A history of chagas disease transmission, control, and re-emergence in peri-rural La Joya, Peru.
The history of Chagas disease control in Peru and many other nations is marked by scattered and poorly documented vector control campaigns. The complexities of human migration and sporadic control campaigns complicate evaluation of the burden of Chagas disease and dynamics of Trypanosoma cruzi transmission. We conducted a cross-sectional serological and entomological study to evaluate temporal and spatial patterns of T. cruzi transmission in a peri-rural region of La Joya, Peru. We use a multivariate catalytic model and Bayesian methods to estimate incidence of infection over time and thereby elucidate the complex history of transmission in the area. Of 1,333 study participants, 101 (7.6%; 95% CI: 6.2-9.0%) were confirmed T. cruzi seropositive. Spatial clustering of parasitic infection was found in vector insects, but not in human cases. Expanded catalytic models suggest that transmission was interrupted in the study area in 1996 (95% credible interval: 1991-2000), with a resultant decline in the average annual incidence of infection from 0.9% (95% credible interval: 0.6-1.3%) to 0.1% (95% credible interval: 0.005-0.3%). Through a search of archival newspaper reports, we uncovered documentation of a 1995 vector control campaign, and thereby independently validated the model estimates. High levels of T. cruzi transmission had been ongoing in peri-rural La Joya prior to interruption of parasite transmission through a little-documented vector control campaign in 1995. Despite the efficacy of the 1995 control campaign, T. cruzi was rapidly reemerging in vector populations in La Joya, emphasizing the need for continuing surveillance and control at the rural-urban interface.


Spontaneous autoimmunization to GIX cell surface antigen in hybrid mice.
The GIX antigen expressed on the thymocytes of GIX+ mice is a type-specific constituent of glycoprotein gp70, which forms the major envelope component of murine leukemia virus. In the prototype GIX+ mouse strain 129, this glycoprotein is a Mendelian character expressed independently of virus production. In the intact thymocyte plasma membrane, part of this glycoprotein, bearing group-specific (gs) antigen, is inaccessible to antibody. The moiety bearing the type-specific GIX determinant is accessible to GIX antibody, which may be an important factor in determining the consequences of autoimmune responses involving GIX. Previously, all attempts to induce GIX antibody in mice had failed. We now find that the hybrid mouse (B6-GIX+ X 129) spontaneously produces substantial amounts of GIX antibody, presumably of the IgM class appearing as early as 2 mo of age. The specificity of the GIX natural mouse antibody is the same as that recognized by the conventional GIX typing serum produced in rats ("anti-NTD"). As neither parent strain produces appreciable GIX antibody, we surmise that this autoimmune response requires two dominant genes, each parent contributing a high-response allele to the hybrid. These can be envisaged as two immune response loci, controlling different immunocompetent cells which must cooperate to produce GIX antibody. Production of GIX antibody by the hybrids increases progressively with age. This is accompanied by decreased expression of GIX antigen on their thymocytes. We attribute this to antigenic modulation. Antibody to gs antigen of gp70 is also found in autoimmune (B6-GIX+ X 129) hybrids but not in either parent strain. We are investigating evidence of a pathological autoimmune syndrome in these hybrids. The special interest of this syndrome is that it presumably signifies the consequences of autoimmunization to a single C-type virus component, expressed without significant virus production, in a mouse with no evident genetic predisposition to such disease in the absence of that antigen.


The Characteristics of Romantic Relationships Associated with Teen Dating Violence.
Studies of teen dating violence have focused heavily on family and peer influences, but little research has been conducted on the relationship contexts within which violence occurs. The present study explores specific features of adolescent romantic relationships associated with the perpetration of physical violence. Relying on personal interviews with a sample of 956 adolescents, results indicate that respondents who self-report violence perpetration are significantly more likely than their non-violent counterparts to report higher levels of other problematic relationship dynamics and behaviors such as jealousy, verbal conflict, and cheating. However, we find no significant differences in levels of love, intimate self-disclosure, or perceived partner caring, and violent relationships are, on average, characterized by longer duration, more frequent contact, sexual intimacy and higher scores on the provision and receipt of instrumental support. Finally, violence is associated with the perception of a relatively less favorable power balance, particularly among male respondents. These findings complicate traditional views of the dynamics within violent relationships, add to our understanding of risk factors, and may also shed light on why some adolescents remain in physically abusive relationships.


Changes in the craniofacial structures and esthetic perceptions of soft-tissue profile alterations after distalization and Herbst appliance treatment.
The purpose of this prospective clinical trial is to evaluate the changes of soft tissues and designate the esthetic perceptions of children with Class II malocclusion after Herbst appliance therapy and maxillary molar distalization using stereophotogrammetry. Thirty patients were allocated either to Herbst (6 boys and 9 girls; mean age = 11.60 ± 0.82 years) or distalization (4 boys and 11 girls; mean age = 11.46 ± 1.30 years) groups. Dentoskeletal and soft-tissue treatment changes were examined objectively by cephalometric analysis and stereophotogrammetry, respectively. Pre- and posttreatment profile views were evaluated subjectively by orthodontists and laypeople using the 7-point Likert scale. Intra- and intergroup comparisons for the repeated measurements were performed with 2-way variance analysis. Bonferroni test was used for multiple comparisons (P ≤0.05). Greater skeletal changes were observed in the Herbst group than in the distalization group. Maxillary incisor retrusion and mandibular incisor protrusion were observed in the distalization and Herbst groups, respectively. Stereophotogrammetric measurements showed that mandibular body length and lower and anterior facial height increased in both treatment groups. Convexity angle (P = 0.020) and labiomental angle (P = 0.033) were greater in the Herbst group than the distalization group. The skeletal contribution to correction of maxillomandibular discrepancy was greater in the Herbst group than the distalization group. Significant profile improvements were recorded for both groups with treatment. After both treatments, orthodontists were found to have higher rates of detection in the profiles than laypeople. The esthetic contribution of treatments to the facial profile was found similar in both groups.


Fosfomycin in the pediatric setting: Evidence and potential indications.
To date, there has been little experience in using fosfomycin in children. However, its broad spectrum of action and excellent safety profile have renewed interest in this antibiotic, especially for treating infections by multidrug-resistant bacteria. The main indication for fosfomycin in pediatrics is currently community-acquired lower urinary tract infection. Given its good activity against bacteria, fosfomycin can also be useful in urinary infections caused by extended-spectrum beta-lactamase-producing enterobacteria. Fosfomycin presents very good dissemination to tissues including bone and is therefore an option in the combined therapy of osteomyelitis, especially in cases produced by methicillin-resistant Staphylococcus aureus (MRSA) or in cases with beta-lactam allergies. Fosfomycin can also be employed in combination for multidrug-resistant Gram-negative bacteremia (especially carbapenemase-producing enterobacteria), S. aureus (if there is a high suspicion of MRSA or complicated infections) and vancomycin-resistant Enterococcus spp. Other infections in which fosfomycin could be part of a combined therapy include staphylococcal endocarditis (in case of beta-lactam allergy or MRSA), central nervous system infections (mainly by MRSA, S. epidermidis, Listeria and resistant pneumococcus), nosocomial pneumonia and infections associated with mechanical ventilation.


Human CD8+ T cell responses to EBV EBNA1: HLA class I presentation of the (Gly-Ala)-containing protein requires exogenous processing.
Epstein-Barr virus (EBV)-induced cytotoxic T lymphocyte (CTL) responses have been detected against many EBV antigens but not the nuclear antigen EBNA1; this has been attributed to the presence of a glycine-alanine repeat (GAr) domain in the protein. Here we describe the isolation of human CD8+ CTL clones recognizing EBNA1-specific peptides in the context of HLA-B35.01 and HLA-A2.03. Using these clones, we show that full-length EBNA1 is not presented when expressed endogenously in target cells, whereas the GAr-deleted form is presented efficiently. However, when supplied as an exogenous antigen, the full-length protein can be presented on HLA class I molecules by a TAP-independent pathway; this may explain how EBNA1-specific CTLs are primed in vivo.


Irrelevance of the Boundary on the Magnetization of Metals.
The macroscopic current density responsible for the mean magnetization M of a uniformly magnetized bounded sample is localized near its surface. In order to evaluate M one needs the current distribution in the whole sample: bulk and boundary. In recent years it has been shown that the boundary has no effect on M in insulators: therein, M admits an alternative expression not based on currents. M can be expressed in terms of the bulk electron distribution only, which is "nearsighted" (exponentially localized); this virtue is not shared by metals, having a qualitatively different electron distribution. We show, by means of simulations on paradigmatic model systems, that even in metals the M value can be retrieved in terms of the bulk electron distribution only.


Conflicts of interests, confidentiality and censorship in health risk assessment: the example of an herbicide and a GMO.
We have studied the long-term toxicity of a Roundup-tolerant GM maize (NK603) and a whole Roundup pesticide formulation at environmentally relevant levels from 0.1 ppb. Our study was first published in Food and Chemical Toxicology (FCT) on 19 September, 2012. The first wave of criticisms arrived within a week, mostly from plant biologists without experience in toxicology. We answered all these criticisms. The debate then encompassed scientific arguments and a wave of ad hominem and potentially libellous comments appeared in different journals by authors having serious yet undisclosed conflicts of interests. At the same time, FCT acquired as its new assistant editor for biotechnology a former employee of Monsanto after he sent a letter to FCT to complain about our study. This is in particular why FCT asked for a post-hoc analysis of our raw data. On 19 November, 2013, the editor-in-chief requested the retraction of our study while recognizing that the data were not incorrect and that there was no misconduct and no fraud or intentional misinterpretation in our complete raw data - an unusual or even unprecedented action in scientific publishing. The editor argued that no conclusions could be drawn because we studied 10 rats per group over 2 years, because they were Sprague Dawley rats, and because the data were inconclusive on cancer. Yet this was known at the time of submission of our study. Our study was however never attended to be a carcinogenicity study. We never used the word 'cancer' in our paper. The present opinion is a summary of the debate resulting in this retraction, as it is a historic example of conflicts of interest in the scientific assessments of products commercialized worldwide. We also show that the decision to retract cannot be rationalized on any discernible scientific or ethical grounds. Censorship of research into health risks undermines the value and the credibility of science; thus, we republish our paper.


