Vertical Distribution of Microplastics in the Water Column and Surficial Sediment from the Milwaukee River Basin to Lake Michigan.
Microplastic contamination was studied along a freshwater continuum from inland streams to the Milwaukee River estuary to Lake Michigan and vertically from the water surface, water subsurface, and sediment. Microplastics were detected in all 96 water samples and 9 sediment samples collected. Results indicated a gradient of polymer presence with depth: low-density particles decreased from the water surface to the subsurface to sediment, and high-density particles had the opposite result. Polymer identification results indicated that water surface and subsurface samples were dominated by low-density polypropylene particles, and sediment samples were dominated by more dense polyethylene terephthalate particles. Of the five particle-type categories (fragments, films, foams, pellets/beads, and fibers/lines), fibers/lines were the most common particle-type and were present in every water and sediment sample collected. Fibers represented 45% of all particles in water samples and were distributed vertically throughout the water column regardless of density. Sediment samples were dominated by black foams (66%, identified as styrene-butadiene rubber) and to a lesser extent fibers/lines (29%) with approximately 89% of all of the sediment particles coming from polymers with densities greater than 1.1 g cm-3. Results demonstrated that polymer density influenced partitioning between the water surface and subsurface and the underlying surficial sediment and the common practice of sampling only the water surface can result in substantial bias, especially in estuarine, harbor, and lake locations where water surface concentrations tend to overestimate mean water column concentrations.


BioDownloader: bioinformatics downloads and updates in a few clicks.
There are many ftp or http servers storing data required for biological research. While some download applications are available, there is no user-friendly download application with a graphical interface specifically designed and adapted to meet the requirements of bioinformatics. BioDownloader is a program for downloading and updating files from ftp and http servers. It is optimized to work robustly with large numbers of files. It allows the selective retrieval of only the required files (batch downloads, multiple file masks, ls-lR file parsing, recursive search, recent updates, etc.). BioDownloader has a built-in repository containing the settings for common bioinformatics file-synchronization needs, including the Protein Data Bank (PDB) and National Center for Biotechnology Information (NCBI) databases. It can post-process downloaded files, including archive extraction and file conversions. The program can be installed from http://dunbrack.fccc.edu/BioDownloader. The software is freely available for both non-commercial and commercial users under the BSD license.


Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis.
The purpose of this study was to evaluate the effects of L-4F, an apolipoprotein A-1 mimetic peptide, alone or with pravastatin, in apoE-/-Fas-/-C57BL/6 mice that spontaneously develop immunoglobulin G (IgG) autoantibodies, glomerulonephritis, osteopenia, and atherosclerotic lesions on a normal chow diet. Female mice, starting at eight to nine weeks of age, were treated for 27 weeks with 1) pravastatin, 2) L-4F, 3) L-4F plus pravastatin, or 4) vehicle control, followed by disease phenotype assessment. In preliminary studies, dysfunctional, proinflammatory high-density lipoproteins (piHDL) were decreased six hours after a single L-4F, but not scrambled L-4F, injection in eight- to nine-week old mice. After 35 weeks, L-4F-treated mice, in the absence/presence of pravastatin, had significantly smaller lymph nodes and glomerular tufts (PL, LP<0.05), lower serum levels of IgG antibodies to double stranded DNA (dsDNA) (PL<0.05) and oxidized phospholipids (oxPLs) (PL, LP<0.005), and elevated total and vertebral bone mineral density (PL, LP<0.01) compared to vehicle controls. Although all treatment groups presented larger aortic root lesions compared to vehicle controls, enlarged atheromas in combination treatment mice had significantly less infiltrated CD68+ macrophages (PLP<0.01), significantly increased mean alpha-actin stained area (PLP<0.05), and significantly lower levels of circulating markers for atherosclerosis progression, CCL19 (PL, LP<0.0005) and VCAM-1 (PL<0.0002). L-4F treatment, alone or with pravastatin, significantly reduced IgG anti-dsDNA and IgG anti-oxPLs, proteinuria, glomerulonephritis, and osteopenia in a murine lupus model of accelerated atherosclerosis. Despite enlarged aortic lesions, increased smooth muscle content, decreased macrophage infiltration, and decreased pro-atherogenic chemokines in L-4F plus pravastatin treated mice suggest protective mechanisms not only on lupus-like disease, but also on potential plaque remodeling in a murine model of systemic lupus erythematosus (SLE) and accelerated atherosclerosis.


Image segmentation by object color: a unifying framework and connection to color constancy.
A unifying framework is presented for algorithms that use the bands of a multispectral image to segment the image at material (i.e., reflectance) boundaries while ignoring spatial inhomogeneities incurred by accidents of lighting and viewing geometry. The framework assumes that the visual stimulus (image field) from a uniformly colored object is the sum of a small number of terms, each term being the product of a spatial and a spectral part. Based on this assumption, several quantities depending on the reflected light can be computed that are spatially invariant within object boundaries. For an image field either from two light sources on a matte surface or from a single light source on a dielectric surface with highlights, the invariants are the components of the unit normal to the plane in color space spanned by the pixels from the object. In some limited cases the normal to the plane can be used to estimate spectral-reflectance parameters of the object. However, in general the connection of color-constancy theories with image segmentation by object color is a difficult problem. The concomitant constraints on segmentation and color-constancy algorithms are discussed in light of this fact.


Oncolytic viruses in head and neck cancer: a new ray of hope in the management protocol.
This paper intends to highlight the different types of oncolytic viruses (OVs), mechanism of tumor specificity, its safety, and various obstacles in the design of treatment and combination therapy utilizing oncotherapy. Search was conducted using the internet-based search engines and scholarly bibliographic databases with key words such as OVs, head and neck cancer, viruses, oral squamous cell carcinoma, and gene therapy. Revolutionary technologies in the field of cancer treatment have gone through a series changes leading to the development of innovative therapeutic strategies. Oncolytic virotherapy is one such therapeutic approach that has awaited phase III clinical trial validation. OVs are self-replicating, tumor selective and lyse cancer cells following viral infection. By modifying the viral genome, it is possible to direct their toxicity toward cancer cells. Viruses that are used for treatment of head and neck cancer are either naturally occurring or genetically modified. OVs are tumor selective and potential anticancer agents. Virotherapy may become the standard of care and part of combination therapy in the management of head and neck cancer in the future.


Impact of Hypertension on Cognitive Function: A Scientific Statement From the American Heart Association.
Age-related dementia, most commonly caused by Alzheimer disease or cerebrovascular factors (vascular dementia), is a major public health threat. Chronic arterial hypertension is a well-established risk factor for both types of dementia, but the link between hypertension and its treatment and cognition remains poorly understood. In this scientific statement, a multidisciplinary team of experts examines the impact of hypertension on cognition to assess the state of the knowledge, to identify gaps, and to provide future directions. Authors with relevant expertise were selected to contribute to this statement in accordance with the American Heart Association conflict-of-interest management policy. Panel members were assigned topics relevant to their areas of expertise, reviewed the literature, and summarized the available data. Hypertension disrupts the structure and function of cerebral blood vessels, leads to ischemic damage of white matter regions critical for cognitive function, and may promote Alzheimer pathology. There is strong evidence of a deleterious influence of midlife hypertension on late-life cognitive function, but the cognitive impact of late-life hypertension is less clear. Observational studies demonstrated a cumulative effect of hypertension on cerebrovascular damage, but evidence from clinical trials that antihypertensive treatment improves cognition is not conclusive. After carefully reviewing the literature, the group concluded that there were insufficient data to make evidence-based recommendations. However, judicious treatment of hypertension, taking into account goals of care and individual characteristics (eg, age and comorbidities), seems justified to safeguard vascular health and, as a consequence, brain health.


How Repeatable Is the Ergogenic Effect of Caffeine? Limited Reproducibility of Acute Caffeine (3 mg.kg-1) Ingestion on Muscular Strength, Power, and Muscular Endurance.
This study aimed to determine the effect of 3 mg.kg−1 acute caffeine ingestion on muscular strength, power and strength endurance and the repeatability of potential ergogenic effects across multiple trials. Twenty-two university standard male rugby union players (20 ± 2 years) completed the study. Using a double-blind, randomized, and counterbalanced within-subject experimental design. Participants completed six experimental trials (three caffeine and three placebo) where force time characteristic of the Isometric Mid-Thigh Pull (IMTP), Countermovement Jump (CMJ) and Drop Jumps (DJ) were assessed followed by assessments of Chest Press (CP), Shoulder Press (SP), Squats (SQ), and Deadlifts (DL) Repetitions Until Failure (RTF at 70% 1 RM). ANOVA indicated that caffeine improved both the CMJ and DJ (p < 0.044) and increased RTF in all RTF assessments (p < 0.002). When individual caffeine trials were compared to corresponding placebo trials, effect sizes ranged from trivial-large favoring caffeine irrespective of a main effect of treatment being identified in the ANOVA. These results demonstrate for the first time that the performance enhancing effects of caffeine may not be repeatable between days, where our data uniquely indicates that this is in part attributable to between sessions variation in caffeine's ergogenic potential.


The therapy of peri-implantitis: a systematic review.
To evaluate the success of treatments aimed at the resolution of peri-implantitis in patients with osseointegrated implants. The potentially relevant literature was assessed independently by two reviewers to identify case series and comparative studies describing the treatment of peri-implantitis with a follow-up of at least 3 months. Medline, Embase, and The Cochrane Library were searched. For the purposes of this review, a composite criterion for successful treatment outcome was used which comprised implant survival with mean probing depth < 5 mm and no further bone loss. A total of 43 publications were included: 4 papers describing 3 nonsurgical case series, 13 papers describing 10 comparative studies of nonsurgical interventions, 15 papers describing 14 surgical case series, and 11 papers describing 6 comparative studies of surgical interventions. No trials comparing nonsurgical with surgical interventions were found. The length of follow-up varied from 3 months to 7.5 years. Due to the heterogeneity of study designs, peri-implantitis case definitions, outcome variables, and reporting, no meta-analysis was performed. Eleven studies could be evaluated according to a composite success criterion. Successful treatment outcomes at 12 months were reported in 0% to 100% of patients treated in 9 studies and in 75% to 93% of implants treated in 2 studies. Commonalities in treatment approaches between studies included (1) a pretreatment phase, (2) cause-related therapy, and (3) a maintenance care phase. While the available evidence does not allow any specific recommendations for the therapy of peri-implantitis, successful treatment outcomes at 12 months were reported in a majority of patients in 7 studies. Although favorable short-term outcomes were reported in many studies, lack of disease resolution as well as progression or recurrence of disease and implant loss despite treatment were also reported. The reported outcomes must be viewed in the context of the varied peri-implantitis case definitions and severity of disease included as well as the heterogeneity in study design, length of follow-up, and exclusion/inclusion criteria.


