lymphocytes. On the other hand, as detected by scanning electron microscopy, WAS cell lines exhibit severe morphological abnormalities, including decreased size and density of the microvillus surface projections. The morphological abnormalities of WAS T cell lines are similar to, or more extensive than, those previously reported for WAS peripheral lymphocytes, indicating that the generation of morphological (cytoarchitectural) defects is an early pathogenic event in this disease. The findings suggest that the gene that is defective in the WAS encodes a protein that normally functions to maintain or regulate the cytoskeletal structure of blood cells.


Reorienting primary health care for addressing chronic conditions in remote Australia and the South Pacific: review of evidence and lessons from an innovative quality improvement process.
This paper reviews what is known about the challenges of implementing quality improvement programs and draws on data from a systematic continuous quality improvement (CQI) project in remote communities in Australia and Fiji, known as Audit and Best practice for Chronic Disease, to synthesise lessons and discuss the potential for broader application in low and middle income countries, including Pacific Island countries and territories. Although a number of systematic reviews have indicated that quality improvement programs can be effective in changing professional practice and improving the quality of care and patient outcomes, little is known about the key ingredients for change or how services use and implement different strategies to achieve improvements. We identify key features of an innovative CQI model and factors related to implementation that support improvement in diabetes service delivery and intermediate outcomes. Requirements for supporting CQI are identified and the potential for wider application discussed. It is argued that the participatory action research approach supports innovation and broad-based change and the evidence it has produced extends the current knowledge base and facilitates the translation of knowledge into action, for both policy and practice.


Photosynthetic temperature responses of tree species in Rwanda: evidence of pronounced negative effects of high temperature in montane rainforest climax species.
The sensitivity of photosynthetic metabolism to temperature has been identified as a key uncertainty for projecting the magnitude of the terrestrial feedback on future climate change. While temperature responses of photosynthetic capacities have been comparatively well investigated in temperate species, the responses of tropical tree species remain unexplored. We compared the responses of seedlings of native cold-adapted tropical montane rainforest tree species with those of exotic warm-adapted plantation species, all growing in an intermediate temperature common garden in Rwanda. Leaf gas exchange responses to carbon dioxide (CO2 ) at different temperatures (20-40°C) were used to assess the temperature responses of biochemical photosynthetic capacities. Analyses revealed a lower optimum temperature for photosynthetic electron transport rates than for Rubisco carboxylation rates, along with lower electron transport optima in the native cold-adapted than in the exotic warm-adapted species. The photosynthetic optimum temperatures were generally exceeded by daytime peak leaf temperatures, in particular in the native montane rainforest climax species. This study thus provides evidence of pronounced negative effects of high temperature in tropical trees and indicates high susceptibility of montane rainforest climax species to future global warming.


Chimaeras and mosaics for dissecting complex mutant phenotypes.
Back at the first half of the 1980s, there was no mammalian experimental embryology in Hungary. One of us, AN, took up the challenge of establishing a small group in the field. In the absence of local information, AN and his former colleague, Andras Paldi (AP), used their tourist passport to visit several laboratories in Western Europe and collect information and advice. This is how AN and AP ended up one day sitting in Anne McLaren's office in the MRC Mammalian Development Unit at University College, London. They never forgot her endless enthusiasm and the way she clearly explained the important points of preimplantation embryo manipulation, chimaera making and embryo transfer. As well as the extremely useful suggestions, which were crucial to starting the lab in Hungary, they also took back her deep love for embryo development. They remember her telling them, 'never waste an embryo--there is always another unanswered question it can solve'. Many who have been lucky and experienced Anne's spirit and advice later realized how useful it was to generate 'new' ideas by following the 'not wasting' principle. Our views on chimaeras presented below definitely contain elements which grew out from this principle.


Gender differences in the relationship between personality dimensions and relative body weight.
The relationship between body mass index (BMI: kg/m(2)) and personality seems to differ for men and women, although these effects may be driven by the extremes of the BMI distribution. It is unclear whether these associations exist for most individuals in the relatively normal range of BMI scores, excluding the thinnest and heaviest extremes in the population. We tested the association of BMI with neuroticism, extraversion, and psychoticism with a trimmed BMI sample. Using a cross-sectional design, we tested the association of BMI with the aforementioned psychological variables in a British population-based sample. Participants were 7889 adult men and women (30 to 50 years old) selectively sampled from four counties in west England. Participants reported their height and weight and completed the Eysenck Personality Inventory (EPQ). We tested the association of BMI with the EPQ subscales among individuals with BMI >or=19.16 kg/m(2) and <or=37.78 kg/m(2), i.e., the approximate 5th and 95th percentiles. Despite elimination of extreme BMIs, different associations between BMI and EPQ subscales emerged for men and women. Among women, increasing BMI was significantly associated with increased neuroticism and reduced extraversion. Among men, increasing BMI was associated with increased extraversion and psychoticism. In all cases, the magnitude of the association was very small. Increasing BMI was associated with potentially poorer adjustment among women but better adjustment among men. These findings are consistent with recent reports and, taken together, suggest that these patterns are not accounted for solely by the extremes of the BMI distribution.