Respiratory component of the orienting reflex: a novel sensitive index of sensory-induced arousal in rats.
In humans, the integrated response to a novel stimulus (orienting reflex, OR) includes behavioral (head turning etc.) and well-characterized physiological components (changes in heart rate, respiration, skin conductance, and EEG patterns). In rodents, the physiological components of the OR include changes in heart rate and cutaneous vasoconstrictor tone, but respiratory changes have so far not been systematically documented. In the present study conducted in adult male Wistar rats, the OR was elicited by 60-dB acoustic tones while animals were in a whole-body plethysmograph for respiratory recordings. In addition to respiration, in different groups of animals we concurrently recorded either EEG, or heart rate (both by biotelemetry), or tail blood flow (using ultrasound Doppler). Acoustic stimuli provoked vigorous tachypneic responses with respiratory rate rising from 80-100 to 450-650 cpm, and with small and variable changes in tidal volume. This respiratory arousal response was often, but not always, accompanied by EEG desynchronization and by variable tail vasoconstriction, and by small and inconsistent changes in the heart rate. We conclude that tachypneic responses are a new highly sensitive index of sensory-induced arousal.


Effect of earthworms on soil physico-hydraulic and chemical properties, herbage production, and wheat growth on arable land converted to ley.
Effects of earthworms on soil physico-hydraulic and chemical properties, herbage production and wheat growth in long-term arable soils following conversion to ley were investigated. Seven intact soil monoliths were collected from each of four arable fields. One monolith per field served as a control. The other six were defaunated by deep-freezing; three were left defaunated (DeF) and three (DeF+E) were repopulated with earthworms to mimic pasture field density and diversity. The monoliths were planted with a grass-clover ley and inserted into pre-established ley strips in their original fields for 12 months. Hydraulic conductivity measurements at -0.5 cm tension (K0.5) were taken five times over the year. K0.5 significantly increased in summer 2017 and spring 2018 and decreased in winter 2017-18. K0.5 was significantly greater (47%) for DeF+E than DeF monoliths. By the end of the experiment, pores >1 mm diameter made a significantly greater contribution to water flow in DeF+E (98%) than DeF (95%) monoliths. After only a year of arable to ley conversion, soil bulk density significantly decreased (by 6%), and organic matter (OM) content increased (by 29%) in the DeF treatments relative to the arable soil. Earthworms improved soil quality further. Compared to DeF monoliths, DeF+E monoliths had significantly increased water-holding capacity (by 9%), plant-available water (by 21%), OM content (by 9%), grass-clover shoot dry biomass (by 58%), water-stable aggregates >250 μm (by 15%) and total N (by 3.5%). In a wheat bioassay following the field experiment, significantly more biomass (20%) was produced on DeF+E than DeF monolith soil, likely due to the changed soil physico-hydraulic properties. Our results show that earthworms play a significant role in improvements to soil quality and functions brought about by arable to ley conversion, and that augmenting depleted earthworm populations can help the restoration of soil qualities adversely impacted by intensive agriculture.


Membrane patches as ion channel probes for scanning ion conductance microscopy.
We describe dual-barrel ion channel probes (ICPs), which consist of an open barrel and a barrel with a membrane patch directly excised from a donor cell. When incorporated with scanning ion conductance microscopy (SICM), the open barrel (SICM barrel) serves to measure the distance-dependent ion current for non-invasive imaging and positioning of the probe in the same fashion of traditional SICM. The second barrel with the membrane patch supports ion channels of interest and was used to investigate ion channel activities. To demonstrate robust probe control with the dual-barrel ICP-SICM probe and verify that the two barrels are independently addressable, current-distance characteristics (approach curves) were obtained with the SICM barrel and simultaneous, current-time (I-T) traces were recorded with the ICP barrel. To study the influence that the distance between ligand-gated ion channels (i.e., large conductance Ca2+-activated K+ channels/BK channels) and the ligand source (i.e., Ca2+ source) has on channel activations, ion channel activities were recorded at two fixed probe-substrate distances (Dps) with the ICP barrel. The two fixed positions were determined from approach curves acquired with the SICM barrel. One position was defined as the "In-control" position, where the probe was in close proximity to the ligand source; the second position was defined as the "Far" position, where the probe was retracted far away from the ligand source. Our results confirm that channel activities increased dramatically with respect to both open channel probability and single channel current when the probe was near the ligand source, as opposed to when the probe was far away from the ligand source.


A model for hydrophobic protrusions on peripheral membrane proteins.
With remarkable spatial and temporal specificities, peripheral membrane proteins bind to biological membranes. They do this without compromising solubility of the protein, and their binding sites are not easily distinguished. Prototypical peripheral membrane binding sites display a combination of patches of basic and hydrophobic amino acids that are also frequently present on other protein surfaces. The purpose of this contribution is to identify simple but essential components for membrane binding, through structural criteria that distinguish exposed hydrophobes at membrane binding sites from those that are frequently found on any protein surface. We formulate the concepts of protruding hydrophobes and co-insertability and have analysed more than 300 families of proteins that are classified as peripheral membrane binders. We find that this structural motif strongly discriminates the surfaces of membrane-binding and non-binding proteins. Our model constitutes a novel formulation of a structural pattern for membrane recognition and emphasizes the importance of subtle structural properties of hydrophobic membrane binding sites.


Use of Immersive Learning and Simulation Techniques to Teach and Research Opioid Prescribing Practices.
Unsafe opioid prescribing practices to treat acute and chronic pain continue to contribute to the opioid overdose crisis in the United States, a growing public health emergency that harms patients and their communities. Poor opioid prescribing practices stem in part from a lack of education and skills training surrounding pain and opioid management. As part of the Clinical Pain Medicine Fellowship at Stanford University, physicians were given the opportunity to participate in a pilot program to practice opioid management in a live, simulated interaction. Twenty-seven physician trainees participated in the simulation with a live, standardized patient actor. Before beginning the simulation, participants were given a detailed patient history that included the patient's risk for opioid abuse. They were also provided with relevant risk evaluation and mitigation (REM) tools. All simulation interactions were video-recorded and coded by two independent reviewers. A detailed coding scheme was developed before video analysis, and an inter-rater reliability score showed substantial agreement between reviewers. Contrary to expectations, many of the observed performances by trainees contained aspects of unsafe opioid prescribing, given the patient history. Many trainees did not discuss their patient's aberrant behaviors related to opioids or the patient's risk for opioid abuse. Marked disparities were also observed between the trainees' active patient interactions and their written progress notes. This simulation addresses a pressing need to further educate, train, and provide point-of-care tools for providers prescribing opioids. We present our experience and preliminary findings.


A sibling method for identifying vQTLs.
The propensity of a trait to vary within a population may have evolutionary, ecological, or clinical significance. In the present study we deploy sibling models to offer a novel and unbiased way to ascertain loci associated with the extent to which phenotypes vary (variance-controlling quantitative trait loci, or vQTLs). Previous methods for vQTL-mapping either exclude genetically related individuals or treat genetic relatedness among individuals as a complicating factor addressed by adjusting estimates for non-independence in phenotypes. The present method uses genetic relatedness as a tool to obtain unbiased estimates of variance effects rather than as a nuisance. The family-based approach, which utilizes random variation between siblings in minor allele counts at a locus, also allows controls for parental genotype, mean effects, and non-linear (dominance) effects that may spuriously appear to generate variation. Simulations show that the approach performs equally well as two existing methods (squared Z-score and DGLM) in controlling type I error rates when there is no unobserved confounding, and performs significantly better than these methods in the presence of small degrees of confounding. Using height and BMI as empirical applications, we investigate SNPs that alter within-family variation in height and BMI, as well as pathways that appear to be enriched. One significant SNP for BMI variability, in the MAST4 gene, replicated. Pathway analysis revealed one gene set, encoding members of several signaling pathways related to gap junction function, which appears significantly enriched for associations with within-family height variation in both datasets (while not enriched in analysis of mean levels). We recommend approximating laboratory random assignment of genotype using family data and more careful attention to the possible conflation of mean and variance effects.


Acute Physiological Responses Following a Bout of Vigorous Exercise in Military Soldiers and First Responders with PTSD: An Exploratory Pilot Study.
Post-traumatic stress disorder (PTSD) is a prevalent and debilitating condition associated with psychological conditions and chronic diseases that may be underpinned by dysfunction in the autonomic nervous system (ANS), the hypothalamic-pituitary-adrenal (HPA) axis and chronic systemic low-grade inflammation. The objective of this pilot study was to determine psychological, ANS [heart rate variability (HRV)], HPA (salivary cortisol) and inflammatory (salivary C-Reactive Protein) responses to a bout of vigorous exercise in male first responders, military veterans and active duty personnel with (n = 4) and without (n = 4) PTSD. Participants (50.1 ± 14.8 years) performed a thirteen-minute, vigorous intensity (70%-80% of heart rate max), one-on-one boxing session with a certified coach. Physiological and psychological parameters were measured before, during, immediately after to 30 min post-exercise, and then at 24 h and 48 h post. The effect sizes demonstrated large to very large reductions in HRV that lasted up to 48 h post-exercise in the PTSD group compared with unclear effects in the trauma-exposed control (TEC) group. There were unclear effects for depression, anxiety and stress as well as salivary biomarkers for both groups at all time-points. Findings may reflect stress-induced changes to the ANS for PTSD sufferers.


Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.
The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.