Supplementation with groundnut haulms for sheep fattening in the West African Sahel.
Groundnut haulms along with cowpea hay are major crop residues used for animal fattening in the West African Sahel. In traditional sheep fattening, feeds are always provided ad-hoc and in an unregulated fashion, which is rather wasteful. As a preliminary study to establish the optimal feeding levels of groundnut haulms for profitable sheep fattening, a feeding trial was conducted for 70 days with four levels of groundnut haulms (0, 150, 300 and 450 g/day) and a basal diet of bush hay. The effects of supplementation with groundnut haulms on feed intake, water consumption, live weight changes and economic return were determined. Twenty-four Peuhl Oudah rams with average initial weight of 28.6 kg (SD = 1.4) were randomly allocated to four treatments defined by the four levels of groundnut haulms in the diet. Faeces and urine were collected in weeks 5 and 9 of the trial. Digestible organic matter intake (g/(kg LW)0.75) and nitrogen intake (g/day) increased linearly with the level of groundnut haulms offered. Sheep that were fed only bush hay lost 18.4 g/day, while those that were offered 150, 300 and 450 g of groundnut haulms gained 1.4, 19.3 and 40.2 g/day, respectively. The gross return ranged from 1883 to 4946 FCFA per ram. Net benefit, after removing the feed and veterinary costs from the gross return, ranged from 368 to 1400 FCFA per ram.


Reduction of spherical aberration: experimental model of photoablation.
Several authors have suggested that a compound ablation for myopia may reduce postoperative spherical aberration. This technique consists of treating myopic ablation by increasing the preoperative sphere 25% and applying a hyperopic ablation of 25% of preoperative sphere. Theoretically, this technique allows optical zone increase, and elimination of the peripheral red ring. Eight eyes of four patients with bilateral moderate myopia received laser epithelial keratomileusus (LASEK) with the Nidek EC-5000 excimer laser. In each patient, one eye was treated with the compound ablation (Group 1), and the fellow eye with the standard cross-cylinder technique (Group 2). Mean preoperative refraction and BSCVA were comparable within the two groups. At 1 month postoperatively, UCVA was significantly better in Group 2 than in Group 1 eyes. In neither group was clinically important haze seen. Subjectively, all patients rated more satisfactorily the eye that received the standard ablation (Group 2) than the one treated with compound ablation (Group 1). Evaluation of keratorefractive indices derived from corneal topography revealed significantly better eccentricity in Group 2 eyes. Corneal topography showed the presence of a central island in all Group 1 eyes. The compound ablation hypothesis was not confirmed. Presence of central island in compound-treated eyes induced significant optical aberrations.


Suicidality in schizophrenia spectrum disorders: the relationship to hallucinations and persecutory delusions.
Assessment of suicide risk is crucial in schizophrenia and results concerning risk contributed by hallucinations and persecutory delusions are inconsistent. We aimed to determine factors associated with suicidal ideation and plans at the time of acute admission in patients suffering from schizophrenia spectrum disorders. One hundred and twenty-four patients older than 18 years admitted to an acute psychiatric ward due to psychosis were consecutively included. Predictors of suicidal ideation and suicide plans at the time of admission were examined with multinominal logistic regression and structural equation modelling (SEM). The study design was pragmatic, thus entailing a clinically relevant representation. Depression Odds Ratio (OR) 12.9, Drug use OR 4.07, Hallucinations OR 2.55 and Negative symptoms OR 0.88 significantly predicted Suicidal ideation. Suspiciousness/ Persecution did not. Only Depression and Hallucinations significantly predicted Suicide plans. In the SEM-model Anxiety, Depression and Hopelessness connected Suspiciousness/Persecution, Hallucinations and Lack of insight with Suicidal ideation and Suicide plans. The study contributes to an increasing evidence base supporting an association between hallucinations and suicide risk. We want to emphasise the importance of treating depression and hallucinations in psychotic disorders, reducing hopelessness while working with insight and reducing drug abuse in order to lower suicide risk. ClinicalTrials.gov ID; URL: http://www.clinicaltrials.gov/NCT00932529.


Sinus node function in patients operated for mitral valve disease. indirect evaluation with epimyocardial electrodes.
To study the interatrial conduction times and atrial node performance in patients submitted to mitral valve surgery with the aid of temporary atrial epicardic electrodes. The atriograms were carried out in the first postoperative day and before the hospital discharge of ten consecutive patients. Sixty percent of the patients could complete the post-operative study protocol. The main results were: a) Post-operative arrhythmias were detected in 50% of the patients; b) There were no statistical differences between the pre and post-operative 12 lead EKGs. c) The interatrial conduction time (IACT) ranged from 90 to 140ms in the first post-operative day, and from 110 to 130ms at hospital discharge; d) The sinus node recovery time (SNRT) ranged from 250 to 560ms in the first post-operative day and from 180 to 360ms at hospital discharge; e) The sinus atrial conduction time (SACT) remained between 70 and 140ms, both in the first post-operative day and at hospital discharge, and; f) The IACT was normal in patients whose left atrium (LA) was less than 50mm in diameter but supra normal in the remaining cases. Sinus node function and inter-atrial conduction are not altered by mitral valve operation. Post-operative programmed epicardic atrial stimulation is easy and safe.


Genetic linkage to chromosome 22q12 for a heavy-smoking quantitative trait in two independent samples.
We conducted a genomewide linkage screen of a simple heavy-smoking quantitative trait, the maximum number of cigarettes smoked in a 24-h period, using two independent samples: 289 Australian and 155 Finnish nuclear multiplex families, all of which were of European ancestry and were targeted for DNA analysis by use of probands with a heavy-smoking phenotype. We analyzed the trait, using a regression of identity-by-descent allele sharing on the sum and difference of the trait values for relative pairs. Suggestive linkage was detected on chromosome 22 at 27-29 cM in each sample, with a LOD score of 5.98 at 26.96 cM in the combined sample. After additional markers were used to localize the signal, the LOD score was 5.21 at 25.46 cM. To assess the statistical significance of the LOD score in the combined sample, 1,000 simulated genomewide screens were conducted, resulting in an empirical P value of .006 for the LOD score of 5.21. This linkage signal is driven mainly by the microsatellite marker D22S315 (22.59 cM), which had a single-point LOD score of 5.41 in the combined sample and an empirical P value <.001 from 1,000 simulated genomewide screens. This marker is located within an intron of the gene ADRBK2, encoding the beta-adrenergic receptor kinase 2. Fine mapping of this linkage region may reveal variants contributing to heaviness of smoking, which will lead to a better understanding of the genetic mechanisms underlying nicotine dependence.


Survey of doctors' perception of professional values.
New challenges in the medical field of the third millennium emphasise the "humanization of medicine" leading to a redefinition of doctors' values, limits and roles. The study aims to assess whether there are different personality dimensions of physicians in relation to their perception of professional values and public expectations. A questionnaire on the perception of professional values and the opinion on work in the medical field, work relationships and public expectations was administered to 374 doctors attending Continuing Medical Education courses. Two personality dimensions were identified: the first dimension (which we termed "Performance Attainment") is associated preeminently with values of competence, advocacy, confidentiality, spirit of enquiry, integrity, responsibility and commitment; the second dimension (which we called "Personal Involvement") focuses on concern and compassion. The doctors that have more difficulty accepting judgements on their activity are those who think that "Performance attainment" is less important (β = 6.01; p-value = 0.007). Instead, the doctors who believe "public expectation of the health system" is not high enough, tend to think that "Performance Attainment" is more important (β = -6.08; p-value = 0.024). The less importance is given to the values of "Personal Involvement", the less is the doctor's perception of having a leading role in respect to other health professionals (β = -2.37; p-value = 0.018). Our results demonstrate that there are two different attitudes in terms of recognition and selection of the essential values to better practice the medical profession. Whether the doctors attach more importance to one dimension or the other, they do not differ in our analysis for how they answered the questions about relationships with patients, colleagues or family commitments in the questionnaire, even if they work in different areas. This suggests that in our research there is no single personal attitude that characterizes "a good doctor".


Non-equilibrium electrokinetic micromixer with 3D nanochannel networks.
We report an active micromixer which utilizes vortex generation due to non-equilibrium electrokinetics near the interface between a microchannnel and a nanochannel networks membrane (NCNM), constructed from geometrically controlled in situ self-assembled nanoparticles. A large interfacing area where it is possible to generate vortices can be realized, because nano-interstices between the assembled nanoparticles are intrinsically collective three-dimensional nanochannel networks, which may be compared to typical silicon-based 2D nanochannels. The proposed mixer shows a 2-fold shorter mixing time (~0.78 ms) and a 34-fold shorter mixing length (~7.86 μm) compared to conventional 2D nanochannels.


Characterizing the metabolic phenotype: a phenotype phase plane analysis.
Genome-scale metabolic maps can be reconstructed from annotated genome sequence data, biochemical literature, bioinformatic analysis, and strain-specific information. Flux-balance analysis has been useful for qualitative and quantitative analysis of metabolic reconstructions. In the past, FBA has typically been performed in one growth condition at a time, thus giving a limited view of the metabolic capabilities of a metabolic network. We have broadened the use of FBA to map the optimal metabolic flux distribution onto a single plane, which is defined by the availability of two key substrates. A finite number of qualitatively distinct patterns of metabolic pathway utilization were identified in this plane, dividing it into discrete phases. The characteristics of these distinct phases are interpreted using ratios of shadow prices in the form of isoclines. The isoclines can be used to classify the state of the metabolic network. This methodology gives rise to a "phase plane" analysis of the metabolic genotype-phenotype relation relevant for a range of growth conditions. Phenotype phase planes (PhPPs) were generated for Escherichia coli growth on two carbon sources (acetate and glucose) at all levels of oxygenation, and the resulting optimal metabolic phenotypes were studied. Supplementary information can be downloaded from our website (http://epicurus.che.udel.edu).