Treating youth in pain: Comparing tailored behavioural medicine treatment provided by physical therapists in primary care with physical exercises.
To study the efficacy of tailored behavioural medicine treatment within a physical therapy framework. The study was a randomized controlled study (RCT): tailored behavioural medicine treatment (EXT) delivered by physical therapists (PTs) was compared with exercise-based treatment (CT). Thirty-two adolescents (mean age 14.3 years) with persistent pain participated. Data on pain-related disability and school attendance (primary outcomes), pain intensity, catastrophizing, fear of movement and self-efficacy were collected. The pain-related disability measured by the Functional Disability Inventory (FDI) resulted in mean score change of EXT = -18 and CT = -11, respectively. A significant change within both groups was found (EXT p = 0.003, CT p = 0.001), and a large effect size for FDI between the conditions was demonstrated (AUC of 0.77). For school attendance post-treatment, no difference was found between conditions. For secondary outcomes, a significant improvement in pain intensity and pain catastrophizing was found for the EXT and self-efficacy for the CT groups but no statistically significant difference between the two conditions was detected. Caution should be given to the small sample size, as it may affect the interpretation and generalizability of the results. In this study, differences between tailored behavioural medicine treatment delivered by PTs and exercise-based treatment could not be demonstrated, although the effect size was large. Patients who received either treatment demonstrated significant changes over time in pain-related disability. The low number of participants and suboptimal tailoring of the psychological components may partly explain the failure to demonstrate differences between groups, and future studies are warranted.


Forensic investigation of incidents involving chemical threat agent: Presentation of the operating procedure developed in Belgium for a field-exercise.
The GIFT CBRN project (Generic Integrated Forensic Toolbox for chemical, biological, radiological and nuclear incidents), funded under the Seventh Framework Programme of the European Commission, has been set up to find solutions for investigating incidents involving CBRN agents. Regarding the forensic point of view, specific tools and procedures to assist forensic investigators to perform a crime scene investigation (CSI) and methodologies to enable the subsequent analysis of the evidences (contaminated with CBRN agents) seized at the crime scene have been developed. To validate the procedures and methods developed within this project and to test them, three field-exercises engaged with one type of agent at the time (i.e. a RN-agent, a B-agent or a C-agent) has been held. The Belgian Defence Laboratories (DLD) in collaboration with Royal Military Academy (RMA) and the National Institute of Criminalistics and Criminology (NICC) has organized the chemical field exercise in Belgium. CSI teams of the Belgian Federal Police (experienced in crime scene investigation, fingerprints and digital forensics but at the time of the exercise not trained to perform their activities in CBRN conditions), SIBCRA teams (experienced in the sampling and identification of CBRN agents in hazardous environments) and the Civil Protection (experienced in entering zones with potential chemical hazards in full individual protective equipment) were involved. Since those teams never worked together in CBRN conditions, the exercise was used to establish the first operating procedure for CSI and laboratory analysis for CBRN and forensic materials in Belgium. The main steps of the procedure applied during this filed-exercise are described is this manuscript. The first step was the reconnaissance performed to (i) identify/quantify the threat agent involved, (ii) to document the scene and (iii) to collect priority forensic evidences. The second step focused on the collection of other forensic evidences, the sampling of DNA traces and the revelation of fingerprints at the scene. The collection of CBRN agents was performed during step 3. Step 4 concentrated on the decontamination and transport of evidences and traces sampled in the contaminated zone. The revelation of fingerprints in a glovebox (step 5) was finally demonstrated. In conclusion, this field-exercise was an opportunity for the different Belgium services to work together, to learn from each other, and to work towards the establishment of a national operating procedure to manage investigations in CBRN conditions.


Intravenous immunoglobulin increases survival time in the acute phase of experimental Chagas disease.
Chagas disease induced by Trypanosoma cruzi (Tc) infection is an important cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are insufficient and largely inadequate. Intravenous immunoglobulin (IVIg) is a therapeutic preparation containing normal polyspecific IgG obtained from plasma pools of several thousand healthy donors and is used in several autoimmune, inflammatory and infectious diseases. In the study of heart from mice chronically infected with Tc, we observed that IVIg restores type 1 atrioventricular block or bradycardia. In the present study, we investigated the effects of IVIg in acute Tc infection. Intravenous immunoglobulin administration after the first week of infection was associated with an increase in survival time. Taken together, results observed in the chronic and in the acute phase associate IVIg treatment with a favourable outcome in T. cruzi infection.


The first living systems: a bioenergetic perspective.
The first systems of molecules having the properties of the living state presumably self-assembled from a mixture of organic compounds available on the prebiotic Earth. To carry out the polymer synthesis characteristic of all forms of life, such systems would require one or more sources of energy to activate monomers to be incorporated into polymers. Possible sources of energy for this process include heat, light energy, chemical energy, and ionic potentials across membranes. These energy sources are explored here, with a particular focus on mechanisms by which self-assembled molecular aggregates could capture the energy and use it to form chemical bonds in polymers. Based on available evidence, a reasonable conjecture is that membranous vesicles were present on the prebiotic Earth and that systems of replicating and catalytic macromolecules could become encapsulated in the vesicles. In the laboratory, this can be modeled by encapsulated polymerases prepared as liposomes. By an appropriate choice of lipids, the permeability properties of the liposomes can be adjusted so that ionic substrates permeate at a sufficient rate to provide a source of monomers for the enzymes, with the result that nucleic acids accumulate in the vesicles. Despite this progress, there is still no clear mechanism by which the free energy of light, ion gradients, or redox potential can be coupled to polymer bond formation in a protocellular structure.