C-peptide normalizes glomerular filtration rate in hyperfiltrating conscious diabetic rats.
Tubular electrolyte transport accounts for a major part of the oxygen consumed by the normal kidney. We have previously reported a close association between diabetes and increased oxygen usage, partly due to increased tubular electrolyte transport secondary to glomerular hyperfiltration during the early onset of diabetes. Several studies have shown that acute administration of C-peptide to diabetic rats with glomerular hyperfiltration results in normalized glomerular filtration rate (GFR). In this study, we validated a novel method for precise and repetitive GFR measurements in conscious rats and used C-peptide injection in diabetic rats for evaluation. First, GFR was determined in normoglycemic control rats before and after C-peptide administration. Thereafter, all rats were made diabetic by an i.v. streptozotocin injection. Fourteen days later, GFR was again determined before and after C-peptide administration. GFR was estimated from plasma clearance curves using a single bolus injection of FITC-inulin, followed by serial blood sampling over 155 min. FITC-inulin clearance was calculated using non-compartmental pharmacokinetic data analysis. Baseline GFR in normoglycemic controls was 2.10 +/- 0.18 ml/min, and was unaffected by C-peptide (2.23 +/- 0.14 ml/min). Diabetic rats had elevated GFR (3.06 +/- .034 ml/min), which was normalized by C-peptide (2.35 +/- 0.30 ml/min). In conclusion, the used method for estimation of GFR in conscious animals result in values that are in good agreement with those obtained from traditional GFR measurements on anaesthetized rats. However, multiple measurements from the same conscious subject can be obtained using this method. Furthermore, as previously shown on anaesthetized rats, C-peptide also normalizes GFR in hyperfiltrating conscious diabetic rats.


Spatial regulation of gene expression in nonsyndromic sagittal craniosynostosis.
OBJECTIVECranial suture patterning and development are highly regulated processes that are not entirely understood. While studies have investigated the differential gene expression for different sutures, little is known about gene expression changes during suture fusion. The aim of this study was to examine gene expression in patent, fusing, and fused regions along sagittal suture specimens in nonsyndromic craniosynostosis patients.METHODSSagittal sutures were collected from 7 patients (average age 4.5 months) who underwent minimally invasive craniotomies at the Children's Hospital of Richmond at VCU under IRB approval. The sutures were analyzed using micro-CT to evaluate patency. The areas were classified as open, fusing, or fused and were harvested, and mRNA was isolated. Gene expression for bone-related proteins, osteogenic and angiogenic factors, transforming growth factor-β (TGF-β) superfamily, and Wnt signaling was analyzed using quantitative polymerase chain reaction and compared with normal sutures collected from fetal demise tissue (control).RESULTSMicro-CT demonstrated that there are variable areas of closure along the length of the sagittal suture. When comparing control samples to surgical samples, there was a significant difference in genes for Wnt signaling, TGF-β, angiogenic and osteogenic factors, bone remodeling, and nuclear rigidity in mRNA isolated from the fusing and fused areas of the sagittal suture compared with patent areas (p < 0.05).CONCLUSIONSIn nonsyndromic sagittal craniosynostosis, the affected suture has variable areas of being open, fusing, and fused. These specific areas have different mRNA expression. The results suggest that BMP-2, FGFR3, and several other signaling pathways play a significant role in the regulation of suture fusion as well as in the maintenance of patency in the normal suture.


Effects of changes in climate on landscape and regional processes, and feedbacks to the climate system.
Biological and physical processes in the Arctic system operate at various temporal and spatial scales to impact large-scale feedbacks and interactions with the earth system. There are four main potential feedback mechanisms between the impacts of climate change on the Arctic and the global climate system: albedo, greenhouse gas emissions or uptake by ecosystems, greenhouse gas emissions from methane hydrates, and increased freshwater fluxes that could affect the thermohaline circulation. All these feedbacks are controlled to some extent by changes in ecosystem distribution and character and particularly by large-scale movement of vegetation zones. Indications from a few, full annual measurements of CO2 fluxes are that currently the source areas exceed sink areas in geographical distribution. The little available information on CH4 sources indicates that emissions at the landscape level are of great importance for the total greenhouse balance of the circumpolar North. Energy and water balances of Arctic landscapes are also important feedback mechanisms in a changing climate. Increasing density and spatial expansion of vegetation will cause a lowering of the albedo and more energy to be absorbed on the ground. This effect is likely to exceed the negative feedback of increased C sequestration in greater primary productivity resulting from the displacements of areas of polar desert by tundra, and areas of tundra by forest. The degradation of permafrost has complex consequences for trace gas dynamics. In areas of discontinuous permafrost, warming, will lead to a complete loss of the permafrost. Depending on local hydrological conditions this may in turn lead to a wetting or drying of the environment with subsequent implications for greenhouse gas fluxes. Overall, the complex interactions between processes contributing to feedbacks, variability over time and space in these processes, and insufficient data have generated considerable uncertainties in estimating the net effects of climate change on terrestrial feedbacks to the climate system. This uncertainty applies to magnitude, and even direction of some of the feedbacks.


Spatio-temporal Organization During Ventricular Fibrillation in the Human Heart.
In this paper, we present a novel approach to quantify the spatio-temporal organization of electrical activation during human ventricular fibrillation (VF). We propose three different methods based on correlation analysis, graph theoretical measures and hierarchical clustering. Using the proposed approach, we quantified the level of spatio-temporal organization during three episodes of VF in ten patients, recorded using multi-electrode epicardial recordings with 30 s coronary perfusion, 150 s global myocardial ischaemia and 30 s reflow. Our findings show a steady decline in spatio-temporal organization from the onset of VF with coronary perfusion. We observed transient increases in spatio-temporal organization during global myocardial ischaemia. However, the decline in spatio-temporal organization continued during reflow. Our results were consistent across all patients, and were consistent with the numbers of phase singularities. Our findings show that the complex spatio-temporal patterns can be studied using complex network analysis.


The effect of low-dose dopamine infusion on anterior pituitary hormone secretion in normal female subjects.
The effect of low-dose dopamine infusion on anterior pituitary hormone secretion in a group of seven healthy female subjects is reported. Subjects were infused with NaCl solution (154 mmol/l) (control) or dopamine (0.01 and 0.1 micrograms min-1 kg-1 for 120 min at each rate) on separate days in the early follicular phase of consecutive menstrual cycles. Serum prolactin decreased during infusion of dopamine at 0.01 micrograms min-1 kg-1 but a similar fall was found in the control group. When the rate of dopamine infusion was increased to 0.1 micrograms min-1 kg-1 a further substantial decrease in prolactin concentration occurred, whereas prolactin in the control group showed no change. At the end of the period of dopamine infusion at 0.1 micrograms min-1 kg-1 serum prolactin remained significantly (P less than 0.025) lower than in the control group (85 +/- 12 vs 180 +/- 21 m-units/1). No change in thyrotrophin (TSH), growth hormone (GH) or luteinizing hormone (LH) was seen during either rate of dopamine infusion compared with control. While dopamine infusion at 0.1 micrograms min-1 kg-1 caused significant inhibition of prolactin secretion in normal female subjects, other pituitary hormone secretion was not affected: it is suggested that under the conditions of this study dopamine in hypophysial portal blood is not of primary importance in the control of basal TSH, GH and LH release.


An association test of the spatial distribution of rare missense variants within protein structures identifies Alzheimer's disease-related patterns.
More than 90% of genetic variants are rare in most modern sequencing studies, such as the Alzheimer's Disease Sequencing Project (ADSP) whole-exome sequencing (WES) data. Furthermore, 54% of the rare variants in ADSP WES are singletons. However, both single variant and unit-based tests are limited in their statistical power to detect an association between rare variants and phenotypes. To best use missense rare variants and investigate their biological effect, we examine their association with phenotypes in the context of protein structures. We developed a protein structure-based approach, protein optimized kernel evaluation of missense nucleotides (POKEMON), which evaluates rare missense variants based on their spatial distribution within a protein rather than their allele frequency. The hypothesis behind this test is that the three-dimensional spatial distribution of variants within a protein structure provides functional context to power an association test. POKEMON identified three candidate genes (TREM2, SORL1, and EXOC3L4) and another suggestive gene from the ADSP WES data. For TREM2 and SORL1, two known Alzheimer's disease (AD) genes, the signal from the spatial cluster is stable even if we exclude known AD risk variants, indicating the presence of additional low-frequency risk variants within these genes. EXOC3L4 is a novel AD risk gene that has a cluster of variants primarily shared by case subjects around the Sec6 domain. This cluster is also validated in an independent replication data set and a validation data set with a larger sample size.


Competitive enzyme-linked immunosorbent assay based on monoclonal antibody and recombinant hemagglutinin for serosurveillance of rinderpest virus.
A competitive enzyme-linked immunosorbent assay (C-ELISA) which detects antibodies unique to rinderpest virus (RPV) has been developed. This test can differentiate antibodies against RPV and those against peste des petits ruminants virus. The recombinant RPV hemagglutinin (H)-protein C-ELISA (recH C-ELISA) is based on the ability of a well-characterized monoclonal antibody (MAb) produced with the soluble, secreted form of the H protein (Sec H protein) of RPV made in a baculovirus expression system to compete with the binding of RPV antibodies in the serum of vaccinated or infected, recovered animals to the Sec H protein. The B-cell epitope recognized by the MAb corresponds to amino acids 575 to 583 on the H protein, which is not present on the antigenically closely related peste des petits ruminants virus hemagglutinin-neuraminidase protein. Initially, a positive-negative threshold cutoff value for percent inhibition of 34 was established with 500 known RPV-negative serum samples. The recH C-ELISA was developed with the enzyme immunoassay software of a commercial RPV C-ELISA kit. Comparative analysis of the test results for 700 serum samples obtained with the commercial kit gave a sensitivity of 112.4% and a specificity of 72.4%. Variations in percent inhibition values were observed for the two assay systems. These variations may have been due to the undefined amount of antigen present in the commercial kit as well as the use of a different MAb. The recH C-ELISA detected more positive serum samples compared to the number detected by the commercial kit, with the results confirmed by a virus neutralization test. Thus, recH C-ELISA is a sensitive tool for RPV serosurveillance in disease eradication programs.