Visible light optical coherence correlation spectroscopy.
Optical coherence correlation spectroscopy (OCCS) allows studying kinetic processes at the single particle level using the backscattered light of nanoparticles. We extend the possibilities of this technique by increasing its signal-to-noise ratio by a factor of more than 25 and by generalizing the method to solutions containing multiple nanoparticle species. We applied these improvements by measuring protein adsorption and formation of a protein monolayer on superparamagnetic iron oxide nanoparticles under physiological conditions.


Local governments and civil society lead breakthrough for tobacco control: lessons from Chandigarh and Chennai.
Smoke-free legislation is gaining popularity; however, it must accompany effective implementation to protect people from secondhand smoke (SHS) which causes 600,000 deaths annually. Increasing numbers of smoke-free cities in the world indicate that municipalities have an important role in promoting smoke-free environments. The objectives were to describe the local initiative to promote smoke-free environments and identify the key factors that contributed to the process. Observations were based on a case study on the municipal smoke-free initiatives in Chandigarh and Chennai, India. India adopted the Cigarette and Other Tobacco Products Act in 2003, the first national tobacco control law including smoke-free provisions. In an effort to enforce the Act at the local level, a civil society organization in Chandigarh initiated activities urging the city to support the implementation of the provisions of the Act which led to the initiation of city-wide law enforcement. After the smoke-free declaration of Chandigarh in 2007, Chennai also initiated a smoke-free intervention led by civil society in 2008, following the strategies used in Chandigarh. These experiences resonate with other cases in Asian cities, such as Jakarta, Davao, and Kanagawa as well as cities in other areas of the world including Mexico City, New York City, Mecca and Medina. The cases of Chandigarh and Chennai demonstrate that civil society can make a great contribution to the enforcement of smoke-free laws in cities, and that cities can learn from their peers to protect people from SHS.


Gamified Design for Health Workshop.
Increasing lifespans for chronic disease sufferers means a population of young patients who require lifestyle intervention from an early age. For multiple sclerosis (MS) patients, social problems begin with the decline of cognitive skills and their quality of life is affected. In this workshop, organizers will propose participants to work on different gamification design approachs to solve MS patients' engagement problem. Participants will obtain skills that can be extrapolated to other conditions that require patients change to adopt a different behavior. At the end, participants will present their proposed gamification design and discuss and comment each solution, assessing potential unintended outcomes and advantages.


Does Combined Anterior-Posterior Approach Improve Outcomes Compared with Posterioronly Approach in Traumatic Thoracolumbar Burst Fractures?: A Systematic Review.
The aim of this systematic review was to evaluate the surgical, radiological, and functional outcomes of posterior-only versus combined anterior-posterior approaches in patients with traumatic thoracolumbar burst fractures. The ideal approach (anterior-only, posterior-only, or combined anterior-posterior) for the surgical management of thoracolumbar burst fracture remains controversial, with each approach having its advantages and disadvantages. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed (registration no., CRD42018115120). The authors reviewed comparative studies evaluating posterior-only approach compared with combined anterior-posterior approaches with respect to clinical, surgical, radiographic, and functional outcome measures. Five retrospective cohort studies were included. Postoperative neurological deterioration was not reported in either group. Operative time, estimated blood loss, and postoperative length of stay were increased among patients in the combined anterior-posterior group in one study and equivalent between groups in another study. No significant difference was observed between the two approaches with regards to long-term postoperative Cobb angle (mean difference, -0.2; 95% confidence interval, -5.2 to 4.8; p =0.936). Moreover, no significant difference in functional patient outcomes was observed in the 36item Short-Form Health Survey, Visual Analog Scale, and return-to-work rates between the two groups. The available evidence does not indicate improved clinical, radiologic (including kyphotic deformity), and functional outcomes in the combined anterior-posterior and posterior-only approaches in the management of traumatic thoracolumbar burst fractures. Further studies are required to ascertain if a subset of patients will benefit from a combined anterior-posterior approach.


Transfer RNA recognition by the Escherichia coli delta2-isopentenyl-pyrophosphate:tRNA delta2-isopentenyl transferase: dependence on the anticodon arm structure.
To elucidate the sequence elements required in the anticodon stem for the recognition of Escherichia coli tRNA(Ser) (GGA) by the E. coli isopentenyl-tRNA:A37 transferase (IPTT), which result in the conversion of A37 into isopentenylated i6A37, we have tested and characterized in vitro T7-runoff transcripts of 17 variants of E. coli tRNA(Ser)(GGA) and 7 other tRNAs from E. coli and yeast. Our results indicate that, instead of a stringent specific anticodon stem and loop sequence, the key feature required for the recognition of E. coli tRNAs by IPTT is the A36A37A38 sequence occurring within the seven-membered anticodon loop, and the retention of the standard helical structure and flexibility, especially in the proximal anticodon stem. The G30*U40 mismatch base pair close to the anticodon loop is strictly avoided. The frequent occurrence of a C-G base pair in the three stem locations closest to the loop (positions 29-41, 30-40 and 31-39) or the occurrence of even one such C-G base pair along with some other similarly less suited, but individually tolerated deviations can also totally abolish the A37 isopentenylation of tRNA. For the position 30-40, the G-C base pair is shown uniquely suited, whereas for the adjoining 29-41 stem location, a purine-pyrimidine base pair with pyrimidine on the 3'-side is strongly preferred. Retention of the overall 3D tRNA structure is favorable for isopentenylation and allows some tolerance of proximal stem sequence deviations. Our data suggest a recognition mode that implies the interaction of IPTT with the strictly conserved A36A37A38 sequence and the other functional groups located in the minor groove of the anticodon stem.


Correlation of radiographic renal cell carcinoma tumor volume utilizing computed tomography and magnetic resonance imaging compared with pathological tumor volume.
New evidence suggests that three-dimensional pathological tumor volume (TV) provides additional prognostic information in renal cell carcinoma (RCC) to that provided by tumor size alone. The aim of this study was to assess the correlation between radiographic TV, by computed tomography (CT) and magnetic resonance imaging (MRI), and pathological tumor volume (TV). Pathological TV from 143 patients treated with surgical removal for unilateral RCC was compared with radiographic TV. Measurements were taken by one central pathologist and one radiologist, who were blinded to each other's findings. The TV for each modality was calculated using the equation for measuring the volume of an ellipsoid: π/6(Length × Width × Height). No statistical differences were noted for relevant clinicopathological covariates between patients who had CT scan or MRI. The correlation coefficient for pathological TV was similar for MRI (0.97) and CT (0.98), although the correlation was lowest for those patients with the smallest tumors (0.82 for pT1a). The TV correlation was weaker among non-obese patients [0.99 for body mass index (BMI) >30 vs 0.89 for BMI <30]. Gender, tumor grade and tumor subtype did not affect TV correlation. Incongruence between radiographic TV and pathological TV is due to overestimation of TV by radiographic imaging. There was a strong correlation between RCC TV on preoperative images (CT and MRI) compared with pathological TV. This correlation was diminished for patients with smaller tumors. Future investigations are needed to validate this observation and more directly explore the ability of radiographic TV to predict RCC progression and patient outcome.


Initial presentation of CNS-restricted acute lymphoblastic B cell leukaemia as peripheral polyneuropathy.
We report a case of a 58-year-old woman who presented with a 1-month course of progressive lower and upper extremity weakness in addition to binocular diplopia. Diagnostic lumbar puncture revealed atypical lymphoid cells with 28% blasts. Immunophenotype was consistent with B cell acute lymphoblastic leukaemia (B-ALL). Further work up showed no systemic involvement but extensive thoracolumbar-sacral leptomeningeal disease. The patient was treated with several courses of intrathecal and systemic chemotherapy followed by craniospinal irradiation for consolidation. There was initial steady improvement in neurological symptoms and leptomeningeal disease, the latter being ascertained through radiological studies and cerebrospinal fluid examination. After 10 months of response, the patient relapsed with central nervous system (CNS) and systemic disease. B-ALL is a rare precursor lymphoid neoplasm that generally presents with systemic disease. While CNS involvement is not uncommon, isolated involvement of this compartment without systemic disease is exceedingly rare.


Implications of Impaired Endurance Performance following Single Bouts of Resistance Training: An Alternate Concurrent Training Perspective.
A single bout of resistance training induces residual fatigue, which may impair performance during subsequent endurance training if inadequate recovery is allowed. From a concurrent training standpoint, such carry-over effects of fatigue from a resistance training session may impair the quality of a subsequent endurance training session for several hours to days with inadequate recovery. The proposed mechanisms of this phenomenon include: (1) impaired neural recruitment patterns; (2) reduced movement efficiency due to alteration in kinematics during endurance exercise and increased energy expenditure; (3) increased muscle soreness; and (4) reduced muscle glycogen. If endurance training quality is consistently compromised during the course of a specific concurrent training program, optimal endurance development may be limited. Whilst the link between acute responses of training and subsequent training adaptation has not been fully established, there is some evidence suggesting that cumulative effects of fatigue may contribute to limiting optimal endurance development. Thus, the current review will (1) explore cross-sectional studies that have reported impaired endurance performance following a single, or multiple bouts, of resistance training; (2) identify the potential impact of fatigue on chronic endurance development; (3) describe the implications of fatigue on the quality of endurance training sessions during concurrent training, and (4) explain the mechanisms contributing to resistance training-induced attenuation on endurance performance from neurological, biomechanical and metabolic standpoints. Increasing the awareness of resistance training-induced fatigue may encourage coaches to consider modulating concurrent training variables (e.g., order of training mode, between-mode recovery period, training intensity, etc.) to limit the carry-over effects of fatigue from resistance to endurance training sessions.


