Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report.
There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.


Cytochrome and alternative pathway respiration in green algae : measurements using inhibitors and o(2) discrimination.
Inhibitor titration curves and discrimination against (18)O(2) by mitochondrial respiration in three strains of green algae (Selenastrum minutum [Naeg.] Collins, and two strains of Chlamydomonas reinhardtii Dangeard) with differing respiratory capabilities were determined. Discrimination for cytochrome pathway respiration ranged from 19.89 to 20.43%. Discrimination for alternative pathway respiration by wild-type C. reinhardtii (measured in the presence of KCN) was 25.46%, while discrimination values for a cytochrome oxidase deficient mutant of C. reinhardtii ranged from 24.24 to 24.96%. In the absence of KCN, the alternative pathway was not engaged in wild-type C. reinhardtii, the only algal strain that possessed both cytochrome and alternative pathway capacities.


Middle-aged women's preferred theory-based features in mobile physical activity applications.
The purpose of this study was to describe which theory-based behavioral and technological features middle-aged women prefer to be included in a mobile application designed to help them adopt and maintain regular physical activity (PA). Women aged 30 to 64 years (N = 120) completed an online survey measuring their demographics and mobile PA application preferences. The survey was developed upon behavioral principles of Social Cognitive Theory, recent mobile app research, and technology adoption principles of the Unified Theory of Acceptance and Use of Technology. Frequencies were calculated and content analyses conducted to identify which features women most preferred. Behavioral features that help women self-regulate their PA (PA tracking, goal-setting, progress monitoring) were most preferred. Technological features that enhance perceived effort expectancy and playfulness were most preferred. Many women reported the desire to interact and compete with others through the application. Theory-based PA self-regulation features and theory-based design features that improve perceived effort expectancy and playfulness may be most beneficial in a mobile PA application for middle-aged women. Opportunities to interact with other people and the employment of social, game-like activities may also be attractive. Interdisciplinary engagement of experts in PA behavior change, technology adoption, and software development is needed.


Cryogenic Infrared Spectroscopy Reveals Structural Modularity in the Vibrational Fingerprints of Heparan Sulfate Diastereomers.
Heparan sulfate and heparin are highly acidic polysaccharides with a linear sequence, consisting of alternating glucosamine and hexuronic acid building blocks. The identity of hexuronic acid units shows a variability along their sequence, as d-glucuronic acid and its C5 epimer, l-iduronic acid, can both occur. The resulting backbone diversity represents a major challenge for an unambiguous structural assignment by mass spectrometry-based techniques. Here, we employ cryogenic infrared spectroscopy on mass-selected ions to overcome this challenge and distinguish isomeric heparan sulfate tetrasaccharides that differ only in the configuration of their hexuronic acid building blocks. High-resolution infrared spectra of a systematic set of synthetic heparan sulfate stereoisomers were recorded in the fingerprint region from 1000 to 1800 cm-1. The experiments reveal a characteristic combination of spectral features for each of the four diastereomers studied and imply structural modularity in the vibrational fingerprints. Strong spectrum-structure correlations were found and rationalized by state-of-the-art quantum chemical calculations. The findings demonstrate the potential of cryogenic infrared spectroscopy to extend the mass spectrometry-based toolkit for the sequencing of heparan sulfate and structurally related biomolecules.


Effect of virtual articulator settings on occlusal morphology of CAD/CAM restorations.
Determinants of mandibular movements, like condylar inclination and incisal guidance, should be considered in the fabrication of restorations in occlusion to prevent posterior excursive occlusal interferences. The aim of this study was to investigate differences in the occlusal morphology of the right mandibular molar resulting from high, average, and low values of settings for determinants of anteroposterior and transverse mandibular movement using a virtual articulation model. The articulation functionalities of computer integrated restorative technology by imaging and new acquisition (CYRTINA, Oratio B.V., Zwaag, The Netherlands) were used as a tool to examine the potential effect of determinants of mandibular movement on occlusal molar design. High, average, and low values for condylar guide inclination, incisal guide angle, and intercuspal contact area (antero-posterior determinants) and laterotrusion, mandibular lateral translation and intercuspal contact area (transverse determinants) were introduced and differences in molar morphology studied. The latter was done by comparing mesiodistal and buccolingual sections of the occlusal designs. These interocclusal differences were quantified as differences in frequency of occlusal distance intervals in an interocclusal range of 1 mm, measured from the occlusal surface of the molar model. The vertical distance with which a standard crown in occlusion had to be corrected to avoid interferences was calculated. Among all parameters, the ipsilateral and contralateral mandibular lateral translation, sagittal condylar guide inclination, the ipsilateral laterotrusion and the incisal guide angle give substantial occlusal surface corrections. The high setting for the ipsilateral mandibular lateral translation required most correction. High and low setting values of mandibular movement determinants require considerable adaptation of the occlusal surface of a crown to prevent occlusal disturbances.


Flash-lamp-pumped Ho:Tm:Cr:YAG and Ho:Tm:Er:YLF lasers: modeling of a single, long pulse length comparison.
Two methods of producing the long pulse lengths that promote efficient extraction of energy from low-gain, quasi-four-level lasers are analyzed. A long pulse length output can mitigate laser-induced damage effects and can be generated in quasi-four-level lasers by two disparate methods. One method utilizes Q-switching techniques in resonators designed to extend the pulse length and another utilizes the first pulse in a relaxation oscillation pulse train. Models for quasi-four-level lasers are derived here taking into account the nonnegligible thermal population of the lower laser level. Closed-form expressions are derived for both modes of operation of quasi-four-level laser systems so the parametric dependencies of both forms of operation become obvious, allowing facile comparison. In addition, a combined absorption and quantum efficiency, germane for flash-lamp pumping, is calculated for both Cr and Er sensitizers. Although the former has the advantage of broad absorption bands, the latter has the advantage of a quantum efficiency approaching 3.


Mini viral RNAs act as innate immune agonists during influenza virus infection.
The molecular processes that determine the outcome of influenza virus infection in humans are multifactorial and involve a complex interplay between host, viral and bacterial factors1. However, it is generally accepted that a strong innate immune dysregulation known as 'cytokine storm' contributes to the pathology of infections with the 1918 H1N1 pandemic or the highly pathogenic avian influenza viruses of the H5N1 subtype2-4. The RNA sensor retinoic acid-inducible gene I (RIG-I) plays an important role in sensing viral infection and initiating a signalling cascade that leads to interferon expression5. Here, we show that short aberrant RNAs (mini viral RNAs (mvRNAs)), produced by the viral RNA polymerase during the replication of the viral RNA genome, bind to and activate RIG-I and lead to the expression of interferon-β. We find that erroneous polymerase activity, dysregulation of viral RNA replication or the presence of avian-specific amino acids underlie mvRNA generation and cytokine expression in mammalian cells. By deep sequencing RNA samples from the lungs of ferrets infected with influenza viruses, we show that mvRNAs are generated during infection in vivo. We propose that mvRNAs act as the main agonists of RIG-I during influenza virus infection.