Vector choice determines immunogenicity and potency of genetic vaccines against Angola Marburg virus in nonhuman primates.
The immunogenicity and durability of genetic vaccines are influenced by the composition of gene inserts and choice of delivery vector. DNA vectors are a promising vaccine approach showing efficacy when combined in prime-boost regimens with recombinant protein or viral vectors, but they have shown limited comparative efficacy as a stand-alone platform in primates, due possibly to suboptimal gene expression or cell targeting. Here, regimens using DNA plasmids modified for optimal antigen expression and recombinant adenovirus (rAd) vectors, all encoding the glycoprotein (GP) gene from Angola Marburg virus (MARV), were compared for their ability to provide immune protection against lethal MARV Angola infection. Heterologous DNA-GP/rAd5-GP prime-boost and single-modality rAd5-GP, as well as the DNA-GP-only vaccine, prevented death in all vaccinated subjects after challenge with a lethal dose of MARV Angola. The DNA/DNA vaccine induced humoral responses comparable to those induced by a single inoculation with rAd5-GP, as well as CD4(+) and CD8(+) cellular immune responses, with skewing toward CD4(+) T-cell activity against MARV GP. Vaccine regimens containing rAd-GP, alone or as a boost, exhibited cellular responses with CD8(+) T-cell dominance. Across vaccine groups, CD8(+) T-cell subset dominance comprising cells exhibiting a tumor necrosis factor alpha (TNF-alpha) and gamma interferon (IFN-gamma) double-positive functional phenotype was associated with an absence or low frequency of clinical symptoms, suggesting that both the magnitude and functional phenotype of CD8(+) T cells may determine vaccine efficacy against infection by MARV Angola.


Formation of microvascular networks: role of stromal interactions directing angiogenic growth.
In the adult, angiogenesis leads to an expanded microvascular network as new vessel segments are added to an existing microcirculation. Necessarily, growing neovessels must navigate through tissue stroma as they locate and grow toward other vessel elements. We have a growing body of evidence demonstrating that angiogenic neovessels reciprocally interact with the interstitial matrix of the stroma resulting in directed neovascular growth during angiogenesis. Given the compliance and the viscoelastic properties of collagen, neovessel guidance by the stroma is likely due to compressive strain transverse to the direction of primary tensile forces present during active tissue deformation. Similar stromal strains control the final network topology of the new microcirculation, including the distribution of arterioles, capillaries, and venules. In this case, stromal-derived stimuli must be present during the post-angiogenesis remodeling and maturation phases of neovascularization to have this effect. Interestingly, the preexisting organization of vessels prior to the start of angiogenesis has no lasting influence on the final, new network architecture. Combined, the evidence describes interplay between angiogenic neovessels and stroma that is important in directed neovessel growth and invasion. This dynamic is also likely a mechanism by which global tissue forces influence vascular form and function.


Diagnoses made in an Emergency Department in rural sub-Saharan Africa.
Information on diagnoses made in emergency departments situated in rural sub-Saharan Africa is scarce. The aim was: to evaluate the frequency of different diagnoses made in a new emergency department to define relevant healthcare requirements; and to find out if in-hospital mortality rates would decrease after the implementation of the emergency department. In this observational study, we prospectively collated diagnoses of all patients presenting to the emergency department of the St Francis Referral Hospital in Ifakara, Tanzania during 1 year. In addition, we compared in-hospital mortality rates before and after the implementation of the emergency department. From July 2016 through to June 2017, a total of 35,903 patients were included. The median age was 33.6 years (range 1 day to 100 years), 57% were female, 25% were children <5 years, 4% were pregnant and 9% were hospitalised. The most common diagnoses were respiratory tract infection (12.6%), urinary tract infection (11.4%), trauma (9.8%), undifferentiated febrile illness (5.4%), and malaria (5.2%). The most common clinical diagnoses per age group were: lower respiratory tract infection (16.1%) in children <5 years old; trauma (21.6%) in 5- to 17-year-olds; urinary tract infection (13.5%) in 18- to 50-year-olds; and hypertensive emergency (12.4%) in >50-year-olds. Respiratory tract infections peaked in April during the rainy season, whereas malaria peaked 3 months after the rainy season. In-hospital mortality rates did not decrease during the study period (5.6% in 2015 vs 7.6% in 2017). The majority of diagnosed disorders were of infectious or traumatic origin. The majority of febrile illnesses were poorly defined because of the lack of diagnostic methods. Trauma systems and inexpensive accurate diagnostic methods for febrile illnesses are needed in rural sub-Saharan Africa.