Triggering Receptor Expressed on Myeloid Cells-2 Expression Tracks With M2-Like Macrophage Activity and Disease Severity in COPD.
Cell and animal models show a key role for Triggering Receptor Expressed on Myeloid Cells (TREM)-2 in chronic airway disease after viral infection, but comparable evidence in humans still needs to be established. Lung tissue samples were obtained from lung transplant recipients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV COPD (n = 16), nontransplantable donor lung tissues (n = 7), and resected lung tissues from patients at risk or with GOLD stage I through IV (n = 55) and were assessed for TREM-2 and TREM-1 messenger RNA (mRNA), protein expression, and other markers of a type 2 immune response. TREM2 (but not TREM1) mRNA levels were increased in GOLD stage IV COPD lung tissues compared with non-COPD lung tissues. TREM2 mRNA was coexpressed with its signaling molecule DAP12 and the macrophage marker CD68 and M2-macrophage markers CD206 and CHIT1. TREM-2 protein was also increased in COPD lung tissues and was localized to CD14+ macrophages by flow cytometry and CD68+ and CCR2+ macrophages by tissue immunostaining. In lung samples from patients at risk and with GOLD stage I through IV COPD, TREM2 but not TREM1 mRNA levels were also increased, and the ratio of TREM2/TREM1 mRNA levels was associated with increases in CHIT1 mRNA and decreases in FEV1 and FEV1/FVC. TREM-2 expression is increased in lung macrophages in COPD, particularly in comparison with TREM-1. Therefore, TREM-2 levels and the ratio of TREM-2/TREM-1 signifies M2 activation in COPD lung tissues and may help to guide therapeutics directed against the type 2 immune response in patients with this disease.


Use of health care by young Asian New Zealanders: findings from a national youth health survey.
To examine the use of health services and perceived barriers to accessing health care among young Asian New Zealanders. Secondary analysis of data from Youth2000, a cross-sectional survey of secondary school students in New Zealand (NZ) conducted in 2001. Of the 9567 survey participants (aged 12-18 years), this study was restricted to students who identified with an 'Asian' ethnic category (n = 922). Chinese and Indian students (the largest Asian ethnic groups in NZ) reported levels of overall health comparable to NZ European (NZE) students. However, relative to NZE students, Chinese students were more likely to report (i) not having a usual location for health care (adjusted OR 3.28; 95% CI: 2.51-4.43); and (ii) having problems getting health care when they needed it (adjusted OR 1.61; 95% CI: 1.32-1.96). Asian students who had been in NZ for 5 years or less (compared with NZ-born students), as well as those who did not speak English at home (compared with those who did) were less likely to report having a usual source of health care, even after adjusting for their overall health (adjusted OR 2.13, 95% CI: 1.27-3.56; and adjusted OR 1.69, 95% CI: 1.11-2.56, respectively). Young Asian New Zealanders are less likely to access health care than their NZE counterparts. The perceived barriers require explicit attention within the broader platforms of health-care quality, and professional and cultural competence of health-care services.


Experimental studies of light-induced charge transfer and charge redistribution in (X(2)-bipyridine)Re(I)(CO)(3)Cl complexes.
Stark emission spectroscopy, transient DC photoconductivity (TDCP), and ground-state dipole moment measurements have been used to evaluate charge transfer (CT) within various (X(2)-bipyridine)Re(I)(CO)(3)Cl complexes following (3)MLCT excited-state formation. The Stark technique reports on vector differences between ground-state (mu(g)) and excited-state (mu(e)) dipole moments, while TDCP, when combined with independently obtained mu(g) information, reports on scalar differences. For systems featuring collinear, same-signed ground- and excited-state dipole moments, the scalar and vector differences are equivalent. However, for the low symmetry systems studied here, they are distinctly different. The vector difference yields the effective adiabatic one-electron-transfer distance (R(12)), while the combined vector and scalar data yield information about dipole rotation upon ground-state/excited-state interconversion. For the systems examined, charge transfer distances are substantially smaller than geometric electron-donor/electron-acceptor site separation distances. The measured distances are significantly affected by changes in acceptor ligand substituent composition. Electron-donating substituents decrease CT distances, while electron-withdrawing substituents increase CT distances, as do aromatic substituents that are capable of expanding the bipyridyl ligand (acceptor ligand) pi system. The Stark measurements additionally indicate that the CT vector and the transition dipole moment are significantly orthogonal, a consequence of strong polarization of the Re-Cl bond (orthogonal to the metal/acceptor-ligand plane) in the ground electronic state and relaxation of the polarization in the upper state. The ground-state Re-Cl bond polarization is sufficiently large that the overall ground-state scalar dipole moment exceeds the overall excited-state scalar dipole moment, despite transfer of an electron from the metal center to the diimine ligand. This finding provides an explanation for the otherwise puzzling negative solvatochromism exhibited in this family of compounds. Combining TDCP and Stark results, we find that the dipole moment can be rotated in some instances by more than 90 degrees upon (3)MLCT excited-state formation. The degree of rotation or reorientation can be modulated by changing the identity of the acceptor ligand substituents. Reorientational effects are smallest when the compounds feature aromatic substituents capable of spatially extending the pi system of the acceptor ligand.


Quantifying early COVID-19 outbreak transmission in South Africa and exploring vaccine efficacy scenarios.
The emergence and fast global spread of COVID-19 has presented one of the greatest public health challenges in modern times with no proven cure or vaccine. Africa is still early in this epidemic, therefore the extent of disease severity is not yet clear. We used a mathematical model to fit to the observed cases of COVID-19 in South Africa to estimate the basic reproductive number and critical vaccination coverage to control the disease for different hypothetical vaccine efficacy scenarios. We also estimated the percentage reduction in effective contacts due to the social distancing measures implemented. Early model estimates show that COVID-19 outbreak in South Africa had a basic reproductive number of 2.95 (95% credible interval [CrI] 2.83-3.33). A vaccine with 70% efficacy had the capacity to contain COVID-19 outbreak but at very higher vaccination coverage 94.44% (95% Crl 92.44-99.92%) with a vaccine of 100% efficacy requiring 66.10% (95% Crl 64.72-69.95%) coverage. Social distancing measures put in place have so far reduced the number of social contacts by 80.31% (95% Crl 79.76-80.85%). These findings suggest that a highly efficacious vaccine would have been required to contain COVID-19 in South Africa. Therefore, the current social distancing measures to reduce contacts will remain key in controlling the infection in the absence of vaccines and other therapeutics.


Efficacy of interventions to combat tobacco addiction: Cochrane update of 2012 reviews.
The Cochrane Collaboration is an international not-for-profit organization which produces and disseminates systematic reviews of health-care interventions. This paper is the first in a series of annual updates of Cochrane reviews on tobacco addiction interventions. It also provides an up-to-date overview of review findings in this area to date and summary statistics for cessation reviews in which meta-analyses were conducted. In 2012, the Group published seven new reviews and updated 13 others. This update summarizes and comments on these reviews. It also summarizes key findings from all the other reviews in this area. New reviews in 2012 found that in smokers using pharmacotherapy, behavioural support improves success rates [risk ratio (RR) 1.16, 95% confidence interval (CI) = 1.09-1.24], and that combining behavioural support and pharmacotherapy aids cessation (RR 1.82, 95% CI = 1.66-2.00). Updated reviews established mobile phones as potentially helpful in aiding cessation (RR 1.71, 95% CI = 1.47-1.99), found that cytisine (RR 3.98, 95% CI = 2.01-7.87) and low-dose varenicline (RR 2.09, 95% CI = 1.56-2.78) aid smoking cessation, and found that training health professionals in smoking cessation improves patient cessation rates (RR 1.60, 95% CI = 1.26-2.03). The updated reviews confirmed the benefits of nicotine replacement therapy, standard dose varenicline and providing cessation treatment free of charge. Lack of demonstrated efficacy remained for partner support, expired-air carbon monoxide feedback and lung function feedback. Cochrane systematic review evidence for the first time establishes the efficacy of behavioural support over and above pharmacotherapy, as well as the efficacy of cytisine, mobile phone technology, low-dose varenicline and health professional training in promoting smoking cessation.


Do state minimum markup/price laws work? Evidence from retail scanner data and TUS-CPS.
Minimum markup/price laws (MPLs) have been proposed as an alternative non-tax pricing strategy to reduce tobacco use and access. However, the empirical evidence on the effectiveness of MPLs in increasing cigarette prices is very limited. This study aims to fill this critical gap by examining the association between MPLs and cigarette prices. State MPLs were compiled from primary legal research databases and were linked to cigarette prices constructed from the Nielsen retail scanner data and the self-reported cigarette prices from the Tobacco Use Supplement to the Current Population Survey. Multivariate regression analyses were conducted to examine the association between MPLs and the major components of MPLs and cigarette prices. The presence of MPLs was associated with higher cigarette prices. In addition, cigarette prices were higher, above and beyond the higher prices resulting from MPLs, in states that prohibit below-cost combination sales; do not allow any distributing party to use trade discounts to reduce the base cost of cigarettes; prohibit distributing parties from meeting the price of a competitor, and prohibit distributing below-cost coupons to the consumer. Moreover, states that had total markup rates >24% were associated with significantly higher cigarette prices. MPLs are an effective way to increase cigarette prices. The impact of MPLs can be further strengthened by imposing greater markup rates and by prohibiting coupon distribution, competitor price matching, and use of below-cost combination sales and trade discounts.