Impact of incorporating the 2C5 crystal structure into comparative models of cytochrome P450 2D6.
Cytochrome P450 2D6 (CYP2D6) metabolizes approximately one third of the drugs in current clinical use. To gain insight into its structure and function, we have produced four different sets of comparative models of 2D6: one based on the structures of P450s from four different microorganisms (P450 terp, P450 eryF, P450 cam, and P450 BM3), another on the only mammalian P450 (2C5) structure available, and the other two based on alternative amino acid sequence alignments of 2D6 with all five of these structures. Principal component analysis suggests that inclusion of the 2C5 crystal structure has a profound effect on the modeling process, altering the general topology of the active site, and that the models produced differ significantly from all of the templates. The four models of 2D6 were also used in conjunction with molecular docking to produce complexes with the substrates codeine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); this identified Glu 216 [in the F-helix; substrate recognition site (SRS) 2] as a key determinant in the binding of the basic moiety of the substrate. Our studies suggest that both Asp 301 and Glu 216 are required for metabolism of basic substrates. Furthermore, they suggest that Asp 301 (I-helix, SRS-4), a residue thought from mutagenesis studies to bind directly to the basic moiety of substrates, may play a key role in positioning the B'-C loop (SRS-1) and that the loss of activity on mutating Asp 301 may therefore be the result of an indirect effect (movement of the B'-C loop) on replacing this residue.


Spatial patterns in herbivory on a coral reef are influenced by structural complexity but not by algal traits.
Patterns of herbivory can alter the spatial structure of ecosystems, with important consequences for ecosystem functions and biodiversity. While the factors that drive spatial patterns in herbivory in terrestrial systems are well established, comparatively less is known about what influences the distribution of herbivory in coral reefs. We quantified spatial patterns of macroalgal consumption in a cross-section of Ningaloo Reef (Western Australia). We used a combination of descriptive and experimental approaches to assess the influence of multiple macroalgal traits and structural complexity in establishing the observed spatial patterns in macroalgal herbivory, and to identify potential feedback mechanisms between herbivory and macroalgal nutritional quality. Spatial patterns in macroalgal consumption were best explained by differences in structural complexity among habitats. The biomass of herbivorous fish, and rates of herbivory were always greater in the structurally-complex coral-dominated outer reef and reef flat habitats, which were also characterised by high biomass of herbivorous fish, low cover and biomass of macroalgae and the presence of unpalatable algae species. Macroalgal consumption decreased to undetectable levels within 75 m of structurally-complex reef habitat, and algae were most abundant in the structurally-simple lagoon habitats, which were also characterised by the presence of the most palatable algae species. In contrast to terrestrial ecosystems, herbivory patterns were not influenced by the distribution, productivity or nutritional quality of resources (macroalgae), and we found no evidence of a positive feedback between macroalgal consumption and the nitrogen content of algae. This study highlights the importance of seascape-scale patterns in structural complexity in determining spatial patterns of macroalgal consumption by fish. Given the importance of herbivory in maintaining the ability of coral reefs to reorganise and retain ecosystem functions following disturbance, structural complexity emerges as a critical feature that is essential for the healthy functioning of these ecosystems.


Advances in the molecular genetics of gliomas - implications for classification and therapy.
Genome-wide molecular-profiling studies have revealed the characteristic genetic alterations and epigenetic profiles associated with different types of gliomas. These molecular characteristics can be used to refine glioma classification, to improve prediction of patient outcomes, and to guide individualized treatment. Thus, the WHO Classification of Tumours of the Central Nervous System was revised in 2016 to incorporate molecular biomarkers - together with classic histological features - in an integrated diagnosis, in order to define distinct glioma entities as precisely as possible. This paradigm shift is markedly changing how glioma is diagnosed, and has important implications for future clinical trials and patient management in daily practice. Herein, we highlight the developments in our understanding of the molecular genetics of gliomas, and review the current landscape of clinically relevant molecular biomarkers for use in classification of the disease subtypes. Novel approaches to the genetic characterization of gliomas based on large-scale DNA-methylation profiling and next-generation sequencing are also discussed. In addition, we illustrate how advances in the molecular genetics of gliomas can promote the development and clinical translation of novel pathogenesis-based therapeutic approaches, thereby paving the way towards precision medicine in neuro-oncology.


Does a higher number of siblings protect against the development of allergy and asthma? A review.
To review the "protective" effects of having a higher number of siblings for the risk of atopic eczema, asthma wheezing, hay fever, and allergic sensitisation. Review of the literature (Medline since 1965 and references). 53 different studies were identified. For eczema, 9 of 11 studies reported an inverse relation with number of siblings; for asthma and wheezing, 21 of 31 reported the inverse association; for hay fever, all 17 studies showed the effect; for allergic sensitisation or immunoglobulin E reactivity 14 of 16 studies supported the "protective" effect of a higher number of siblings. The studies emphasise a "theory" that is based exclusively on epidemiological associations. Research has not yet answered the question of which causal factors explain the sibling effect. Causal factors must meet two criteria; they must vary with sibship size and they must protect against atopic manifestations. The prevailing "hygiene hypothesis" failed to explain the findings adequately. Alternative explanations include in utero programming or endocrine explanatory models. The epidemiology research into siblings and atopic disorders has entered an intellectually challenging phase. Possessing sufficient knowledge about the causal factors might prevent at least 30% of all cases of asthma, eczema, and hay fever.


Antibacterial effects of water soluble green tea extracts on multi-antibiotic resistant isolates of Pseudomonas aeruginosa.
In this research we evaluated the antibacterial activity of water soluble green tea extracts on 43 hospital isolates of Pseudomonas aeruginosa. A total of 43 strains of Pseudomonas aeruginosa were collected from clinical specimens at two hospitals in Tehran, Iran. The susceptibilities of isolates to different antibiotics were tested using agar disk diffusion method. Antibacterial activity of water soluble green tea extract was measured by Minimum Inhibitory Concentrations (MICs) and Minimum Bactericidal Concentrations (MBCs). 35.6% of isolated strains showed resistance to 5 antibiotics or more and 55.8% of all strains were Multi-Drug Resistant (MDR) strains. The average MICs and MBCs of the extract against all strains of Pseudomonas auroginosa were 2.06 +/- 1.76 and 2.54 +/- 2.22 mg mL(-1) respectively.Our study suggests that green tea has significant activity with bactericidal action on multi-drug resistant strains of Pseudomonas aeruginosa.