A comparison of transjugular and plugged-percutaneous liver biopsy in patients with impaired coagulation.
Patients with liver disease frequently have impaired blood coagulation. The optimal method for liver biopsy in this situation is not established. To investigate this issue we randomised 117 patients with impaired blood coagulation, in whom liver biopsy was required, to receive either transjugular or plugged-percutaneous biopsy. Seventeen patients were excluded prior to biopsy and a protocol biopsy was performed in 100 patients (44 transjugular, 56 plugged-percutaneous). Liver tissue was obtained in 97 (42 transjugular, 55 plugged-percutaneous). Plugged-percutaneous liver biopsy was quicker and easier than transjugular liver biopsy and the biopsies obtained were significantly larger (12 +/- 5 mm vs. 6 +/- 4 mm; p < 0.001). However, 2 of 56 (3.5%) patients who received plugged-percutaneous biopsy had haemorrhage which required transfusion, while none of the 44 patients who received transjugular biopsy had haemorrhage (not significant). Both methods of liver biopsy were associated with a high success rate and a low incidence of complications. Plugged-percutaneous liver biopsy provides larger biopsies but may be associated with an increased risk of haemorrhage.


Molecular targets for the protodynamic action of cis-urocanic acid in human bladder carcinoma cells.
cis-urocanic acid (cis-UCA) is an endogenous amino acid metabolite capable of transporting protons from the mildly acidic extracellular medium into the cell cytosol. The resulting intracellular acidification suppresses many cellular activities. The current study was aimed at characterizing the molecular mechanisms underlying cis-UCA-mediated cytotoxicity in cultured cancer cells. 5367 bladder carcinoma cells were left untreated or treated with cis-UCA. Cell death was assessed by measuring caspase-3 activity, mitochondrial membrane polarization, formation and release of cytoplasmic histone-associated DNA fragments, and cellular permeabilization. Cell viability and metabolic activity were monitored by colorimetric assays. Nuclear labelling was used to quantify the effects of cis-UCA on cell cycle. The activity of the ERK and JNK signalling pathways was studied by immunoblotting with specific antibodies. Phosphatase activity in cis-UCA-treated cells was determined by assay kits measuring absorbance resulting from the dephosphorylation of an artificial substrate. All statistical analyses were performed using the two-way Student's t-test (p < 0.05). Here we report that treatment of the 5637 human bladder carcinoma cells with 2% cis-UCA induces both apoptotic and necrotic cell death. In addition, metabolic activity of the 5637 cells is rapidly impaired, and the cells arrest in cell cycle in response to cis-UCA. Importantly, we show that cis-UCA promotes the ERK and JNK signalling pathways by efficiently inhibiting the activity of serine/threonine and tyrosine phosphatases. Our studies elucidate how cis-UCA modulates several cellular processes, thereby inhibiting the proliferation and survival of bladder carcinoma cells. These anti-cancer effects make cis-UCA a potential candidate for the treatment of non-muscle invasive bladder carcinoma.


Intracapsular decompression or radical resection followed by Gamma Knife surgery for patients harboring a large vestibular schwannoma.
Microsurgery is the primary treatment used for patients harboring a large vestibular schwannoma (VS). However, its outcome may lead to hearing impairment and facial nerve dysfunction particularly when resection is extended outside the tumor capsule. When surgery for a large VS consists of intracapsular resection and decompression, better preservation of facial and hearing function are obtained. In this study, the authors compared outcomes of intracapsular decompression followed by Gamma Knife surgery (GKS) with outcomes of standard microsurgery followed by radiosurgery. Between August 2003 and October 2008, 35 patients harboring large VSs (> 3 cm in diameter) were enrolled in this study. Eighteen patients underwent intracapsular decompression followed by GKS (Group I), and 17 patients underwent radical extracapsular resection followed by GKS (Group II). In all cases GKS was performed with a margin dose of 12 Gy. All patients were followed up for at least 3 years. All patients also underwent periodic audiography, electroneuronography (ENoG), MR imaging, and testing with the SF-36 form. The Student t-test and repeated ANOVA were used for statistical analysis. The mean ages of the patients (± SEM) in Groups I and II were 50 ± 3.0 and 49 ± 2.3 years, respectively. The female/male ratios were 8:10 in Group I and 7:10 in Group II. All patients had excellent facial function as measured according to the House-Brackmann Facial Grading System (Grade I or II) preoperatively. After the operation, 16 patients (89%) in Group I retained excellent facial function, whereas only 6 patients (35%) in Group II had excellent facial function (p < 0.01). In Group I, 11 patients had serviceable hearing, and all 11 (100%) retained hearing function after the operation. In Group II, 11 patients had serviceable hearing, but none retained hearing function postoperatively (p < 0.001). In Group I, the mean tumor volume (± SEM) was 17.5 ± 1.1 cm(3), and the postoperative volume was 9.35 ± 1.02 cm(3). In Group II, the mean tumor volume was 16.4 ± 0.95 cm(3), whereas the postoperative volume was 1.1 ± 0.14 cm(3) (p < 0.001). After GKS, the tumor volume was reduced to 5.12 ± 1.1 cm(3) and 0.9 ± 0.1 cm(3) in Groups I and II, respectively. No patients experienced adverse effects after GKS. The mean return-to-work times were 2.4 ± 0.16 and 33.4 ± 4.3 weeks in Groups I and II, respectively (p < 0.001). According to the results obtained using the 36-Item Short Form Health Survey (SF-36), patients in Group I enjoyed more significant improvements in quality of life than patients in Group II (p < 0.001). Intracapsular decompression followed by GKS afforded a better neurological outcome and quality of life than radical extracapsular resection followed by GKS. Further application of this approach in patients harboring large VSs seems warranted.


Evaluation of teleoperated surgical robots in an enclosed undersea environment.
The ability to support surgical care in an extreme environment is a significant issue for both military medicine and space medicine. Telemanipulation systems, those that can be remotely operated from a distant site, have been used extensively by the National Aeronautics and Space Administration (NASA) for a number of years. These systems, often called telerobots, have successfully been applied to surgical interventions. A further extension is to operate these robotic systems over data communication networks where robotic slave and master are separated by a great distance. NASA utilizes the National Oceanographic and Atmospheric Administration (NOAA) Aquarius underwater habitat as an analog environment for research and technology evaluation missions, known as NASA Extreme Environment Mission Operations (NEEMO). Three NEEMO missions have provided an opportunity to evaluate teleoperated surgical robotics by astronauts and surgeons. Three robotic systems were deployed to the habitat for evaluation during NEEMO 7, 9, and 12. These systems were linked via a telecommunications link to various sites for remote manipulation. Researchers in the habitat conducted a variety of tests to evaluate performance and applicability in extreme environments. Over three different NEEMO missions, components of the Automated Endoscopic System for Optimal Positioning (AESOP), the M7 Surgical System, and the RAVEN were deployed and evaluated. A number of factors were evaluated, including communication latency and semiautonomous functions. The M7 was modified to permit a remote surgeon the ability to insert a needle into simulated tissue with ultrasound guidance, resulting in the world's first semi-autonomous supervisory-controlled medical task. The deployment and operation of teleoperated surgical systems and semi-autonomous, supervisory-controlled tasks were successfully conducted.


Linear ubiquitination prevents inflammation and regulates immune signalling.
Members of the tumour necrosis factor (TNF) receptor superfamily have important functions in immunity and inflammation. Recently linear ubiquitin chains assembled by a complex containing HOIL-1 and HOIP (also known as RBCK1 and RNF31, respectively) were implicated in TNF signalling, yet their relevance in vivo remained uncertain. Here we identify SHARPIN as a third component of the linear ubiquitin chain assembly complex, recruited to the CD40 and TNF receptor signalling complexes together with its other constituents, HOIL-1 and HOIP. Mass spectrometry of TNF signalling complexes revealed RIP1 (also known as RIPK1) and NEMO (also known as IKKγ or IKBKG) to be linearly ubiquitinated. Mutation of the Sharpin gene (Sharpin(cpdm/cpdm)) causes chronic proliferative dermatitis (cpdm) characterized by inflammatory skin lesions and defective lymphoid organogenesis. Gene induction by TNF, CD40 ligand and interleukin-1β was attenuated in cpdm-derived cells which were rendered sensitive to TNF-induced death. Importantly, Tnf gene deficiency prevented skin lesions in cpdm mice. We conclude that by enabling linear ubiquitination in the TNF receptor signalling complex, SHARPIN interferes with TNF-induced cell death and, thereby, prevents inflammation. Our results provide evidence for the relevance of linear ubiquitination in vivo in preventing inflammation and regulating immune signalling.


Radioimmunoassay of estrone sulfate in the serum of normal men after a non-chromatographic procedure that eliminates interference from dehydroepiandrosterone sulfate.
Duplicate aliquots of 20 fresh-frozen normal human male sera were prepared for estrone sulfate (ES) radioimmunoassay (RIA) by each of three different methods: the thin-layer chromatography (TLC) procedure we previously reported, a new procedure including overnight heating (100 C) of an ethanol extract reconstituted in dilute acetate buffer, and the new procedure with the hot incubation omitted. The purpose of the 100 C incubation was the selective thermal solvolysis of dehydroepiandrosterone sulfate (DS), the only steroid conjugate present in serum in high enough concentrations to interfere with a high-specificity ES RIA. Dehydroepiandrosterone released by solvolysis and endogenous unconjugated steroids were extracted from the samples with ether before RIA. Estrone sulfate values obtained after the thermal solvolysis preparation averaged 854 +/- 501 pg/ml (SD) versus 826 +/- 474 pg/ml (SD) after the TLC method, with excellent correlation between the two (r = 0.97). Samples prepared by the new method but with thermal solvolysis omitted averaged a 33.8% elevation of measured ES level, an elevation significantly correlated (P less than 0.02) with DS levels obtained from the same specimens. In addition, a single specimen showed no elevation after preparation by the thermal solvolysis method when up to 8 micrograms/ml authentic DS as added before extraction. Compared with the TLC method, the new method also provides substantial savings in specimen volume requirements and sample processing time.


Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia.
Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.