Health care costs of formula-feeding in the first year of life.
To determine the excess cost of health care services for three illnesses in formula-fed infants in the first year of life, after adjusting for potential confounders. Frequency of health service utilization for three illnesses (lower respiratory tract illnesses, otitis media, and gastrointestinal illness) in the first year of life was assessed in relation to duration of exclusive breastfeeding in the Tucson Children's Respiratory Study (n = 944) and the Dundee Community Study (Scottish study, n = 644). Infants in both studies were healthy at birth and represented nonselected, population-based samples. Children were classified as never breastfed, partially breastfed, or exclusively breastfed, based on their feeding status during the first 3 months of life. Frequency of office visits and hospitalizations for the three illnesses was adjusted for maternal education and maternal smoking, using analysis of variance. Cost estimates, from the perspective of the health care provider/payer, were based on the direct medical costs during 1995 within a large managed care health care system. In the first year of life, after adjusting for confounders, there were 2033 excess office visits, 212 excess days of hospitalization, and 609 excess prescriptions for these three illnesses per 1000 never-breastfed infants compared with 1000 infants exclusively breastfed for at least 3 months. These additional health care services cost the managed care health system between $331 and $475 per never-breastfed infant during the first year of life. In addition to having more illnesses, formula-fed infants cost the health care system money. Health care plans will likely realize substantial savings, as well as providing improved care, by supporting and promoting exclusive breastfeeding.


Testing for sexually transmitted infections in general practice: cross-sectional study.
Primary care is an important provider of sexual health care in England. We sought to explore the extent of testing for chlamydia and HIV in general practice and its relation to associated measures of sexual health in two contrasting geographical settings. We analysed chlamydia and HIV testing data from 64 general practices and one genitourinary medicine (GUM) clinic in Brent (from mid-2003 to mid-2006) and 143 general practices and two GUM clinics in Avon (2004). We examined associations between practice testing status, practice characteristics and hypothesised markers of population need (area level teenage conception rates and Index of Multiple Deprivation, IMD scores). No HIV or chlamydia testing was done in 19% (12/64) of general practices in Brent, compared to 2.1% (3/143) in Avon. In Brent, the mean age of general practitioners (GPs) in Brent practices that tested for chlamydia or HIV was lower than in those that had not conducted testing. Practices where no HIV testing was done had slightly higher local teenage conception rates (median 23.5 vs. 17.4/1000 women aged 15-44, p = 0.07) and served more deprived areas (median IMD score 27.1 vs. 21.8, p = 0.05). Mean yearly chlamydia and HIV testing rates, in practices that did test were 33.2 and 0.6 (per 1000 patients aged 15-44 years) in Brent, and 34.1 and 10.3 in Avon, respectively. In Brent practices only 20% of chlamydia tests were conducted in patients aged under 25 years, compared with 39% in Avon. There are substantial geographical differences in the intensity of chlamydia and HIV testing in general practice. Interventions to facilitate sexually transmitted infection and HIV testing in general practice are needed to improve access to effective sexual health care. The use of routinely-collected laboratory, practice-level and demographic data for monitoring sexual health service provision and informing service planning should be more widely evaluated.


Initial genome scan of the NIMH genetics initiative bipolar pedigrees: chromosomes 1, 6, 8, 10, and 12.
A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods. Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals. The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed.


Nondestructive Analysis of Debonds in a Composite Structure under Variable Temperature Conditions.
This paper presents a nondestructive analysis of debonds in an adhesively-bonded carbon-fibre reinforced composite structure under variable temperature conditions. Towards this, ultrasonic guided wave propagation based experimental analysis and numerical simulations are carried out for a sample composite structure to investigate the wave propagation characteristics and detect debonds under variable operating temperature conditions. The analysis revealed that the presence of debonds in the structure significantly reduces the wave mode amplitudes, and this effect further increases with the increase in ambient temperature and debond size. Based on the debond induced differential amplitude phenomenon, an online monitoring strategy is proposed that directly uses the guided wave signals from the distributed piezoelectric sensor network to localize the hidden debonds in the structure. Debond index maps generated from the proposed monitoring strategy show the debond identification potential in the adhesively-bonded composite structure. The accuracy of the monitoring strategy is successfully verified with non-contact active infrared-thermography analysis results. The effectiveness of the proposed monitoring strategy is further investigated for the variable debond size and ambient temperature conditions. The study establishes the potential for using the proposed damage index constructed from the differential guided wave signal features as a basis for localization and characterization of debond damages in operational composite structures.


Diagnostic value of procalcitonin and presepsin for sepsis in critically ill adult patients: a systematic review and meta-analysis.
Early and accurate diagnosis of sepsis is challenging. Although procalcitonin and presepsin have been identified as potential biomarkers to differentiate between sepsis and other non-infectious causes of systemic inflammation, the diagnostic accuracy of these biomarkers remains controversial. Herein, we performed a comprehensive meta-analysis to assess the overall diagnostic value of procalcitonin and presepsin for the diagnosis of sepsis. We searched three electronic databases (MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials) for relevant studies. Two authors independently screened articles on the basis of inclusion and exclusion criteria. The pooled sensitivity, specificity, and summary receiver operating characteristic curves were estimated. The quality of evidence for diagnostic accuracy in absolute effects, i.e., the number of true or false positives and true or false negatives, gave a particular pre-test probability. We included 19 studies (19 observational studies and no randomized controlled trials) that had enrolled 3012 patients. Analyses of summary receiver operating characteristic curves revealed areas under the receiver operating characteristic curves of 0.84 for procalcitonin and 0.87 for presepsin. The pooled sensitivities and specificities were 0.80 (95% confidence interval 0.75 to 0.84) and 0.75 (95% confidence interval 0.67 to 0.81) for procalcitonin. For presepsin, these values were 0.84 (95% confidence interval 0.80 to 0.88) and 0.73 (95% confidence interval 0.61 to 0.82), respectively. There were no statistically significant differences in both pooled sensitivities (p = 0.48) and specificities (p = 0.57) between procalcitonin and presepsin. Our meta-analysis provided evidence that the diagnostic accuracy of procalcitonin and presepsin in detecting infection was similar and that both are useful for early diagnosis of sepsis and subsequent reduction of mortality in critically ill adult patients. The study was registered in PROSPERO under the registration number CRD42016035784.


Ecology impacts the decrease of Spirochaetes and Prevotella in the fecal gut microbiota of urban humans.
Compared to the huge microbial diversity in most mammals, human gut microbiomes have lost diversity while becoming specialized for animal-based diets - especially compared to chimps, their genetically closest ancestors. The lowered microbial diversity within the gut of westernized populations has also been associated with different kinds of chronic inflammatory diseases in humans. To further deepen our knowledge on phylogenetic and ecologic impacts on human health and fitness, we established the herein presented biobank as well as its comprehensive microbiota analysis. In total, 368 stool samples from 38 different animal species, including Homo sapiens, belonging to four diverse mammalian orders were collected at seven different locations and analyzed by 16S rRNA gene amplicon sequencing. Comprehensive data analysis was performed to (i) determine the overall impact of host phylogeny vs. diet, location, and ecology and to (ii) examine the general pattern of fecal bacterial diversity across captive mammals and humans.By using a controlled study design with captive mammals we could verify that host phylogeny is the most dominant driver of mammalian gut microbiota composition. However, the effect of ecology appears to be able to overcome host phylogeny and should therefore be studied in more detail in future studies. Most importantly, our study could observe a remarkable decrease of Spirochaetes and Prevotella in westernized humans and platyrrhines, which is probably not only due to diet, but also to the social behavior and structure in these communities.Our study highlights the importance of phylogenetic relationship and ecology within the evolution of mammalian fecal microbiota composition. Particularly, the observed decrease of Spirochaetes and Prevotella in westernized communities might be associated to lifestyle dependent rapid evolutionary changes, potentially involved in the establishment of dysbiotic microbiomes, which promote the etiology of chronic diseases.


One-year experience with an inpatient asthma clinical pathway.
To study the effects of an inpatient asthma clinical pathway on the processes and outcomes for children who were admitted to a hospital for the treatment of asthma. Before-and-after study. A private nonprofit academic children's hospital in Seattle, Wash. Three hundred forty-two admissions of 297 patients in the first year of the asthma clinical pathway were compared with 353 admissions of 292 similar patients in the previous year. Patients who required intensive care, were younger than 2 years, or had a major chronic disease were excluded. Asthma was chosen for the development of a clinical pathway because of its large number of admissions, involvement of multiple health care providers (nurses, physicians, and respiratory therapists), predictable hospital course, and variable lengths of hospital stay. The pathway was a consensus-based guideline for patient management that was intended to be adapted to the care of an individual patient. Prior to the implementation of the clinical pathway, nurses, attending physicians, house staff, and respiratory therapists were trained in its use. The main hospital chart of each patient who was admitted to the pathway had a flowchart that outlined day-to-day guidelines for monitoring and care. Nursing staff were responsible for documenting when a patient's care varied from the pathway, and these variances were entered into a computer database. Use of peak flowmeters, steroids, laboratory studies, radiological studies, and respiratory therapy was assessed by analyzing the patients' electronic billing records. For patients enrolled in the pathway, additional data on process of care were obtained by analyzing the variance database. For both groups, the total charges, length of stay, and rate of readmission to the hospital were measured by use of the billing records. There were no significant differences in the use of steroids or peak flowmeters, average lengths of stay, or total charges between the 2 groups. However, patients in the "pathway group" had significantly lower average charges for laboratory ($26 vs $39; P < .05) and radiology ($32 vs $55; P < .001) services. Variances from the pathway guidelines were most often related to the patients' responses to therapy. The asthma clinical pathway had no effect on clinical outcomes and small effects on the use of resources. Further development, including physician and nurse training, computer and administrative support, and clinical severity scales, are needed to develop the potential utility of the clinical pathway as a research and quality assurance tool.