Study of Mothers' and Infants' Life Events Affecting Oral Health (SMILE) birth cohort study: cohort profile.
The long-term goal of the Study of Mothers' and Infants' Life Events Affecting Oral Health (SMILE) birth cohort study is to identify and evaluate the relative importance and timing of critical factors that shape the oral health of young children. It will then evaluate those factors in their inter-relationship with socioeconomic influences. SMILE is a single-centre study conducted in Adelaide, Australia. All newborns at the main three public hospitals between July 2013 and August 2014 were eligible for inclusion. The final recruited sample at birth was 2181 mother/infant dyads. Participants were followed up with questionnaires when the child was 3 and 6 months of age, and 1, 2 and 5 years of age. Oral epidemiological examinations and anthropometric assessments were conducted at age 2 and 5 years. SMILE has contributed comprehensive data on dietary patterns of young children. Intakes of free sugars, core and discretionary foods and drinks have been detailed. There was a sharp increase in free sugars intake with age. Determinants of dietary patterns, oral health status and body weight during the first 5 years of life have been evaluated. Socioeconomic characteristics such as maternal education and household income and area-level socioeconomic profile influenced dietary patterns and oral health behaviours and status. Funding has been obtained to conduct oral epidemiological examinations and anthropometric assessments at age 7-8 years. Plans are being developed to follow the cohort into adolescent years.


Bio-acoustic signals from stenotic tube flow: state of the art and perspectives for future methodological development.
To study the degree of stenosis from the acoustic signal generated by the turbulent flow in a stenotic vessel, so-called phonoangiography was first suggested over 20 years ago. A reason for the limited use of the technique today may be that, in the early work, the theory of how to relate the spectrum of the acoustic signal to the degree of the stenosis was not clear. However, during the last decade, the theoretical basis for this and other biological tube flow applications has been clarified. Now there is also easy access to computers for frequency analysis. A further explanation for the limited diagnostic use of bio-acoustic techniques for tube flow is the strong competition from ultrasound Doppler techniques. In the future, however, applications may be expected in biological tube flow where the non-invasive, simple and inexpensive bio-acoustic techniques will have a definite role as a diagnostic method.


Web 2.0 chronic disease self-management for older adults: a systematic review.
Participatory Web 2.0 interventions promote collaboration to support chronic disease self-management. Growth in Web 2.0 interventions has led to the emergence of e-patient communication tools that enable older adults to (1) locate and share disease management information and (2) receive interactive healthcare advice. The evolution of older e-patients contributing to Web 2.0 health and medical forums has led to greater opportunities for achieving better chronic disease outcomes. To date, there are no review articles investigating the planning, implementation, and evaluation of Web 2.0 chronic disease self-management interventions for older adults. To review the planning, implementation, and overall effectiveness of Web 2.0 self-management interventions for older adults (mean age ≥ 50) with one or more chronic disease(s). A systematic literature search was conducted using six popular health science databases. The RE-AIM (Reach, Efficacy, Adoption, Implementation and Maintenance) model was used to organize findings and compute a study quality score (SQS) for 15 reviewed articles. Most interventions were adopted for delivery by multidisciplinary healthcare teams and tested among small samples of white females with diabetes. Studies indicated that Web 2.0 participants felt greater self-efficacy for managing their disease(s) and benefitted from communicating with health care providers and/or website moderators to receive feedback and social support. Participants noted asynchronous communication tools (eg, email, discussion boards) and progress tracking features (eg, graphical displays of uploaded personal data) as being particularly useful for self-management support. Despite high attrition being noted as problematic, this review suggests that greater Web 2.0 engagement may be associated with improvements in health behaviors (eg, physical activity) and health status (eg, HRQoL). However, few studies indicated statistically significant improvements in medication adherence, biological outcomes, or health care utilization. Mean SQS scores were notably low (mean=63%, SD 18%). Studies were judged to be weakest on the Maintenance dimension of RE-AIM; 13 reviewed studies (87%) did not describe any measures taken to sustain Web 2.0 effects past designated study time periods. Detailed process and impact evaluation frameworks were also missing in almost half (n=7) of the reviewed interventions. There is need for a greater understanding of the costs and benefits associated with using patient-centered Web 2.0 technologies for chronic disease self-management. More research is needed to determine whether the long-term effectiveness of these programs is sustainable among larger, more diverse samples of chronically ill patients. The effective translation of new knowledge, social technologies, and engagement techniques will likely result in novel approaches for empowering, engaging, and educating older adults with chronic disease.


PICCOLO: a tool for combinatorial library design via multicriterion optimization.
Combinatorial library design is by nature a multicriterion problem. These criteria often include reagent diversity, product similarity to lead compounds and product novelty with respect to a corporate compound bank. More recently, developability and druglikeness have also attracted much attention in library design practices. To address this multicriterion design problem, we have developed a computer program (PICCOLO) that simultaneously optimizes all the factors under consideration using a weighted sum optimization technique. In this paper, we describe the overall design of this program and the formulation of individual penalty functions that characterize the underlying design criteria. We also give an example to illustrate the process and the result of a library design using this program.


SCID genotype and 6-month posttransplant CD4 count predict survival and immune recovery.
The Primary Immune Deficiency Treatment Consortium (PIDTC) performed a retrospective analysis of 662 patients with severe combined immunodeficiency (SCID) who received a hematopoietic cell transplantation (HCT) as first-line treatment between 1982 and 2012 in 33 North American institutions. Overall survival was higher after HCT from matched-sibling donors (MSDs). Among recipients of non-MSD HCT, multivariate analysis showed that the SCID genotype strongly influenced survival and immune reconstitution. Overall survival was similar for patients with RAG, IL2RG, or JAK3 defects and was significantly better compared with patients with ADA or DCLRE1C mutations. Patients with RAG or DCLRE1C mutations had poorer immune reconstitution than other genotypes. Although survival did not correlate with the type of conditioning regimen, recipients of reduced-intensity or myeloablative conditioning had a lower incidence of treatment failure and better T- and B-cell reconstitution, but a higher risk for graft-versus-host disease, compared with those receiving no conditioning or immunosuppression only. Infection-free status and younger age at HCT were associated with improved survival. Typical SCID, leaky SCID, and Omenn syndrome had similar outcomes. Landmark analysis identified CD4+ and CD4+CD45RA+ cell counts at 6 and 12 months post-HCT as biomarkers predictive of overall survival and long-term T-cell reconstitution. Our data emphasize the need for patient-tailored treatment strategies depending upon the underlying SCID genotype. The prognostic significance of CD4+ cell counts as early as 6 months after HCT emphasizes the importance of close follow-up of immune reconstitution to identify patients who may need additional intervention to prevent poor long-term outcome.