Controlling the 3-D morphology of Ni-Fe-based nanocatalysts for the oxygen evolution reaction.
Controlling the 3-D morphology of nanocatalysts is one of the underexplored but important approaches for improving the sluggish kinetics of the oxygen evolution reaction (OER) in water electrolysis. This work reports a scalable, oil-based method based on thermal decomposition of organometallic complexes to yield highly uniform Ni-Fe-based nanocatalysts with a well-defined morphology (i.e. Ni-Fe core-shell, Ni/Fe alloy, and Fe-Ni core-shell). Transmission electron microscopy reveals their morphology and composition to be NiOx-FeOx/NiOx core-mixed shell, NiOx/FeOx alloy, and FeOx-NiOx core-shell. X-ray techniques resolve the electronic structures of the bulk and are supported by electron energy loss spectroscopy analysis of individual nanoparticles. These results suggest that the crystal structure of Ni is most likely to contain α-Ni(OH)2 and that the chemical environment of Fe is variable, depending on the morphology of the nanoparticle. The Ni diffusion from the amorphous Ni-based core to the iron oxide shell makes the NiOx-NiOx/FeOx core-mixed shell structure the most active and the most stable nanocatalyst, which outperforms the comparison NiOx/FeOx alloy nanoparticles expected to be active for the OER. This study suggests that the chemical environment of the mixed NiOx/FeOx alloy composition is important to achieve high electrocatalytic activity for the OER and that the 3-D morphology plays a key role in the optimization of the electrocatalytic activity and stability of the nanocatalyst for the OER.


Human protectin (CD59), an 18-20-kD homologous complement restriction factor, does not restrict perforin-mediated lysis.
Human protectin (CD59) is an 18-20-kD membrane glycoprotein that restricts lysis of human erythrocytes and leukocytes by homologous complement. By directly incorporating protectin into membranes of heterologous cells we observed that protectin did not prevent perforin-mediated killing, whereas complement killing was effectively restricted. Further, no significant enhancement of cell-mediated killing or target killing by purified perforin was observed with anti-protectin antibodies. Thus, in contrast with complement lysis, restriction of lysis by protectin does not apply to cell-mediated killing.


Three-dimensional structure of a cysteine-rich repeat from the low-density lipoprotein receptor.
The low-density lipoprotein (LDL) receptor plays a central role in mammalian cholesterol metabolism, clearing lipoproteins which bear apolipoproteins E and B-100 from plasma. Mutations in this molecule are associated with familial hypercholesterolemia, a condition which leads to an elevated plasma cholesterol concentration and accelerated atherosclerosis. The N-terminal segment of the LDL receptor contains a heptad of cysteine-rich repeats that bind the lipoproteins. Similar repeats are present in related receptors, including the very low-density lipoprotein receptor and the LDL receptor-related protein/alpha 2-macroglobulin receptor, and in proteins which are functionally unrelated, such as the C9 component of complement. The first repeat of the human LDL receptor has been expressed in Escherichia coli as a glutathione S-transferase fusion protein, and the cleaved and purified receptor module has been shown to fold to a single, fully oxidized form that is recognized by the monoclonal antibody IgG-C7 in the presence of calcium ions. The three-dimensional structure of this module has been determined by two-dimensional NMR spectroscopy and shown to consist of a beta-hairpin structure, followed by a series of beta turns. Many of the side chains of the acidic residues, including the highly conserved Ser-Asp-Glu triad, are clustered on one face of the module. To our knowledge, this structure has not previously been described in any other protein and may represent a structural paradigm both for the other modules in the LDL receptor and for the homologous domains of several other proteins. Calcium ions had only minor effects on the CD spectrum and no effect on the 1H NMR spectrum of the repeat, suggesting that they induce no significant conformational change.


Correlation between manometric and pH tests for gastro-oesophageal reflux.
A series of tests, including gastro-oesophageal sphincter pressure measurement, short-term pH tests, and 15-hour overnight oesophageal pH recording were applied to 42 normal subjects and 214 patients with typical reflux symptoms. The results were compared by multivariate discriminant analysis. Sphincter pressure measurements misclassified 32%, stressed provocative manoeuvres 14-5%, and the best single discriminator from the overnight pH study was time below pH 5, which misclassified 13%. However, a combination of the number of reflux episodes in 15 hours with their mean duration reduced misclassification to 8-8%. Using this function, a boundary between normal and reflux can be drawn, and the degree of abnormality can be expressed visually as well as numerically.


Filtered-backprojection reconstruction for a cone-beam computed tomography scanner with independent source and detector rotations.
A new cone-beam CT scanner for image-guided radiotherapy (IGRT) can independently rotate the source and the detector along circular trajectories. Existing reconstruction algorithms are not suitable for this scanning geometry. The authors propose and evaluate a three-dimensional (3D) filtered-backprojection reconstruction for this situation. The source and the detector trajectories are tuned to image a field-of-view (FOV) that is offset with respect to the center-of-rotation. The new reconstruction formula is derived from the Feldkamp algorithm and results in a similar three-step algorithm: projection weighting, ramp filtering, and weighted backprojection. Simulations of a Shepp Logan digital phantom were used to evaluate the new algorithm with a 10 cm-offset FOV. A real cone-beam CT image with an 8.5 cm-offset FOV was also obtained from projections of an anthropomorphic head phantom. The quality of the cone-beam CT images reconstructed using the new algorithm was similar to those using the Feldkamp algorithm which is used in conventional cone-beam CT. The real image of the head phantom exhibited comparable image quality to that of existing systems. The authors have proposed a 3D filtered-backprojection reconstruction for scanners with independent source and detector rotations that is practical and effective. This algorithm forms the basis for exploiting the scanner's unique capabilities in IGRT protocols.


Cost-effectiveness of Chagas disease interventions in latin america and the Caribbean: Markov models.
Chagas disease is a parasitic disease in Latin America. Despite vector control programs that have reduced incidence by 70%, there are at least 12-14 million prevalent cases. We used a Markov model to examine strategies for control and treatment of Chagas disease that compared annual costs, life expectancies, and cost-effectiveness of three vector control and drug treatment strategies. Vector control programs alone and vector control plus drug treatment are dominant over no vector control (i.e., less costly and save more lives), and vector control plus drug is highly cost-effective compared with vector control alone. We demonstrated expected changes in deaths over time resulting from various prevention approaches. Vector control affects primarily incidence, not decreasing deaths and prevalence for 30 years, while drug treatment affects prevalence and deaths immediately. The best strategy to combat Chagas disease is combinations of vector control and a potential new drug.


Regulation of the clathrin-coated vesicle cycle by reversible phosphorylation.
Reversible phosphorylation has long been an attractive mechanism to control cycles of coat assembly and disassembly during clathrin-mediated endocytosis. Many of the coat proteins are phosphorylated in vivo and in vitro. Our work has focused on the role of phosphorylation of the mu2 subunit of AP-2 (adaptor protein 2), which appears to be necessary for efficient cargo recruitment. Studies to probe the regulation of mu2 phosphorylation demonstrated that clathrin is a specific activator of the mu2 kinase, and, in permeabilized cells, cargo sequestration, driven by exogenously added clathrin, results in elevated levels of m2 phosphorylation. Furthermore, phosphorylated mu2 is mainly associated with assembled clathrin in vivo and its steady-state level is strongly reduced in cells depleted of clathrin heavy chain. Our results imply a central role for clathrin in the regulation of cargo selection via modulation of phospho-mu2 levels. This is therefore a novel regulatory role for clathrin that is independent of its structural role and that provides elegant spatial control of AP-2 and cargo interactions, ensuring that AP-2 is only activated at the correct cellular location and in the correct functional context. Ongoing studies are exploring further the roles of reversible phosphorylation in the coated vesicle cycle.


No improvement of repeated-sprint performance with dietary nitrate.
Nitrate supplementation improves endurance exercise and single bouts of high-intensity activity, but its effect on repeated sprints is unclear. This study is the first to investigate the effects of acute dietary nitrate supplementation during a high-intensity intermittent-sprint test to exhaustion. Team-sport athletes (9 male, age 22.3 ± 2.1 y, VO2max 57.4 ± 8.5 mL · kg-1 · min-1; 7 female, age 20.7 ± 1.3 y, VO2max 47.2 ± 8.5 mL · kg-1 · min-1) were assigned to a double-blind, randomized, crossover design. Participants consumed 70 mL of concentrated beetroot juice containing a minimum of 0.3 g of nitrate (NT) or 70 mL of placebo (PL) 2 h before a repeated-sprint protocol involving repeated 8-s sprints with 30-s recovery on a cycle ergometer to exhaustion. Fewer sprints (NT = 13 ± 5 vs PL = 15 ± 6, P = .005, d = 0.41) and less total work (NT = 49.2 ± 24.2 kJ vs PL = 57.8 ± 34.0 kJ, P = .027, d = 0.3) were completed in NT relative to PL. However there was no difference in overall mean power output or the mean power output for each individual 8-s sprint. These findings suggest that dietary nitrate is not beneficial for improving repeated-sprint performance, at least when such sprints are near-maximal and frequent in nature. The lack of an effect of nitrate at near-maximal oxygen uptake supports the suggestion that at greater exercise intensities nitrate does not have an ergogenic effect.


Green tea and coffee intake and risk of cognitive decline in older adults: the National Institute for Longevity Sciences, Longitudinal Study of Aging.
To examine the association between green tea and coffee intake and cognitive decline in older adults. A prospective cohort study. The average intake of green tea and coffee in the previous year was assessed through a dietitian interview using a dietary questionnaire. A Mini-Mental State Examination (MMSE) was conducted up to six times biennially. Cognitive decline was screened using the MMSE; its incidence was defined as the first time a score of <27 points was obtained in a biennial test from the baseline. Hazard ratios for incidence of cognitive decline were estimated according to the intake of the two beverages using multivariable Cox proportional hazard regression, controlling for sociodemographic and lifestyle factors. The National Institute for Longevity Sciences, Longitudinal Study of Aging (NILS-LSA) in Japan. Men (n 620) and women (n 685), aged 60-85 years, from the NILS-LSA. During a mean of 5·3 (sd 2·9) years of follow-up, 432 incident cases of cognitive decline were observed. Compared with participants who consumed green tea <once/d, the multivariable hazard ratio (95 % CI) was 0·70 (0·45, 1·06), 0·71 (0·52, 0·97) and 0·72 (0·54, 0·98) among those who consumed green tea once/d, 2-3 times/d and ≥4 times/d, respectively (Ptrend < 0·05). No significant association was found between coffee intake and cognitive decline. The intake of green tea, but not coffee, was shown to reduce the risk of cognitive decline in older adults.