Concentrations of human cardiac phosphorus metabolites determined by SLOOP 31P NMR spectroscopy.
Human cardiac 31P nuclear magnetic resonance (NMR) spectra are usually quantified in relative terms, i.e., the ratio of metabolite signals is calculated. If 31P NMR spectroscopy of the heart is to emerge as a clinically relevant diagnostic modality, reliable quantification of absolute concentrations of 31P metabolites is required. We applied spectral localization with optimal point spread function (SLOOP) 31P NMR spectroscopy to measure absolute concentrations of phosphocreatine (PCr) and adenosine triphosphate (ATP) in human myocardium. The accuracy of the quantification was first validated in a phantom study. Seven healthy volunteers (aged 19-29 years) were then examined at 1.5 T using a nominal spatial resolution of 25 mL. SLOOP allowed us to obtain localized spectra from compartments anatomically matched to the left ventricular wall. The a priori knowledge of the anatomical structure was obtained from 1H images. The spatially varying effects of saturation, off-resonance, and sensitivity were considered during the reconstruction process. Metabolites were quantified with reference to an external 31P standard. Concentrations of 9.0 +/- 1.2 and 5.3 +/- 1.2 mmol/kg wet wt (mean +/- SD, n = 9) were determined for PCr and ATP in normal heart, respectively. The influence of nuclear Overhauser enhancement on metabolite quantification is discussed.


Changes in stroke distance in response to haemorrhage in a swine model.
To determine, using an animal model of blood loss, (1) if stroke distance, derived non-invasively from the time integral of the maximum velocity of red cells in the aorta, changed to a greater extent than heart rate and mean arterial pressure (MAP), which are recognised to be unreliable indicators of blood loss; (2) if changes in stroke distance reflected changes in stroke volume derived from thermodilution cardiac output measurements. Eight anaesthetised swine had baseline measurements of heart rate, MAP, stroke volume, and stroke distance and were then exsanguinated at a rate of 1 ml/kg/min. Percentage changes from baseline of heart rate, MAP, stroke volume, and stroke distance were compared after 10, 20, and 30 ml/kg blood loss. The animal's blood was then reinfused at the rate of 2 ml/kg/min for 15 min, followed by normal saline 1 ml/kg/min. Percentage changes from baseline measurement of stroke volume and stroke distance over the whole experiment were evaluated by regression analysis. Heart rate, MAP, and stroke distance changed +7.9%, -22.5%, and -18.1% respectively (from baseline values) after 10 ml/kg blood loss; +23.2%, -44.0%, and -47.4% after 20 ml/kg blood loss; and +55.7%, -62.0%, and -69.8% after 30 ml/kg blood loss. Regression analysis of percentage changes in stroke volume and stroke distance from their baseline values at experimental time zero is stroke volume = 1.014 x stroke distance -2.156, r = 0.92, n = 54, P < 0.0001. (1) At maximal blood loss, stroke distance changes to a greater extent than heart rate and MAP. (2) Changes in stroke distance reflected changes in stroke volume but with less variability at lower values. Stroke distance may be a more useful measure of blood loss than heart rate and MAP.


Global transcriptome analysis of porcine oocytes in correlation with follicle size.
Although our knowledge regarding oocyte quality and development has improved significantly, the molecular mechanisms that regulate and determine oocyte developmental competence are still unclear. Therefore, the objective of this study was to identify and analyze the transcriptome profiles of porcine oocytes derived from large or small follicles using RNA high-throughput sequencing technology. RNA libraries were constructed from oocytes of large (LO; 3-6 mm) or small (SO; 1.5-1.9 mm) ovarian follicles and then sequenced in an Illumina HiSeq4000. Transcriptome analysis showed a total of 14,557 genes were commonly detected in both oocyte groups. Genes related to the cell cycle, oocyte meiosis, and quality were among the top highly expressed genes in both groups. Differential expression analysis revealed 60 up- and 262 downregulated genes in the LO compared with the SO group. BRCA2, GPLD1, ZP3, ND3, and ND4L were among the highly abundant and highly significant differentially expressed genes (DEGs). The ontological classification of DEGs indicated that protein processing in endoplasmic reticulum was the top enriched pathway. In addition, biological processes related to cell growth and signaling, gene expression regulations, cytoskeleton, and extracellular matrix organization were among the highly enriched processes. In conclusion, this study provides new insights into the global transcriptome changes and the abundance of specific transcripts in porcine oocytes in correlation with follicle size.


Role of Toll-Like Receptors in Actuating Stem/Progenitor Cell Repair Mechanisms: Different Functions in Different Cells.
Toll-like receptors (TLRs) represent one of the bridges that regulate the cross-talk between the innate and adaptive immune systems. TLRs interact with molecules shared and preserved by the pathogens of origin but also with endogenous molecules (damage/danger-associated molecular patterns (DAMPs)) that derive from injured tissues. This is probably why TLRs have been found to be expressed on several kinds of stem/progenitor cells (SCs). In these cells, the role of TLRs in the regulation of the basal motility, proliferation, differentiation processes, self-renewal, and immunomodulation has been demonstrated. In this review, we analyze the many different functions that the TLRs assume in SCs, pointing out that they can have different effects, depending on the background and on the kind of ligands that they recognize. Moreover, we discuss the TLR involvement in the response of SC to specific tissue damage and in the reparative processes, as well as how the identification of molecules mediating the differential function of TLR signaling could be decisive for the development of new therapeutic strategies. Considering the available studies on TLRs in SCs, here we address the importance of TLRs in sensing an injury by stem/progenitor cells and in determining their behavior and reparative activity, which is dependent on the conditions. Therefore, it could be conceivable that SCs employed in therapy could be potentially exposed to TLR ligands, which might modulate their therapeutic potential in vivo. In this context, to modulate SC proliferation, survival, migration, and differentiation in the pathological environment, we need to better understand the mechanisms of action of TLRs on SCs and learn how to control these receptors and their downstream pathways in a precise way. In this manner, in the future, cell therapy could be improved and made safer.


Computer vision analysis captures atypical attention in toddlers with autism.
To demonstrate the capability of computer vision analysis to detect atypical orienting and attention behaviors in toddlers with autism spectrum disorder. One hundered and four toddlers of 16-31 months old (mean = 22) participated in this study. Twenty-two of the toddlers had autism spectrum disorder and 82 had typical development or developmental delay. Toddlers watched video stimuli on a tablet while the built-in camera recorded their head movement. Computer vision analysis measured participants' attention and orienting in response to name calls. Reliability of the computer vision analysis algorithm was tested against a human rater. Differences in behavior were analyzed between the autism spectrum disorder group and the comparison group. Reliability between computer vision analysis and human coding for orienting to name was excellent (intra-class coefficient 0.84, 95% confidence interval 0.67-0.91). Only 8% of toddlers with autism spectrum disorder oriented to name calling on >1 trial, compared to 63% of toddlers in the comparison group (p = 0.002). Mean latency to orient was significantly longer for toddlers with autism spectrum disorder (2.02 vs 1.06 s, p = 0.04). Sensitivity for autism spectrum disorder of atypical orienting was 96% and specificity was 38%. Older toddlers with autism spectrum disorder showed less attention to the videos overall (p = 0.03). Automated coding offers a reliable, quantitative method for detecting atypical social orienting and reduced sustained attention in toddlers with autism spectrum disorder.


Genome-scale identification of membrane-associated human mRNAs.
The subcellular localization of proteins is critical to their biological roles. Moreover, whether a protein is membrane-bound, secreted, or intracellular affects the usefulness of, and the strategies for, using a protein as a diagnostic marker or a target for therapy. We employed a rapid and efficient experimental approach to classify thousands of human gene products as either "membrane-associated/secreted" (MS) or "cytosolic/nuclear" (CN). Using subcellular fractionation methods, we separated mRNAs associated with membranes from those associated with the soluble cytosolic fraction and analyzed these two pools by comparative hybridization to DNA microarrays. Analysis of 11 different human cell lines, representing lymphoid, myeloid, breast, ovarian, hepatic, colon, and prostate tissues, identified more than 5,000 previously uncharacterized MS and more than 6,400 putative CN genes at high confidence levels. The experimentally determined localizations correlated well with in silico predictions of signal peptides and transmembrane domains, but also significantly increased the number of human genes that could be cataloged as encoding either MS or CN proteins. Using gene expression data from a variety of primary human malignancies and normal tissues, we rationally identified hundreds of MS gene products that are significantly overexpressed in tumors compared to normal tissues and thus represent candidates for serum diagnostic tests or monoclonal antibody-based therapies. Finally, we used the catalog of CN gene products to generate sets of candidate markers of organ-specific tissue injury. The large-scale annotation of subcellular localization reported here will serve as a reference database and will aid in the rational design of diagnostic tests and molecular therapies for diverse diseases.


Controlled synthesis of biodegradable lactide polymers and copolymers using novel in situ generated or single-site stereoselective polymerization initiators.
Polylactides and their copolymers are key biodegradable polymers used widely in biomedical, pharmaceutical and ecological applications. The development of synthetic pathways and catalyst/initiator systems to produce pre-designed polylactides, as well as the fundamental understanding of the polymerization reactions, has continuously been an important topic. Here, we will address the recent advances in the ring-opening polymerization of lactides, with an emphasis on the highly versatile in situ generated initiator systems and single-site stereoselective initiators. The in situ generated initiators including in situ formed yttrium, calcium and zinc alkoxides all have been shown to bring about a rapid and living polymerization of lactides under mild conditions, which facilitated the preparation of a variety of advanced lactide-based biomaterials. For example, well-defined di- and tri-block copolymers consisting of hydrophilic poly(ethylene glycol) blocks and hydrophobic polyester blocks, which form novel biodegradable polymersomes or biodegradable thermosensitive hydrogels, have been prepared. In the past few years, significant progress has also been made in the area of stereoselective polymerization of lactides. This new generation of initiators has enabled the production of polylactide materials with novel microstructures and/or properties, such as heterotactic (--RRSSRRSSRRSS--) polylactide, crystalline syndiotactic (--RSRSRSRSRSRS--) polylactide and isotactic stereoblock (--Rn Sn Rn Sn--) polylactide, exhibiting a high melting temperature. The recently developed polymerizations using in situ generated initiators and stereoselective polymerizations have no doubt opened a brand-new avenue for the design and exploration of polylactides and their copolymers.