Characteristics of left and right scanning in schizophrenia patients using exploratory eye movements: comparison with healthy subjects.
To characterize the left and right scanning function and the effect of affection in schizophrenia patients exploratory eye movements as biologic markers were recorded in 44 schizophrenia patients and 72 age-matched healthy controls. The total eye scanning length (TESL) and total number of gaze points (TNGP) in the left and right visual fields were calculated as subjects viewed neutral or affectively charged pictures. TESL of patients was shorter than that of controls when viewing pictures of smiling babies and open circles. TESL of patients was shorter for smiling faces than for crying babies, but TESL of controls was longer for smiling faces than for crying babies. Left TNGP for smiling faces and circles was lower in patients than in controls. In patients, left TNGP for crying babies was higher than for either smiling babies or circles. In controls, left TNGP for smiling babies was higher than crying babies. In patients, left TNGP for smiling babies and circles was smaller than the right TNGP. In controls, left TNGP was larger for smiling than for crying babies. When viewing smiling babies, both TESL and TNGP were negatively correlated with negative symptom scores in patients. Patients' eye movements in the left visual field were clearly different from controls', suggesting that visual cognitive function is impaired in schizophrenia patients. Exploratory eye movements are a useful marker of visual cognitive function, and are a useful tool to evaluate the influence of affection in schizophrenia patients.


Understanding Misclassification between Neonatal Deaths and Stillbirths: Empirical Evidence from Malawi.
Improving the counting of stillbirths and neonatal deaths is important to tracking Sustainable Development Goal 3.2 and improving vital statistics in low- and middle-income countries (LMICs). However, the validity of self-reported stillbirths and neonatal deaths in surveys is often threatened by misclassification errors between the two birth outcomes. We assessed the extent and correlates of stillbirths being misclassified as neonatal deaths by comparing two recent and linked population surveys conducted in Malawi, one being a full birth history (FBH) survey, and the other a follow-up verbal/social autopsy (VASA) survey. We found that one-fifth of 365 neonatal deaths identified in the FBH survey were classified as stillbirths in the VASA survey. Neonatal deaths with signs of movements in the last few days before delivery reported were less likely to be misclassified stillbirths (OR = 0.08, p<0.05). Having signs of birth injury was found to be associated with higher odds of misclassification (OR = 6.17, p<0.05). We recommend replicating our study with larger sample size in other settings. Additionally, we recommend conducting validation studies to confirm accuracy and completeness of live births and neonatal deaths reported in household surveys with events reported in a full birth history and the extent of underestimation of neonatal mortality resulting from misclassifications. Questions on fetal movement, signs of life at delivery and improved probing among older mother may be useful to improve accuracy of reported events.


Agmatine: an endogenous clonidine-displacing substance in the brain.
Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors. The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain. This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain. Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells. Its biosynthetic enzyme, arginine decarboxylase, is present in brain. Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter.


Substrate binding analysis of the 23S rRNA methyltransferase RrmJ.
The 23S rRNA methyltransferase RrmJ (FtsJ) is responsible for the 2'-O methylation of the universally conserved U2552 in the A loop of 23S rRNA. This 23S rRNA modification appears to be critical for ribosome stability, because the absence of functional RrmJ causes the cellular accumulation of the individual ribosomal subunits at the expense of the functional 70S ribosomes. To gain insight into the mechanism of substrate recognition for RrmJ, we performed extensive site-directed mutagenesis of the residues conserved in RrmJ and characterized the mutant proteins both in vivo and in vitro. We identified a positively charged, highly conserved ridge in RrmJ that appears to play a significant role in 23S rRNA binding and methylation. We provide a structural model of how the A loop of the 23S rRNA binds to RrmJ. Based on these modeling studies and the structure of the 50S ribosome, we propose a two-step model where the A loop undocks from the tightly packed 50S ribosomal subunit, allowing RrmJ to gain access to the substrate nucleotide U2552, and where U2552 undergoes base flipping, allowing the enzyme to methylate the 2'-O position of the ribose.


The ELPAT living organ donor Psychosocial Assessment Tool (EPAT): from 'what' to 'how' of psychosocial screening - a pilot study.
Thorough psychosocial screening of donor candidates is required in order to minimize potential negative consequences and to strive for optimal safety within living donation programmes. We aimed to develop an evidence-based tool to standardize the psychosocial screening process. Key concepts of psychosocial screening were used to structure our tool: motivation and decision-making, personal resources, psychopathology, social resources, ethical and legal factors and information and risk processing. We (i) discussed how each item per concept could be measured, (ii) reviewed and rated available validated tools, (iii) where necessary developed new items, (iv) assessed content validity and (v) pilot-tested the new items. The resulting ELPAT living organ donor Psychosocial Assessment Tool (EPAT) consists of a selection of validated questionnaires (28 items in total), a semi-structured interview (43 questions) and a Red Flag Checklist. We outline optimal procedures and conditions for implementing this tool. The EPAT and user manual are available from the authors. Use of this tool will standardize the psychosocial screening procedure ensuring that no psychosocial issues are overlooked and ensure that comparable selection criteria are used and facilitate generation of comparable psychosocial data on living donor candidates.


A HElium NanoDroplet Isolation (HENDI) investigation of the weak hydrogen bonding in the propyne dimer (CH3CCH)2.
A HElium Nanodroplet Isolation (HENDI) experiment was performed to explore the absorption spectra of the propyne monomer (CH3CCH), dimer and (CH3CCH)≥3 multimers in the vicinity of the CH stretch region ν1 of the monomer. Ab initio calculations were performed at the MP2 level to document the potential energy surface of the dimer. This provided the necessary parameters to simulate the absorption spectrum of the dimer and thus facilitate the interpretation of the experiment. The central result was to observe three isomers of the dimer, hence reflecting the complexity of the weak CHπ H-bonding when several H-donors are at play.