Absolute serum hormone levels predict the magnitude of change in anterior knee laxity across the menstrual cycle.
This study aimed to determine whether absolute sex hormone concentrations predict the magnitude of knee joint laxity changes across the menstrual cycle. Twenty-two females (18-30 years, body mass index <or=30), who reported normal menstrual cycles for the previous 6 months were tested daily across one complete menstrual cycle for serum levels of estradiol (E=pg/mL), progesterone (P=ng/mL), and testosterone (T=ng/dL), and knee joint laxity (K(Lax)=mm displacement at 134N) measured with a standard knee arthrometer. The change in K(Lax) across the cycle (maximum-minimum), and minimum (early follicular) and peak (postovulatory) hormone concentrations were recorded for each subject. A stepwise linear regression determined if the minimum, peak, or absolute change in hormone concentrations would predict the magnitude of change in K(Lax) across the cycle. K(Lax) changed on average 3.2+/-1.1 mm across the menstrual cycle (range, 1.5-5.3 mm). Minimum levels of E (39.9+/-11.8 pg/mL) and P (0.61+/-0.27 ng/mL), coupled with peak concentrations of E (199.6+/-54.9 pg/mL) and T (22.5+/-10.5 ng/dL) explained 57.6% of the change in K(Lax) across the cycle. Greater absolute changes in K(Lax) were observed in response to peak E and T levels when minimum E concentrations were lower and minimum P concentrations were higher in the early follicular phase. The absolute minimum concentrations of E and P in the early follicular phase appear to be important factors in determining the sensitivity of the knee joint's response to changing hormone levels.


Changes in pathologic outcomes and operative trends with robot-assisted laparoscopic radical prostatectomy.
We hypothesized that there is a reverse stage migration, or a shift toward operating on higher-risk prostate cancer, in patients undergoing robot-assisted laparoscopic prostatectomy (RALP). We therefore evaluated the stage of disease at the time of surgery for patients with prostate cancer at a large tertiary academic medical center. After institutional review board approval, we reviewed all patients that had undergone robotic prostatectomy. These patients were separated into three categories: An early era of 2005-2008, intermediate era of 2009-2010, and a current era of 2011-2012. A total of 3451 patients underwent robotic prostatectomy from 2005 to 2012. The proportion men with clinical T1 tumors declined from 88.3% in the early era to 72.2% in the current era (P < 0.0001). Men with preoperative biopsy Gleason 6 disease decreased from the early to the current era (P < 0.0001), while men with preoperative biopsy Gleason ≥ 8 showed the opposite trend, increasing from the early to the current era (P = 0.0002). From the early to the current era, the proportion of patients with National Comprehensive Cancer Network (NCCN) low risk prostate cancer decreased, while those with NCCN intermediate and high-risk disease increased. The proportion of pathologic T3 disease increased from 15.5% in the early to 30.6% in the current era (P < 0.0001). On the other hand, the proportion of pathologic T2/+ SMS (surgical margin status) decreased from 6.6% in the early era to 3.1% in the current era (P = 0.0002). We have demonstrated a reverse stage migration in men undergoing robotic prostatectomy. Despite the increasing proportion of men with extra-capsular disease undergoing RALP, the surgical margin status has remained similar. This could reflect both the changing dynamics of the population opting for surgery as well as the learning curve of the surgeons.


High-speed and dense three-dimensional surface acquisition using defocused binary patterns for spatially isolated objects.
The three-dimensional (3-D) shape measurement using defocused Ronchi grating is advantageous for the high contrast of fringe. This paper presents a method for measuring spatially isolated objects using defocused binary patterns. Two Ronchi grating with horizontal position difference of one-third of a period and an encoded pattern are adopted. The phase distribution of fringe pattern is obtained by Fourier analysis method. The measurement depth and range is enlarged because the third harmonic component and background illumination is eliminated with proposed method. The fringe order is identified by the encoded pattern. Three gray levels are used and the pattern is converted to binary image with error diffusion algorithm. The tolerance of encoded pattern is large. It is suited for defocused optical system. We also present a measurement system with a modified DLP projector and a high-speed camera. The 3-D surface acquisition speed of 60 frames per second (fps), with resolution of 640 × 480 points and that of 120 fps, with resolution of 320 × 240 points are archived. If the control logic of DMD was modified and a camera with higher speed was employed, the measurement speed would reach thousands fps. This makes it possible to analyze dynamic objects.


Dechloromonas agitata gen. nov., sp. nov. and Dechlorosoma suillum gen. nov., sp. nov., two novel environmentally dominant (per)chlorate-reducing bacteria and their phylogenetic position.
Previous studies on the ubiquity and diversity of microbial (per)chlorate reduction resulted in the isolation of 20 new strains of dissimilatory (per)chlorate-reducing bacteria. Phylogenetic analysis revealed that all of the isolates were members of the Proteobacteria with representatives in the alpha-, beta- and gamma-subclasses. The majority of the new isolates were located in the beta-subclass and were closely related to each other and to the phototrophic Rhodocyclus species. Here an in-depth analysis of these organisms which form two distinct monophyletic groups within the Rhodocyclus assemblage is presented. Two new genera, Dechloromonas and Dechlorosoma, are proposed for these beta-subclass lineages which represent the predominant (per)chlorate-reducing bacteria in the environment. The type species and strains for these new genera are Dechloromonas agitata strain CKBT and Dechlorosoma suillum strain PST, respectively.


Ellipticity dependence of the near-threshold harmonics of H2 in an elliptical strong laser field.
We study the ellipticity dependence of the near-threshold (NT) harmonics of pre-aligned H2 molecules using the time-dependent density functional theory. The anomalous maximum appearing at a non-zero ellipticity for the generated NT harmonics can be attributed to multiphoton effects of the orthogonally polarized component of the elliptical driving laser field. Our calculation also shows that the structure of the bound-state, such as molecular alignment and bond length, can be sensitively reflected on the ellipticity dependence of the near-threshold harmonics.


Self in time: imagined self-location influences neural activity related to mental time travel.
Conscious awareness of the self as continuous through time is attributed to the human ability to remember the past and to predict the future, a cogitation that has been called "mental time travel" (MTT). MTT allows one to re-experience one's own past by subjectively "locating" the self to a previously experienced place and time, or to pre-experience an event by locating the self into the future. Here, we used a novel behavioral paradigm in combination with evoked potential mapping and electrical neuroimaging, revealing that MTT is composed of two different cognitive processes: absolute MTT, which is the location of the self to different points in time (past, present, or future), and relative MTT, which is the location of one's self with respect to the experienced event (relative past and relative future). These processes recruit a network of brain areas in distinct time periods including the occipitotemporal, temporoparietal, and anteromedial temporal cortices. Our findings suggest that in addition to autobiographical memory processes, the cognitive mechanisms of MTT also involve mental imagery and self-location, and that relative MTT, but not absolute MTT, is more strongly directed to future prediction than to past recollection.


Silicon photomultiplier (SPM) detection of low-level bioluminescence for the development of deployable whole-cell biosensors: possibilities and limitations.
Whole-cell bacterial bioreporters await miniaturized photon counting modules with high sensitivity and robust compatible hardware to fulfill their promise of versatile, on-site biosensor functionality. In this study, we explore the photon counting readout properties of the silicon photomultiplier (SPM) with a thermoelectric cooler and the possibilities of detecting low-level bioluminescent signals. Detection performance was evaluated through a simulated LED light source and the bioluminescence produced by the genetically engineered Pseudomonas fluorescens bacterial bioreporter 5RL. Compared with the conventional photomultiplier tube (PMT), the results revealed that the cooled SPM exhibits a wider linear response to inducible substrate concentrations (salicylate) ranging from 250 to 5000 ppb. Although cooling of the SPM lowered dark count rates and improved the minimum detectable signal, and the application of a digital filter enhanced the signal-to-noise ratio, the detection of very low light signals is still limited and remains a challenge in the design of compact photon counting systems.


Transplant center quality assessment using a continuously updatable, risk-adjusted technique (CUSUM).
Access to timely, risk-adjusted measures of transplant center outcomes is crucial for program quality improvement. The cumulative summation technique (CUSUM) has been proposed as a sensitive tool to detect persistent, clinically relevant changes in transplant center performance over time. Scientific Registry of Transplant Recipients data for adult kidney and liver transplants (1/97 to 12/01) were examined using logistic regression models to predict risk of graft failure (kidney) and death (liver) at 1 year. Risk-adjusted CUSUM charts were constructed for each center and compared with results from the semi-annual method of the Organ Procurement and Transplantation Network (OPTN). Transplant centers (N = 258) performed 59 650 kidney transplants, with a 9.2% 1-year graft failure rate. The CUSUM method identified centers with a period of significantly improving (N = 92) or declining (N = 52) performance. Transplant centers (N = 114) performed 18 277 liver transplants, with a 13.9% 1-year mortality rate. The CUSUM method demonstrated improving performance at 48 centers and declining performance at 24 centers. The CUSUM technique also identified the majority of centers flagged by the current OPTN method (20/22 kidney and 8/11 liver). CUSUM monitoring may be a useful technique for quality improvement, allowing center directors to identify clinically important, risk-adjusted changes in transplant center outcome.