A region of the 20 bp repeats lies 3' of human Ig Calpha1 and Calpha2 genes.
The murine Ig heavy chain gene locus is regulated by multiple elements. In addition to the intron enhancer, Emu, there is a complex regulatory region 3' of the Calpha gene, which spans approximately 40 kb and contains several enhancers. In contrast to mouse, the human IgH cluster contains two Calpha genes, each associated with duplicated arrays of other CH genes. There is evidence to suggest that each array is individually regulated. In this report, we describe an approximately 2 kb region containing 20 bp repeats that lies 3' of both human Calpha1 and Calpha2 genes. This repeat region appears to be the site of integration of the Epstein-Barr virus in the RGN1 B lymphoma cell line. The repeat region is homologous to a 420 bp segment in mouse that is located downstream of the Calpha membrane exon in the interval preceding the second of three poly(A) termination sites. However, in contrast to human, the murine segment contains degenerate repeats. The human repeat region bears significant homology to switch sequences, in particular to Smu and Salpha. We hypothesize that the human repeat regions may play a role in the class switch process by contributing to the stabilization of interactions between the two switch regions. The presence of a Sau3A site within the repeats presents a barrier to cloning with several existing human genomic libraries, most of which are based on partial Sau3A digestion. Furthermore, the homology of the repeat region with Smu and Salpha sequences may contribute to the difficulty in isolating YAC clones containing Calpha genes since homologous recombination could potentially have deleted this entire segment. Our map of these DNA segments provides a guide to their isolation and characterization.


Diet and risk of Type II diabetes: the role of types of fat and carbohydrate.
Although diet and nutrition are widely believed to play an important part in the development of Type II (non-insulin-dependent) diabetes mellitus, specific dietary factors have not been clearly defined. Much controversy exists about the relations between the amount and types of dietary fat and carbohydrate and the risk of diabetes. In this article, we review in detail the current evidence regarding the associations between different types of fats and carbohydrates and insulin resistance and Type II diabetes. Our findings indicate that a higher intake of polyunsaturated fat and possibly long-chain n-3 fatty acids could be beneficial, whereas a higher intake of saturated fat and trans-fat could adversely affect glucose metabolism and insulin resistance. In dietary practice, exchanging nonhydrogenated polyunsaturated fat for saturated and trans-fatty acids could appreciably reduce risk of Type II diabetes. In addition, a low-glycaemic index diet with a higher amount of fiber and minimally processed whole grain products reduces glycaemic and insulinaemic responses and lowers the risk of Type II diabetes. Dietary recommendations to prevent Type II diabetes should focus more on the quality of fat and carbohydrate in the diet than quantity alone, in addition to balancing total energy intake with expenditure to avoid overweight and obesity.


Sexual Partner Types and Incident HIV Infection Among Rural South African Adolescent Girls and Young Women Enrolled in HPTN 068: A Latent Class Analysis.
Sexual partners are the primary source of incident HIV infection among adolescent girls and young women (AGYW) in sub-Saharan Africa. Identifying partner types at greatest risk of HIV transmission could guide the design of tailored HIV prevention interventions. We conducted a secondary analysis of data from AGYW (aged 13-23 years) enrolled in a randomized controlled trial of cash transfers for HIV prevention in South Africa. Annually, AGYW reported behavioral and demographic characteristics of their 3 most recent sexual partners, categorized each partner using prespecified labels, and received HIV testing. We used latent class analysis (LCA) to identify partner types from reported characteristics, and generalized estimating equations to estimate the relationship between both LCA-identified and prespecified partner types and incident HIV infection. Across 2140 AGYW visits, 1034 AGYW made 2968 partner reports and 63 AGYW acquired HIV infection. We identified 5 LCA partner types, which we named monogamous HIV-negative peer partner; one-time protected in-school peer partner; out-of-school older partner; anonymous out-of-school peer partner; and cohabiting with children in-school peer partner. Compared to AGYW with only monogamous HIV-negative peer partners, AGYW with out-of-school older partners had 2.56 times the annual risk of HIV infection (95% confidence interval: 1.23 to 5.33), whereas AGYW with anonymous out-of-school peer partners had 1.72 times the risk (95% confidence interval: 0.82 to 3.59). Prespecified partner types were not associated with incident HIV. By identifying meaningful combinations of partner characteristics and predicting the corresponding risk of HIV acquisition among AGYW, LCA-identified partner types may provide new insights for the design of tailored HIV prevention interventions.


Improving the gas barrier property of clay-polymer multilayer thin films using shorter deposition times.
Relatively fast exposure times (5 s) to aqueous solutions were found to improve the gas barrier of clay-polymer thin films prepared using layer-by-layer (LbL) assembly. Contrary to the common belief about deposition time (i.e., the longer the better), oxygen transmission rates (OTRs) of these nano-brick-wall assemblies are improved by reducing exposure time (from 1 min to 5 s). Regardless of composition, LbL films fabricated using shorter deposition time are always thicker in the first few layers, which correspond to greater clay spacing and lower OTR. A quadlayer (QL) assembly consisting of three repeat units of branched polyethylenimine (PEI), poly(acrylic acid) (PAA), PEI and montmorillonite (MMT) clay is only 24 nm thick when deposited with 1 min exposure to each ingredient. Reducing the exposure time of polyelectrolytes to 5 s not only increases this film thickness to 55 nm but also reduces the oxygen transmission rate (OTR) to 0.05 cm3/(m2 day atm), which is 2 orders of magnitude lower than the same film made using 1 min exposures. A conceptual model is proposed to explain the differences in growth and barrier, which are linked to polyelectrolyte relaxation, desorption, and interdiffusion. The universality of these findings is further exemplified by depositing clays with varying aspect ratios. This ability to quickly deposit high-barrier nanocomposite thin films opens up a tremendous opportunity in terms of commercial-scale processing of LbL assemblies.


Pooled PCR testing strategy and prevalence estimation of submicroscopic infections using Bayesian latent class models in pregnant women receiving intermittent preventive treatment at Machinga District Hospital, Malawi, 2010.
Low malaria parasite densities in pregnancy are a diagnostic challenge. PCR provides high sensitivity and specificity in detecting low density of parasites, but cost and technical requirements limit its application in resources-limited settings. Pooling samples for PCR detection was explored to estimate prevalence of submicroscopic malaria infection in pregnant women at delivery. Previous work uses gold-standard based methods to calculate sensitivity and specificity of tests, creating a challenge when newer methodologies are substantially more sensitive than the gold standard. Thus prevalence was estimated using Bayesian latent class models (LCMs) in this study. Nested PCR (nPCR) for the 18S rRNA gene subunit of Plasmodium falciparum was conducted to detect malaria infection in microscopy-negative Malawian women on IPTp. Two-step sample pooling used dried blood spot samples (DBSs) collected from placenta or periphery at delivery. Results from nPCR and histology as well as previously published data were used to construct LCMs to estimate assay sensitivity and specificity. Theoretical confidence intervals for prevalence of infection were calculated for two-step and one-step pooling strategies. Of 617 microscopy-negative Malawian women, 39 (6.3%) were identified as actively infected by histology while 52 (8.4%) were positive by nPCR. One hundred forty (22.7%) individuals had past infection assessed by histology. With histology as a reference, 72% of women in the active infection group, 7.1% in the past infection group and 3.2% in histology-negative group were nPCR positive. Using latent class models without a gold standard, histology had a median sensitivity of 49.7% and specificity of 97.6% for active infection while PCR had a median sensitivity of 96.0% and specificity of 99.1%. The true prevalence of active infection was estimated at 8.0% (CI: 5.8-10.5%) from PCR. PCR also had similar sensitivity for detecting either peripheral or placental malaria for submicroscopic infections. One-step pooling would give similar confidence intervals for pool sizes less than 20 while reducing the number of tests performed. Pooled nPCR testing was a sensitive and resource-efficient strategy and LCMs provided precise prevalence estimates of submicroscopic infections. Compared to two-step pooling, one-step pooling could provide similar prevalence estimates at population levels with many fewer tests required.


White matter magnetic resonance hyperintensities in dementia of the Alzheimer type: morphological and regional cerebral blood flow correlates.
In a prospective MRI study the presence, appearance, volume, and regional cerebral blood flow (rCBF) correlates of periventricular hyperintensities (PVHs) and deep white matter hyperintensities (DWMHs) were examined in 18 patients with probable Alzheimer's disease and in 10 age matched healthy control subjects, all without major cerbrovascular risk factors. The 133Xe inhalation method and the [99mTc]-d,l-hexamethyl-propylene-amine-oxime (HMPAO) technique with single photon emission computed tomography (SPECT) were used to measure rCBF. Rating scores for PVHs were significantly higher in the Alzheimer's disease group (p < 0.01) and correlated significantly with the volume of ventricles (p < 0.05) and with systolic arterial blood pressure (p < 0.01), but not with rCBF. By contrast, there was no significant difference in the rating scores or volumes of DWMHs between the two groups, although three patients had extensive DWMH lesions in the central white matter. In the group of patients with Alzheimer's disease as a whole, the volume of DWMHs correlated well with rCBF in the hippocampal region ( r = -0.72; p < 0.001), but not with frontal, temporal, parietal, or occipital rCBF. Postmortem histopathology of extensive DWMH lesions in one patient with definite Alzheimer's disease showed a partial loss of myelin and astrocytic gliosis, but no ischaemic changes. It is concluded that DWMH lesions may be associated with reduced rCBF in the hippocampal region. The heterogenous topography of neocortical rCBF deficits in Alzheimer's disease could not be explained by deafferentation from underlying white matter hyperintensities and therefore may reflect variations in the topography of cortical abnormalities.