An experimental study on the effectiveness of a mutual support group for family caregivers of a relative with dementia in mainland China.
When caring for an older relative with dementia, family members experience considerable distress and burden. Literature reviews show that supportive group interventions for these caregivers have significant positive effects on improving their distress and quality of life, but not consistent and conclusive. Limited research is found in Asian populations. This study tested the effectiveness of a 12-session bi-weekly mutual support group program for Chinese family caregivers of a relative with dementia in Hong Kong, when compared with standard family support service. An experimental study with pre- and post-test, parallel groups design was conducted. A randomized sample of 78 family caregivers, 39 in each of the experimental and control groups, from one regional dementia care center participated in the study. A protocol was specifically designed by an advanced practice nurse to guide the mutual support group process and the facilitator and peer leader training, based on evidence from the literature on family support group intervention in Western countries. The results of ANOVA tests indicated that the mutual support group participants had significantly greater improvements in distress levels and quality of life than the control group. There were only mild changes in the demands for mental health services in both groups at post-test. These findings support the effectiveness of mutual support groups to offer psychosocial support to Chinese family caregivers in dementia care beyond routine community mental health care.


Extent of digestion affects the success of amplifying human DNA from blood meals of Anopheles gambiae (Diptera: Culicidae).
The success of distinguishing blood meal sources of Anopheles gambiae Giles through deoxyribonucleic acid (DNA) profiling was investigated by polymerase chain reaction (PCR) amplification at the TC-11 and VWA human short tandem repeats (STR) loci. Blood meal size and locus had no significant effect on the success of amplifying human DNA from blood meals digested for 0, 8, 16, 24 and 32 h (P = 0.85 and 0.26 respectively). However, logistic regression found a significant negative relationship between time since ingestion and the success probability of obtaining positive PCR products among meals digested for between 8 and 32 h (P = 0.001). Approximately 80% of fresh blood meals were successfully profiled. After 8 h, the proportion of blood meals that could be successfully profiled decreased slowly with time after ingestion, dropping to below 50% after approximately 15 h. There was no significant difference in the success of amplifying human DNA from blood meals of mosquitoes killed at time 0 and 8 h after ingestion (P = 0.272).


Accelerated fast iterative shrinkage thresholding algorithms for sparsity-regularized cone-beam CT image reconstruction.
The development of iterative image reconstruction algorithms for cone-beam computed tomography (CBCT) remains an active and important research area. Even with hardware acceleration, the overwhelming majority of the available 3D iterative algorithms that implement nonsmooth regularizers remain computationally burdensome and have not been translated for routine use in time-sensitive applications such as image-guided radiation therapy (IGRT). In this work, two variants of the fast iterative shrinkage thresholding algorithm (FISTA) are proposed and investigated for accelerated iterative image reconstruction in CBCT. Algorithm acceleration was achieved by replacing the original gradient-descent step in the FISTAs by a subproblem that is solved by use of the ordered subset simultaneous algebraic reconstruction technique (OS-SART). Due to the preconditioning matrix adopted in the OS-SART method, two new weighted proximal problems were introduced and corresponding fast gradient projection-type algorithms were developed for solving them. We also provided efficient numerical implementations of the proposed algorithms that exploit the massive data parallelism of multiple graphics processing units. The improved rates of convergence of the proposed algorithms were quantified in computer-simulation studies and by use of clinical projection data corresponding to an IGRT study. The accelerated FISTAs were shown to possess dramatically improved convergence properties as compared to the standard FISTAs. For example, the number of iterations to achieve a specified reconstruction error could be reduced by an order of magnitude. Volumetric images reconstructed from clinical data were produced in under 4 min. The FISTA achieves a quadratic convergence rate and can therefore potentially reduce the number of iterations required to produce an image of a specified image quality as compared to first-order methods. We have proposed and investigated accelerated FISTAs for use with two nonsmooth penalty functions that will lead to further reductions in image reconstruction times while preserving image quality. Moreover, with the help of a mixed sparsity-regularization, better preservation of soft-tissue structures can be potentially obtained. The algorithms were systematically evaluated by use of computer-simulated and clinical data sets.


Reaction monitoring reveals poisoning mechanism of Pd2(dba)3 and guides catalyst selection.
We have discovered that the dba ligand in the commonly used Pd2(dba)3·CHCl3 cross-coupling pre-catalyst is susceptible to bis-arylation when used in the presence of aryl iodides. The in situ formed dbaAr2 ligands result in Pd-species with altered catalytic activity. In the case of study, the room temperature C3 arylation of benzo[b]thiophenes with aryl iodides, we have observed a marked catalyst deactivation when dba is arylated with electron-deficient aryl iodides, accounting for the poor yields obtained in the C3 arylation reactions with these aryl iodides. Based on these studies, we report a new catalytic system, employing a dba-free Pd catalyst, which allows for the first time the direct C3 arylation of benzo[b]thiophenes with electron-deficient aryl iodides at room temperature.


Shear Bond Comparison between 4 Bioceramic Materials and Dual-cure Composite Resin.
Bioceramic materials have shown biologic and physical properties favorable for regenerative treatment. A key to treatment success is an adequate restoration to prevent microleakage; however, research is limited regarding the bond strength between restorative and bioceramic materials used in regenerative procedures. This study compared the bond strength between 4 bioceramic materials and a dual-cure composite resin. Eighty wells in Teflon (ePlastics, San Diego, CA) blocks were filled with bioceramic materials representing 4 groups: White ProRoot mineral trioxide aggregate (MTA) (Dentsply Tulsa Dental, Tulsa, OK), Biodentine (Septodont, Saint Maur des Fosses, France), EndoSequence Root Repair Material Fast Set Putty (Brasseler USA, Savannah, GA), and NeoMTA (Avalon Biomed Inc, Houston, TX). After allowing samples to set according to the manufacturers' instructions, exposed surfaces of the bioceramic materials were prepared using ClearFil SE Bond (Kuraray America, Inc., New York, NY) followed by restoration with ClearFil DC Core Plus (Kuraray America, Inc.). To test shear bond strength, each block was secured in a universal testing machine, and the crosshead was advanced at 0.5 mm/min until fracture. Newton peak force was recorded and megapascals calculated followed by data comparison. The mean shear bond strengths between ClearFil DC Core Plus and the bioceramic materials were as follows: White ProRoot MTA, 7.96 MPa; Biodentine, 9.18 MPa; EndoSequence Root Repair Material Fast Set Putty, 4.47 MPa; and NeoMTA, 5.72 MPa. White ProRoot MTA and Biodentine were statistically similar, with a higher stress bond strength than NeoMTA, which had a statistically greater bond strength than EndoSequence Root Repair Material. All these values were lower than typical bond strengths shown for dentin-composite resin bonding. The choice of which bioceramic material to use in regenerative procedures should be based on factors other than the bond between that material and the overlying coronal resin restoration.