Genomic rearrangements during evolution of the obligate intracellular parasite Rickettsia prowazekii as inferred from an analysis of 52015 bp nucleotide sequence.
In this study a description is given of the sequence and analysis of 52 kb from the 1.1 Mb genome of Rickettsia prowazekii, a member of the alpha-Proteobacteria. An investigation was made of nucleotide frequencies and amino acid composition patterns of 41 coding sequences, distributed in 10 genomic contigs, of which 32 were found to have putative homologues in the public databases. Overall, the coding content of the individual contigs ranged from 59 to 97%, with a mean of 81%. The genes putatively identified included genes involved in the biosynthesis of nucleotides, macromolecules and cell wall structures as well as citric acid cycle component genes. In addition, a putative identification was made of a member of the regulatory response family of two-component signal transduction systems as well as a gene encoding haemolysin. For one gene, the homologue of metK, an internal stop codon was discovered within a region that is otherwise highly conserved. Comparisons with the genomic structures of Escherichia coli, Haemophilus influenzae and Bacillus subtilis have revealed several atypical gene organization patterns in the R. prowazekii genome. For example, R. prowazekii was found to have a unique arrangement of genes upstream of dnaA in a region that is highly conserved among other microbial genomes and thought to represent the origin of replication of a primordial replicon. The results presented in this paper support the hypothesis that the R. prowazekii genome is a highly derived genome and provide examples of gene order structures that are unique for the Rickettsia.


Comparative genomic analysis of Acinetobacter strains isolated from murine colonic crypts.
A restricted set of aerobic bacteria dominated by the Acinetobacter genus was identified in murine intestinal colonic crypts. The vicinity of such bacteria with intestinal stem cells could indicate that they protect the crypt against cytotoxic and genotoxic signals. Genome analyses of these bacteria were performed to better appreciate their biodegradative capacities. Two taxonomically different clusters of Acinetobacter were isolated from murine proximal colonic crypts, one was identified as A. modestus and the other as A. radioresistens. Their identification was performed through biochemical parameters and housekeeping gene sequencing. After selection of one strain of each cluster (A. modestus CM11G and A. radioresistens CM38.2), comparative genomic analysis was performed on whole-genome sequencing data. The antibiotic resistance pattern of these two strains is different, in line with the many genes involved in resistance to heavy metals identified in both genomes. Moreover whereas the operon benABCDE involved in benzoate metabolism is encoded by the two genomes, the operon antABC encoding the anthranilate dioxygenase, and the phenol hydroxylase gene cluster are absent in the A. modestus genomic sequence, indicating that the two strains have different capacities to metabolize xenobiotics. A common feature of the two strains is the presence of a type IV pili system, and the presence of genes encoding proteins pertaining to secretion systems such as Type I and Type II secretion systems. Our comparative genomic analysis revealed that different Acinetobacter isolated from the same biological niche, even if they share a large majority of genes, possess unique features that could play a specific role in the protection of the intestinal crypt.


Genetic and environmental factors and the distribution of multiple sclerosis in Europe.
The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease-associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors. We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe. We observed that HLA alleles unequivocally interact with a population-wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence. Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.


Baseline prostate-specific antigen compared with median prostate-specific antigen for age group as predictor of prostate cancer risk in men younger than 60 years old.
Limited data are available concerning the extent to which the initial prostate-specific antigen (PSA) measurement in men younger than age 60 predicts for the risk of prostate cancer (CaP) and how this compares to other known risk factors. From 1991 to 2001, 13,943 men younger than 60 years old participated in a CaP screening study. Men aged 40 to 49 years were eligible for the study if they had a positive family history or African-American heritage, and men older than 50 years were screened without respect to risk factors. The CaP detection rate, PSA velocity, pathologic features, and treatment outcomes were evaluated as a function of the baseline PSA level. The median PSA level was 0.7 ng/mL for men aged 40 to 49 years and 0.9 ng/mL for men aged 50 to 59. A baseline PSA level between the median and 2.5 ng/mL was associated with a 14.6-fold and 7.6-fold increased risk of CaP in men aged 40 to 49 and 50 to 59 years, respectively. A greater baseline PSA value was also associated with a significantly greater PSA velocity, more aggressive tumor features, a greater biochemical progression rate, and a trend toward a greater cancer-specific mortality rate. In men younger than 60, a baseline PSA value between the age-specific median and 2.5 ng/mL was a significant predictor of later CaP and was associated with a significantly greater PSA velocity. A young man's baseline PSA value was a stronger predictor of CaP than family history, race, or suspicious digital rectal examination findings. A greater baseline PSA level was associated with significantly more adverse pathologic features and biochemical progression.


Survival of patients with SLE admitted to an intensive care unit-a retrospective study.
We examined the demography, reasons for admission and cause of death in systemic lupus erythematosus (SLE) patients admitted to a medical intensive care unit (ICU) over a 7-year period. Fourteen patients were admitted during this period-all were female, 13 were of mixed ethnic ancestry and one a black South African. Of the 14 patients, 12 were admitted as a result of lupus activity, 2 had sepsis as the major cause of admission, although 5 other patients developed infection during their admission. Five patients had a generalised flare of their disease or progressive renal failure. Seven patients were admitted with a variety of lupus-related pathologies. In general the precise cause of death was difficult to determine. Of the 14 patients, 9 had impaired renal function on admission including 1 with sepsis and 1 of the survivors. Three patients (21%) survived, one with respiratory failure due to shrinking lung, a second with an acute flare of SLE and a third with pulmonary emboli. This study demonstrates that lupus in our community may produce life-threatening flares. Although cause of death was not always definitely identified, admission to the ICU was primarily due to active SLE and not sepsis or iatrogenic disease.


Special operations: a hidden chapter in the histories of facial surgery and human enhancement.
During the Second World War, Britain's Special Operations Executive (SOE), a secret service established to encourage resistance and carry out sabotage, employed various techniques of enhancing the ability of its personnel to operate undetected in enemy territory. One of these methods was surgery. Drawing on recently declassified records, this article illuminates SOE's reasons for commissioning this procedure, the needs and wants of those who received it, and the surgeons employed to carry it out. It also aims to underline the role of context in shaping perceptions of facial surgery, and the potential for surgery for wartime disguise to resonate with current debates about human enhancement.


Managing the difficult physician-patient relationship.
A difficult physician-patient relationship can have significant consequences for both the physician and the patient. Difficult relationships can lead to frustrating, dissatisfying, adversarial and expensive medical care. The difficult relationship is often a consequence of a breakdown in communication between physician and patient. Specific causes include technical communication barriers, difficulty in discussing certain topics, unmet or violated norms and expectations (both the physician's and the patient's) and a mismatch between the physician's and the patient's personality styles. Management goals for the difficult relationship include maintaining professional self-esteem, maintaining physician-patient continuity, minimizing the "medicalization" of the problem by limiting the use of tests and procedures, and minimizing hospitalization and referral. It is also important to remember that although the relationship may continue to be frustrating or conflictual, it can be effectively managed with appropriate strategies.


The impact of Pleistocene climate change on an ancient arctic-alpine plant: multiple lineages of disparate history in Oxyria digyna.
The ranges of arctic-alpine species have shifted extensively with Pleistocene climate changes and glaciations. Using sequence data from the trnH-psbA and trnT-trnL chloroplast DNA spacer regions, we investigated the phylogeography of the widespread, ancient (>3 million years) arctic-alpine plant Oxyria digyna (Polygonaceae). We identified 45 haplotypes and six highly divergent major lineages; estimated ages of these lineages (time to most recent common ancestor, T(MRCA)) ranged from ∼0.5 to 2.5 million years. One lineage is widespread in the arctic, a second is restricted to the southern Rocky Mountains of the western United States, and a third was found only in the Himalayan and Altai regions of Asia. Three other lineages are widespread in western North America, where they overlap extensively. The high genetic diversity and the presence of divergent major cpDNA lineages within Oxyria digyna reflect its age and suggest that it was widespread during much of its history. The distributions of individual lineages indicate repeated spread of Oxyria digyna through North America over multiple glacial cycles. During the Last Glacial Maximum it persisted in multiple refugia in western North America, including Beringia, south of the continental ice, and within the northern limits of the Cordilleran ice sheet. Our data contribute to a growing body of evidence that arctic-alpine species have migrated from different source regions over multiple glacial cycles and that cryptic refugia contributed to persistence through the Last Glacial Maximum.


Appearances can be deceptive: revealing a hidden viral infection with deep sequencing in a plant quarantine context.
Comprehensive inventories of plant viral diversity are essential for effective quarantine and sanitation efforts. The safety of regulated plant material exchanges presently relies heavily on techniques such as PCR or nucleic acid hybridisation, which are only suited to the detection and characterisation of specific, well characterised pathogens. Here, we demonstrate the utility of sequence-independent next generation sequencing (NGS) of both virus-derived small interfering RNAs (siRNAs) and virion-associated nucleic acids (VANA) for the detailed identification and characterisation of viruses infecting two quarantined sugarcane plants. Both plants originated from Egypt and were known to be infected with Sugarcane streak Egypt Virus (SSEV; Genus Mastrevirus, Family Geminiviridae), but were revealed by the NGS approaches to also be infected by a second highly divergent mastrevirus, here named Sugarcane white streak Virus (SWSV). This novel virus had escaped detection by all routine quarantine detection assays and was found to also be present in sugarcane plants originating from Sudan. Complete SWSV genomes were cloned and sequenced from six plants and all were found to share >91% genome-wide identity. With the exception of two SWSV variants, which potentially express unusually large RepA proteins, the SWSV isolates display genome characteristics very typical to those of all other previously described mastreviruses. An analysis of virus-derived siRNAs for SWSV and SSEV showed them to be strongly influenced by secondary structures within both genomic single stranded DNA and mRNA transcripts. In addition, the distribution of siRNA size frequencies indicates that these mastreviruses are likely subject to both transcriptional and post-transcriptional gene silencing. Our study stresses the potential advantages of NGS-based virus metagenomic screening in a plant quarantine setting and indicates that such techniques could dramatically reduce the numbers of non-intercepted virus pathogens passing through plant quarantine stations.