CpG sites associated with cigarette smoking: analysis of epigenome-wide data from the Sister Study.
Smoking increases the risk of many diseases, and it is also linked to blood DNA methylation changes that may be important in disease etiology. We sought to identify novel CpG sites associated with cigarette smoking. We used two epigenome-wide data sets from the Sister Study to identify and confirm CpG sites associated with smoking. One included 908 women with methylation measurements at 27,578 CpG sites using the HumanMethylation27 BeadChip; the other included 200 women with methylation measurements for 473,844 CpG sites using the HumanMethylation450 BeadChip. Significant CpGs from the second data set that were not included in the 27K assay were validated by pyrosequencing in a subset of 476 samples from the first data set. Our study successfully confirmed smoking associations for 9 previously established CpGs and identified 2 potentially novel CpGs: cg26764244 in GNG12 (p = 9.0 × 10-10) and cg22335340 in PTPN6 (p = 2.9 × 10-05). We also found strong evidence of an association between smoking status and cg02657160 in CPOX (p = 7.3 × 10-7), which has not been previously reported. All 12 CpGs were undermethylated in current smokers and showed an increasing percentage of methylation in former and never-smokers. We identified 2 potentially novel smoking related CpG sites, and provided independent replication of 10 previously reported CpGs sites related to smoking, one of which is situated in the gene CPOX. The corresponding enzyme is involved in heme biosynthesis, and smoking is known to increase heme production. Our study extends the evidence base for smoking-related changes in DNA methylation.


Telomere measurement in individuals occupationally exposed to pesticide mixtures in tobacco fields.
Occupational exposure to pesticides in tobacco fields causes genetic damage in farmers. The aim of this study was to analyze tobacco farmers chronically exposed to low doses of pesticides and nicotine (present in the tobacco leaves) in relation to absolute telomere length (aTL), and explore the influence of lifestyle characteristics, oxidative stress, and inorganic element levels. DNA was isolated from peripheral blood samples from agricultural workers and non-exposed individuals, and aTL was measured by quantitative real time polymerase chain reaction (qPCR) analysis. Oxidative stress (thiobarbituric acid reactive substances [TBARS], which measures oxidative damage to lipids; and toxic equivalent antioxidant capacity [TEAC], which measures total equivalent antioxidant capacity) was evaluated in serum, and inorganic element content was analyzed in whole blood through particle-induced X-ray emission technique. It was found that exposure to pesticides and tobacco smoking had significant effects on aTL. Individuals occupationally exposed to complex mixtures of pesticides in tobacco fields and individuals who smoked had decreased aTL compared with the non-exposed group. TBARS and TEAC were significantly elevated in the exposed group. There were no significant differences in inorganic elements. There was no evidence of an influence of age, gender, consumption of alcoholic beverages, or intake of fruits and vegetables on aTL within the groups. In addition, years of work in the tobacco field in the exposed group did not influence any of the variables analyzed. Although further studies were needed, these results suggested differences in telomere maintenance in tobacco farmers compared with the control group, indicating that telomere length may be a good biomarker of occupational exposure.


Preoperative plasmapheresis for elective thymectomy in myasthenia patient: is it necessary?
Background. Role of plasmapheresis before thymectomy remains controversial. The aim of this study is to determine the peri-operative and post-operative outcome of a thymectomy between performing and not performing a pre-operative plasmaphreresis. Patients and Methods. A retrospective chart review study was conducted in Chiang Mai University Hospital between January 2006 and December 2011. There were 86 myasthenia patients divided into two groups; Preoperative plasmapheresis group (PPG) and no preoperative plasmapheresis group (NPPG). The primary outcome involved post-operative extubation and the secondary outcome included post-operative complications, 28 day mortality and length of hospital stay. Results. Eighty-six patients were enrolled in this study. The number of patients who had a history of myasthenic crisis at any time or within one month in the PPG was significantly more than those in the NPPG. Muscle power and forced expiratory vital capacity in the NPPG was higher than that in the PPG. The postoperative extubation rate was similar in both groups. After controlling for the propensity score, there were no statistically significant differences in both of primary and secondary outcomes. Conclusion. The results of this study shows no significant differences between both groups in all outcomes, therefore the pre-operative plasmaphresis is not necessary for elective thymectomy.


Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial.
A substantial proportion of patients with type 2 diabetes are elderly (≥65 years) but this group has been largely excluded from clinical studies of glucose-lowering drugs. We aimed to assess the effectiveness of linagliptin, a dipeptidyl peptidase-4 inhibitor, in elderly patients with type 2 diabetes. In this randomised, double-blind, parallel-group, multinational phase 3 study, patients aged 70 years or older with type 2 diabetes, glycated haemoglobin A1c (HbA1c) of 7·0% or more, receiving metformin, sulfonylureas, or basal insulin, or combinations of these drugs, were randomised (by computer-generated randomisation sequence, concealed with a voice-response system, stratified by HbA1c level [<8·5% vs ≥8·5%] and insulin use [yes vs no], block size four) in a 2:1 ratio to once-daily oral treatment with linagliptin 5 mg or matching placebo for 24 weeks. Investigators and participants were masked to assignment throughout the study. The primary endpoint was change in HbA1c from baseline to week 24. This trial is registered with ClinicalTrials.gov, number NCT01084005. 241 community-living outpatients were randomised (162 linagliptin, 79 placebo). Mean age was 74·9 years (SD 4·3). Mean HbA1c was 7·8% (SD 0·8). At week 24, placebo-adjusted mean change in HbA1c with linagliptin was -0·64% (95% CI -0·81 to -0·48, p<0·0001). Overall safety and tolerability were much the same between the linagliptin and placebo groups; 75·9% of patients in both groups had an adverse event (linagliptin n=123, placebo n=60). No deaths occurred. Serious adverse events occurred in 8·6% (14) of patients in the linagliptin group and 6·3% (five) patients in the placebo group; none were deemed related to study drug. Hypoglycaemia was the most common adverse event in both groups, but did not differ between groups (24·1% [39] in the linagliptin group, 16·5% [13] in the placebo group; odds ratio 1·58, 95% CI 0·78-3·78, p=0·2083). In elderly patients with type 2 diabetes linagliptin was efficacious in lowering glucose with a safety profile similar to placebo. These findings could inform treatment decisions for achieving individualised glycaemic goals with minimal risk in this important population of patients. Boehringer Ingelheim.


Tissue-type plasminogen activator release in healthy subjects and hypertensive patients: relationship with beta-adrenergic receptors and the nitric oxide pathway.
The relationship between adrenergic stimuli and NO in modulating tissue-type plasminogen activator (t-PA) release from endothelial cells was investigated in normotensive subjects and essential hypertensive patients. Sympathetic activation, a well-known stimulus for endogenous fibrinolysis, is also involved in the determination of cardiovascular risk in essential hypertension. However, the existence of cross-talk between adrenergic stimuli and NO availability in modulating t-PA release is not well established yet. We assessed the release of t-PA in the forearm microcirculation of 58 normotensive subjects (mean age: 47+/-9 years) and 44 essential hypertensive patients (mean age: 48+/-11 years) under specific intra-arterial adrenergic stimuli. Intrabrachial infusion of epinephrine (0.1 to 0.3 microg/100 mL per minute) induced greater t-PA release in normotensive subjects as compared with essential hypertensive patients (P<0.05). However, inhibition of NO synthase with N(G)-monomethyl-L-arginine (100 microg/100 mL per minute) infusion blunted epinephrine-induced t-PA release in normotensive subjects (P<0.05) but not in essential hypertensive patients. In normotensive subjects, t-PA release by epinephrine was not affected by phentolamine (8 microg/100 mL per minute) coinfusion and was abolished in the presence of propanolol (10 microg/100 mL per minute). Intrabrachial isoproterenol (0.03 microg/100 mL per minute) induced a significant increase in t-PA release (P<0.01), an effect blunted by N(G)-monomethyl-L-arginine (P<0.05). In essential hypertensive patients, the response to isoproterenol was impaired as compared with normotensive subjects and was unaffected by N(G)-monomethyl-L-arginine coinfusion. In conclusion, the results of the present study demonstrate that adrenergic-induced t-PA release is mediated by beta-adrenoreceptors via a mechanism involving the NO pathway. Our results show an impaired adrenergic-stimulated t-PA release among essential hypertensive patients, probably mediated via a reduced NO availability. This impaired fibrinolytic activity might contribute to the increased cardiovascular risk associated with hypertension.


Rare Fibroepithelial Polyp Extending Along the Ureter: A Case Report
Fibroepithelial polyps of the urinary tract are rare tumors, and their occurrence in the upper urinary tract is highly unusual. This study reports a 9-year-old boy who presented to our clinic with complaints of unilateral flank pain and macroscopic hematuria. The direct urinary system graph did not show stone formation; therefore, magnetic resonance urography was performed. This revealed a filling defect in the left proximal ureter. On cystoscopy, a polyp was seen in the orifice of the left ureter, extending along the ureter. The polyp was resected by laser ablation and removed from the ureter. Histopathologic examination revealed a fibroepithelial polyp comprising fibrovascular stroma covered with transitional epithelium. Although extremely rare, a fibroepithelial polyp should be considered in the differential diagnosis when a young patient presents with flank pain and macroscopic hematuria. Endoscopic procedures may be the treatment of choice for polyps located in the upper ureter.