ARF6 and Rab11 as intrinsic regulators of axon regeneration.
Adult central nervous system (CNS) axons do not regenerate after injury because of extrinsic inhibitory factors, and a low intrinsic capacity for axon growth. Developing CNS neurons have a better regenerative ability, but lose this with maturity. This mini-review summarises recent findings which suggest one reason for regenerative failure is the selective distribution of growth machinery away from axons as CNS neurons mature. These studies demonstrate roles for the small GTPases ARF6 and Rab11 as intrinsic regulators of polarised transport and axon regeneration. ARF6 activation prevents the axonal transport of integrins in Rab11 endosomes in mature CNS axons. Decreasing ARF6 activation permits axonal transport, and increases regenerative ability. The findings suggest new targets for promoting axon regeneration after CNS injury.


Care of general practice patients preceding and following a suicide attempt: observational study in Flemish general practices.
First, to examine general practitioner (GP) knowledge about the care (needs) of their patients; second, to examine the quality of GP follow-up care; third, to examine the transmission of patient care information from hospitals/emergency services (ES) to GPs. 105 general practices from the representative Belgian Network of Sentinel General Practices (SGP) in Flanders, the largest region of Belgium, during 2013-2016. 245 suicide attempts by regular patients. Ten care-related measures, including three indicators of quality of follow-up care, were based on data reported by the SGP on structured forms at baseline and at two follow-up points in time. As for GP knowledge, 10.5% of SGP failed to report whether suicidal risk was noticed in patients seen in the month preceding the attempt; 9.0% whether there were previous attempts; 22.5% whether the patient was receiving mental health treatment at follow-up and 22.0% whether suicidal behaviour was repeated at follow-up. Relatively more patients≥65 years had no suicide risk evaluation (OR 3.54; 95% CI 1.11 to 11.26). As for quality of follow-up care, there was a GP-patient contact following 90.5% of the attempts, follow-up appointments were planned following 43.4% of the attempts and there was a GP contact with patient proxies following 62.8% of the attempts. Patient age ≥65 years (OR 4.09; 95% CI 1.79 to 9.33), a recent GP-patient contact preceding the attempt (OR 1.97; 95% CI 1.13 to 3.43), depression of patient (OR 1.96; 95% CI 1.14 to 3.37) and a suburban SGP area (OR 2.34; 95% CI 1.13 to 4.82) were determinants of an increased quality of care sum. GPs received patient care information from a hospital (ES) for 67.8% of eligible attempts, with SGP practice location being a determinant. GPs are highly involved in the care of suicide attempters but there is room for improvement, also in informational continuity from hospital (ES) to GPs.


Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration.
We studied endothelial-mediated microvascular blood flow in neuropathic diabetic patients to determine the association between endothelial regulation of the microcirculation and the expression of endothelial constitutive nitric oxide synthetase (ecNOS) in the skin. Vasodilation on the dorsal foot in response to heating and iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were measured using single-point laser Doppler and laser Doppler imaging in diabetic patients with neuropathy (DN), with neuropathy and vascular disease (DI), with Charcot arthropathy (DA), and without complications (D), and in healthy control subjects (C). The response to heat was reduced in the DN (321 [21-629] percentage of increase over the baseline, median [interquartile range]) and DI (225 [122-470]) groups but was preserved in the DA (895 [359-1,229]), D (699 [466-1,029]), and C (810 [440-1,064], P < 0.0001) groups. The endothelial-mediated response to acetylcholine was reduced in the DN (17 [11-25]), DA (22 [2-34]), and DI (13 [2-30]) groups compared with the D (47 [24-58]) and C (44 [31-70], P < 0.001) groups. The non-endothelial-mediated response to sodium nitroprusside was also reduced in the DI (4 [0-18]), DN (17 [9-26]), and DA (21 [11-31]) groups compared with the D (37 [19-41]) and C (44 [26-67], P < 0.0001) groups. There was a significant reduction in vasodilation in the DI group compared with all other groups (P < 0.0001). Full thickness skin biopsies from the dorsum of the foot of 15 DN, 10 DI, and 11 C study subjects were immunostained with antiserum to human ecNOS, the functional endothelial marker GLUT1, and the anatomical endothelial marker von Willebrand factor. The staining intensity of ecNOS was reduced in both diabetic groups. No differences were found among the three groups in the staining intensity of von Willebrand factor and GLUT1. We conclude that the endothelium-dependent and endothelium-independent vasodilations are impaired in diabetic patients predisposed to foot ulceration and that neuropathy is the main factor associated with this abnormality. Reduced expression of ecNOS may be a major contributing factor for endothelial dysfunction. These data provide support for a close association of neuropathy and microcirculation in the pathogenesis of foot ulceration.


Functional significance of a novel 7-factor model of DSM-5 PTSD symptoms: results from the National Health and Resilience in Veterans study.
While posttraumatic stress disorder (PTSD) symptoms in the recently published Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) are clustered into four factors, emerging confirmatory factor analytic studies suggest that this disorder is best characterized by seven symptom clusters, including re-experiencing, avoidance, negative affect, anhedonia, externalizing behaviors, and anxious and dysphoric arousal symptoms. To date, however, data are lacking regarding the relation between this novel model of DSM-5 PTSD symptoms and measures of clinical significance in this population (e.g., functioning). Using data from the National Health and Resilience in Veterans Study (NHRVS), a contemporary, nationally representative sample of 1484 U.S. veterans, we evaluated clinical and functional correlates of a novel 7-factor model of DSM-5 PTSD symptoms. Differential patterns of associations were observed between DSM-5 PTSD symptom clusters, and psychiatric comorbidities, suicidal ideation, hostility, and functioning and quality of life. Anhedonia symptoms, in particular, were strongly related to current depression, as well as reduced mental functioning and quality of life. Externalizing behaviors were most strongly related to hostility, supporting the convergent validity of this construct. Cross-sectional design and employment of self-report measures. These results suggest that a more refined 7-factor model of DSM-5 PTSD symptoms may provide greater specificity in understanding associations with comorbid psychopathology, suicidal ideation, and functioning and quality of life in U.S. veterans. They further suggest that prevention and treatment efforts that target distinct aspects of the PTSD phenotype may be more effective in mitigating key clinical and functional outcomes in this population.