[Deleterious Results of Safety Seeking Behaviours in Panic Disorder: Polydipsia and Diabetes Mellitus Type 2].
Panic disorder is an anxiety disorder that involves recurrent panic attacks, which emerge when a harmless stimulus is interpreted as "catastrophic". In an attempt to avoid the panic attack or prevent confrontation, the patient exhibits a dysfunctional attitude and behavior, such as evasion and safety-seeking behavior (SSB). Dysfunctional behavior leads to an increase in the recurrence of panic attacks and affects the patient's life in a negative way. According to the cognitive behavioral therapy model, SSB contributes to the continuation of unrealistic beliefs (e.g. physical experiences) regarding and prevents the patient from grasping new information that may potentially contradict the unrealistic cognitions. In this paper, we present a case with a primary diagnosis of panic disorder. Interestingly, this patient developed diabetes mellitus (DM) type 2 and psychogenic polydipsia (PPD) as a consequence of his SSB. PPD is a common occurrence in patients with psychiatric disorders, especially in schizophrenia. Up to now, no case of a panic disorder with either DM or PPD has been reported in the literature. While it is accepted that major depression poses a risk for DM type 2, panic disorder may also increase this risk. Treatment of the panic disorder with cognitive behavioral therapy (CBT) resulted in improvement of PPD and DM type 2. In conclusion, the role of SSB in medical disorders accompanied by psychiatric disorders should be kept in mind when treating these patients.


Multimodal optical characterisation of collagen photodegradation by femtosecond infrared laser ablation.
Collagen is a structural component of the human body, as a connective tissue it can become altered as a result of pathophysiological conditions. Although the collagen degradation mechanism is not fully understood, it plays an important role in ageing, disease progression and applications in therapeutic laser treatments. To fully understand the mechanism of collagen alteration, in our study photo-disruptive effects were induced in collagen I matrix by point-irradiation with a femtosecond Ti-sapphire laser under controlled laser ablation settings. This was followed by multi-modal imaging of the irradiated and surrounding areas to analyse the degradation mechanism. Our multi-modal methodology was based on second harmonic generation (SHG), scanning electron microscope (SEM), autofluorescence (AF) average intensities and the average fluorescence lifetime. This allowed us to quantitatively characterise the degraded area into four distinct zones: (1) depolymerised zone in the laser focal spot as indicated by the loss of SHG signal, (2) enhanced crosslinking zone in the inner boundary of the laser induced cavity as represented by the high fluorescence ring, (3) reduced crosslinking zone formed the outer boundary of the cavity as marked by the increased SHG signal and (4) native collagen. These identified distinct zones were in good agreement with the expected photochemical changes shown using Raman spectroscopy. In addition, imaging using polarisation-resolved SHG (p-SHG) revealed both a high degree of fibre re-orientation and a SHG change in tensor ratios around the irradiation spot. Our multi-modal optical imaging approach can provide a new methodology for defining distinct zones that can be used in a clinical setting to determine suitable thresholds for applying safe laser treatments without affecting the surrounding tissues. Furthermore this technique can be extended to address challenges observed in collagen based tissue engineering and used as a minimally invasive diagnostic tool to characterise diseased and non-diseased collagen rich tissues.


A practical approach to vaccination of patients with autoimmune inflammatory rheumatic diseases in Australia.
Autoimmune inflammatory rheumatic diseases (AIIRD), such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are often complicated by infection, which results in significant morbidity and mortality. The increased risk of infection is probably due to a combination of immunosuppressive effects of the AIIRD, comorbidities and the use of immunosuppressive conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and more recently, targeted synthetic DMARDs and biologic DMARDs that block specific pro-inflammatory enzymes, cytokines or cell types. The use of these various DMARDs has revolutionised the treatment of AIIRD. This has led to a marked improvement in quality of life for AIIRD patients, who often now travel for prolonged periods. Many infections are preventable with vaccination. However, as protective immune responses induced by vaccination may be impaired by immunosuppression, where possible, vaccination may need to be performed prior to initiation of immunosuppression. Vaccination status should also be reviewed when planning overseas travel. Limited data regarding vaccine efficacy in patients with AIIRD make prescriptive guidelines difficult. However, a vaccination history should be part of the initial work-up in all AIIRD patients. Those caring for AIIRD patients should regularly consider vaccination to prevent infection within the practicalities of routine clinical practice.


Analysis of the glycoproteome of Toxoplasma gondii using lectin affinity chromatography and tandem mass spectrometry.
Glycoproteins are involved in many important molecular recognition processes including invasion, adhesion, differentiation, and development. To identify the glycoproteins of Toxoplasma gondii, a proteomic analysis was undertaken. T. gondii proteins were prepared and fractioned using lectin affinity chromatography. The proteins in each fraction were then separated using SDS-PAGE and identified by tryptic in gel digestion followed by tandem mass spectrometry. Utilizing these methods 132 proteins were identified. Among the identified proteins were 17 surface proteins, 9 microneme proteins, 15 rhoptry proteins, 11 heat shock proteins (HSP), and 32 hypothetical proteins. Several proteins had 1-5 transmembrane domains (TMD) with some being as large as 608.3 kDa. Both lectin-fluorescence labeling and lectin blotting were employed to confirm the presence of carbohydrates on the surface or cytoplasm of T. gondii parasites. PCR demonstrated that selected hypothetical proteins were expressed in T. gondii tachyzoites. This data provides a large-scale analysis of the T. gondii glycoproteome. Studies of the function of glycosylation of these proteins may help elucidate mechanism(s) involved in invasion improving drug therapy as well as identify glycoproteins that may prove to be useful as vaccine candidates.


Dynamics and stability of a class of low Reynolds number swimmers near a wall.
We study the dynamic stability of low Reynolds number swimming near a plane wall from a control-theoretic viewpoint. We consider a special class of swimmers having a constant shape, focus on steady motion parallel to the wall, and derive conditions under which it is passively stable without sensing or feedback. We study the geometric structure of the swimming equation and highlight the relation between stability and reversing symmetry of the dynamical system. Finally, our numerical simulations reveal the existence of stable periodic motion. The results have implications for design of miniature robotic swimmers, as well as for explaining the attraction of micro-organisms to surfaces.


Mesomartoxin, a new K(v)1.2-selective scorpion toxin interacting with the channel selectivity filter.
Venom-derived neurotoxins are ideal probes for the investigation of structure-function relationship of ion channels and promising scaffolds for the design of ion channel-targeted drug leads as well. The discovery of highly selective toxins against a specific channel subtype facilitates the development of drugs with reduced side effects. Here, we describe the systemic characterization of a new scorpion short-chain K(+) channel blocker from Mesobuthus martensii, termed mesomartoxin (MMTX). MMTX is synthesized as a precursor comprising a signal peptide and a mature peptide of 29 residues. Nuclear magnetic resonance analysis confirmed that recombinant MMTX adopts a typical cysteine-stabilized α-helical and β-sheet fold. Electrophysiological experiments showed that MMTX exhibits high affinity for the Drosophila Shaker K(+) channel but differential selectivity on different members of the rat voltage-gated K(+) channel (Kv) family, with nanomolar affinity (IC50=15.6 nM) for rKv1.2, micromolar affinity for rKv1.3 (IC50=12.5 μM) and no activity on rKv1.1 at >50 μM. Site-directed mutagenesis of the channel pore identified a key site located on the selectivity filter of the pore, which is directly implicated in toxin binding and controls target's selectivity of the toxin. Given a key role of Kv1.2 in epilepsy, MMTX might serve as a potential drug lead for the disease.


Zinc absorption by young adults from supplemental zinc citrate is comparable with that from zinc gluconate and higher than from zinc oxide.
The water-soluble zinc salts gluconate, sulfate, and acetate are commonly used as supplements in tablet or syrup form to prevent zinc deficiency and to treat diarrhea in children in combination with oral rehydration. Zinc citrate is an alternative compound with high zinc content, slightly soluble in water, which has better sensory properties in syrups but no absorption data in humans. We used the double-isotope tracer method with (67)Zn and (70)Zn to measure zinc absorption from zinc citrate given as supplements containing 10 mg of zinc to 15 healthy adults without food and compared absorption with that from zinc gluconate and zinc oxide (insoluble in water) using a randomized, double-masked, 3-way crossover design. Median (IQR) fractional absorption of zinc from zinc citrate was 61.3% (56.6-71.0) and was not different from that from zinc gluconate with 60.9% (50.6-71.7). Absorption from zinc oxide at 49.9% (40.9-57.7) was significantly lower than from both other supplements (P < 0.01). Three participants had little or no absorption from zinc oxide. We conclude that zinc citrate, given as a supplement without food, is as well absorbed by healthy adults as zinc gluconate and may thus be a useful alternative for preventing zinc deficiency and treating diarrhea. The more insoluble zinc oxide is less well absorbed when given as a supplement without food and may be minimally absorbed by some individuals. This trial was registered at clinicaltrials.gov as NCT01576627.


Diagnosis and treatment of allergic rhinitis and sinusitis during pregnancy and lactation.
Upper airway congestive symptoms during pregnancy have been recognized since the late 19th century (1). Among randomly selected pregnancies, as many as 18-30% of patients will report substantial symptoms of rhinitis and sinusitis, and this figure may be higher among patients with pre-existing atopic disease (2-4). "Rhinitis of pregnancy" can take many forms. In another chapter in this review, Dr. Elergard discusses a form of rhinitis in pregnancy that occurs as a result of physiologic changes specific to pregnancy. This is to be distinguished from other forms of rhinitis coincident sometimes aggravated by pregnancy such as allergic rhinitis and sinusitis. The incidence of allergic conditions is 20-30% among women of childbearing years (5). Of those pregnant women with known allergies, some studies suggest that as many as 10-30% will experience increasing allergic symptoms during their pregnancy returning to their normal pre-pregnancy state after delivery (5-7). Postulated causes include those responsible for "rhinitis of pregnancy" such as increased circulating blood volume giving rise to nasal vascular engorgement and hormonal influences on nasal mucosal secretions and have been discussed in another chapter of this review (8,9).


Suboptimal choice by dogs: when less is better than more.
The less is more effect, an example of an affect heuristic, can be shown in humans when they give greater value to a set of six baseball cards in perfect condition, than to the same set of six perfect cards together with three additional cards each with some value but in fair condition. A similar effect has been reported in monkeys which will eat both grapes and cucumbers but prefer grapes, when they prefer a single grape over a single grape plus a slice of cucumber. In the present experiment, we tested the less is more effect with a nonprimate but social species, dogs. We used dogs that would eat a slice of carrot and a slice of cheese but preferred the cheese. When we then gave them a choice between a slice of cheese and a slice of cheese plus a slice of carrot, most dogs preferred the single slice of cheese. Thus, the less is more effect appears to occur in several species.