N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways.
Recent studies propose that N-arachidonyl glycine (NAGly), a carboxylic analogue of anandamide, is an endogenous ligand of the Gα(i/o) protein-coupled receptor 18 (GPR18). However, a high-throughput β-arrestin-based screen failed to detect activation of GPR18 by NAGly (Yin et al., 2009; JBC, 18:12328). To address this inconsistency, this study investigated GPR18 coupling in a native neuronal system with endogenous signaling pathways and effectors. GPR18 was heterologously expressed in rat sympathetic neurons, and the modulation of N-type (Ca(v)2.2) calcium channels was examined. Proper expression and trafficking of receptor were confirmed by the "rim-like" fluorescence of fluorescently tagged receptor and the positive staining of external hemagglutinin-tagged GPR18-expressing cells. Application of NAGly on GPR18-expressing neurons did not inhibit calcium currents but instead potentiated currents in a voltage-dependent manner, similar to what has previously been reported (Guo et al., 2008; J Neurophysiol, 100:1147). Other proposed agonists of GPR18, including anandamide and abnormal cannabidiol, also failed to induce inhibition of calcium currents. Mutants of GPR18, designed to constitutively activate receptors, did not tonically inhibit calcium currents, indicating a lack of GPR18 activation or coupling to endogenous G proteins. Other downstream effectors of Gα(i/o)-coupled receptors, G protein-coupled inwardly rectifying potassium channels and adenylate cyclase, were not modulated by GPR18 signaling. Furthermore, GPR18 did not couple to other G proteins tested: Gα(s), Gα(z), and Gα(15). These results suggest NAGly is not an agonist for GPR18 or that GPR18 signaling involves noncanonical pathways not examined in these studies.


Brain, know thy transcriptome, know thyself.
In this issue of Neuron, Konopka et al. (2012) describe their comparison of transcriptomes from frontal pole, caudate nucleus, and hippocampus of multiple adult humans, chimpanzees, and rhesus monkeys. The data provide an initial opportunity for linking genomic and brain differences among these primate species.


Planning for healthcare services during the COVID-19 pandemic in the Southeast of England: a system dynamics modelling approach.
To develop, test, validate and implement a system dynamics model to simulate the pandemic progress and the impact of various interventions on viral spread, healthcare utilisation and demand in secondary care. We adopted the system dynamics model incorporating susceptible, exposed, infection and recovery framework to simulate the progress of the pandemic and how the interventions for the COVID-19 response influence the outcomes with a focus on secondary care. This study was carried out covering all the local health systems in Southeast of England with a catchment population of six million with a specific focus on Kent and Medway system. Six local health systems in Southeast of England using Kent and Medway as a case study. Short to medium 'what if' scenarios incorporating human behaviour, non-pharmaceutical interventions and medical interventions were tested using the model with regular and continuous feedback of the model results to the local health system leaders for monitoring, planning and rapid response as needed. Daily output from the model which included number infected in the population, hospital admissions needing COVID-19 care, occupied general beds, continuous positive airway pressure beds, intensive care beds, hospital discharge pathways and deaths. We successfully implemented a regional series of models based on the local population needs which were used in healthcare planning as part of the pandemic response. In this study, we have demonstrated the utility of system dynamics modelling incorporating local intelligence and collaborative working during the pandemic to respond rapidly and take decisions to protect the population. This led to strengthened cooperation among partners and ensured that the local population healthcare needs were met.


Strand break repair, DNA polymerase activity and heat radiosensitization in thermotolerant cells.
HeLa S3 cells were made thermotolerant by 'chronic' (5 h at 42 degrees C) or 'acute' (15 min at 44 degrees C followed by 5 h at 37 degrees C) heat treatments. Cell survival, repair of radiation-induced DNA strand breaks, alpha and beta DNA polymerase activity and radiation sensitivity following hyperthermia were all measured in both control and thermotolerant cells. The ability to repair DNA strand breaks correlated well with cell survival following hyperthermia. Hyperthermic inhibition of strand break repair was reduced in thermotolerant relative to control cells, although the thermal tolerance ratios for repair were less than for hyperthermic cell killing. Both radiosensitization and DNA polymerase inactivation by hyperthermia were only slightly reduced in thermotolerant relative to control cells. Hence a poor correlation was found between these two parameters and hyperthermic cell survival. For all heat treatments applied, alpha and beta DNA polymerase activity correlated well with the extent of hyperthermic radiosensitization.


Vertical farming increases lettuce yield per unit area compared to conventional horizontal hydroponics.
Vertical farming systems (VFS) have been proposed as an engineering solution to increase productivity per unit area of cultivated land by extending crop production into the vertical dimension. To test whether this approach presents a viable alternative to horizontal crop production systems, a VFS (where plants were grown in upright cylindrical columns) was compared against a conventional horizontal hydroponic system (HHS) using lettuce (Lactuca sativa L. cv. "Little Gem") as a model crop. Both systems had similar root zone volume and planting density. Half-strength Hoagland's solution was applied to plants grown in perlite in an indoor controlled environment room, with metal halide lamps providing artificial lighting. Light distribution (photosynthetic photon flux density, PPFD) and yield (shoot fresh weight) within each system were assessed. Although PPFD and shoot fresh weight decreased significantly in the VFS from top to base, the VFS produced more crop per unit of growing floor area when compared with the HHS. Our results clearly demonstrate that VFS presents an attractive alternative to horizontal hydroponic growth systems and suggest that further increases in yield could be achieved by incorporating artificial lighting in the VFS.


[Assessment of exposure to tobacco smoke in a selected group of patients with multiple sclerosis from the Upper Silesia region].
In recent years, the increase in the incidence of multiple sclerosis (MS - Multiple Sclerosis) is observed. and the direct cause of the symptoms of multiple sclerosis is myelin nerves damage. It can be concluded that the environmental factor is at least partly responsible for the occurrence of this disease. For the development of this disease are responsible, in addition to genetic factors, compounds present in many parts of the environment. Many of these compounds may adversely affect the redox equilibrium of the body, exacerbating radicalgenesis and decreasing antioxidant defenses. Multiple sclerosis is usually diagnosed in early adulthood, during most daily activities. Effects of SM on living standards includes not only the medical aspect, but also social, economic and emotional aspect. Polish population is a high risk zone regarding multiple sclerosis. The aim of this study was a preliminary assessment of selected environmental exposure factors in the pathogenesis of multiple sclerosis with regard to exposure to tobacco smoke with the author's survey of patients from the region of Upper Silesia. Most MS patients (32) in the study group (suffering from MS from 2 to 44 years) are inhabitants of agglomeration of over 50 thousand citizens, from the area of Gliwice, Bytom and Zabrze (43.75%). In investigated group 46.88% MS patients from Silesia region were exposed to tobacco smoke, of which 21.88% actively smoke. Patients with MS, in order not to worsen their disease manifestation, should stop smoking and increase, if possible, any physical activities. These data will be incorporated into a wide-ranging research to clarify the role of selected environmental factors in a very complex and still not fully explored the pathogenesis of multiple sclerosis in Upper Silesia.


Randomized Effectiveness Trial of the New Beginnings Program for Divorced Families with Children and Adolescents.
This study presents findings from a randomized effectiveness trial of the New Beginnings Program (NBP), which has demonstrated efficacy in 2 prior randomized efficacy trials. Family courts in 4 counties facilitated recruitment of divorcing and separating parents, and providers in community agencies delivered the program. Participants were 830 parents of children ages 3-18 who were randomized to receive either the 10-session NBP or an active 2-session comparison condition in which parents learned about the same parenting skills but did not complete home practice of these skills. Parents were ethnically diverse (59.4% non-Hispanic White, 31.4% Hispanic, 9.2% other race or ethnicity). Multiple rater assessments of parenting, interparental conflict, and child mental health problems were conducted at pretest, posttest, and 10-month follow-up. The results indicated positive moderated effects of the NBP as compared with the active control condition to strengthen parenting at posttest and to reduce child mental health problems at posttest and 10 months. Many of these moderated effects showed positive benefits for non-Hispanic White families but not for Hispanic families. The findings indicate support for the effectiveness of the NBP when delivered by community-based agencies but also indicate the need for further adaptations to make the program effective for Hispanic parents.


Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients.
Real-life long-term data on infliximab treatment in ulcerative colitis are limited. To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined. A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age ≥18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant. Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy. Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.


A novel mixing device for the reproducible generation of nonviral gene therapy formulations.
Nonviral gene therapy utilizing plasmid DNA (pDNA) complexed with cationic lipids (lipoplexes) or cationic polymers (polyplexes) has demonstrated considerable potential for the treatment of a variety of diseases. However, progress toward clinical application is often delayed by the lack of reliable and scalable mixing of components sufficient to guarantee consistent performance in vivo. Attempts to improve and standardize mixing have been limited by the sensitivity of pDNA to shear-related degradation. Here we describe a simple pneumatic mixing device that enables the rapid and reproducible production of large volumes of nonviral gene therapy formulations and demonstrate its suitability for use with shear-sensitive pDNA.


Possible Role of Common Spices as a Preventive and Therapeutic Agent for Alzheimer's Disease.
For centuries, spices have been consumed as food additives or medicinal agents. However, there is increasing evidence indicating the plant-based foods in regular diet may lower the risk of neurodegenerative diseases including Alzheimer disease. Spices, as one of the most commonly used plant-based food additives may provide more than just flavors, but as agents that may prevent or even halt neurodegenerative processes associated with aging. In this article, we review the role and application of five commonly used dietary spices including saffron turmeric, pepper family, zingiber, and cinnamon. Besides suppressing inflammatory pathways, these spices may act as antioxidant and inhibit acetyl cholinesterase and amyloid β aggregation. We summarized how spice-derived nutraceuticals mediate such different effects and what their molecular targets might be. Finally, some directions for future research are briefly discussed.


Birds and longevity: does flight driven aerobicity provide an oxidative sink?
Birds generally age slower and live longer than similar sized mammals. For birds this occurs despite elevated blood glucose levels that for mammals would in part define them as diabetic. However these data were acquired in respiration states that have little resemblance to conditions in healthy tissues and mitochondrial RS production is probably minimal in healthy animals. Indeed mitochondria probably act as net consumers rather than producers of RS. Here we propose that (1) if mitochondria are antioxidant systems, the greater mitochondrial mass in athletic species, such as birds, is advantageous as it should provide a substantial sink for RS. (2) The intense drive for aerobic performance and decreased body density to facilitate flight may explain the relative insensitivity of birds to insulin, as well as depressed insulin levels and apparent sensitization to glucagon. Glucagon also associates with the sirtuin protein family, most of which are associated with caloric restriction regulated pathways, mitochondrial biogenesis and life span extension. (3) We note that telomeres, which appear to be unusually long in birds, bind Sirtuins 2 and 4 and therefore may stabilize and protect nuclear DNA. Ultimately these flight driven responses may suppress somatic growth and protect DNA from oxidative damage that would otherwise lead to ageing and non-viral cancers.


Metabolic activity and collagen turnover in human tendon in response to physical activity.
Connective tissue of the human tendon plays an important role in force transmission. The extracellular matrix turnover of tendon is influenced by physical activity. Blood flow, oxygen demand, and the level of collagen synthesis and matrix metalloproteinases increase with mechanical loading. Gene transcription and especially post-translational modifications of proteins of the extracellular matrix are enhanced following exercise. Conversely, inactivity markedly decreases collagen turnover. Training leads to a chronically increased collagen turnover, and dependent on the type of collagen also to some degree of net collagen synthesis. These changes modify the biomechanical properties of the tissue (for example, viscoelastic characteristics) as well as the structural properties of the in collagen (for example, cross-sectional area). Mechanical loading of human tendon does result in a marked interstitial increase in growth factors that are known potentially to stimulate synthesis of collagen and other extracellular matrix proteins. Taken together, human tendon tissue mounts a vigorous acute and chronic response to mechanical loading in terms of metabolic-circulatory changes as well as of extracellular matrix formation. These changes may contribute to training-induced adaptation of biomechanical properties consisting of altered resistance to loading and enhanced tolerance to strenuous exercise. Understanding of such changes is a pre-requisite in the development of measures aimed at prevention of overuse tendon injuries occurring during sport, work or leisure-related activities.


Interneural tissue clearance in axillary dissection for breast cancer: What is the importance?
Breast cancer is the most common cancer in women and second most common type of cancer overall. The prime objectives of axillary surgery in the management of breast cancer are 1) accurate staging, 2) treatment to cure and 3) quantitative information of metastatic lymph nodes for prognostic purposes and allocation to adjuvant protocols. During axillary dissection, all 3 level lymphnodes are removed, while the important axillary structures (axillary vein, long thoracic and thoracodorsal nerves) are preserved. The latter two structures are particularly vulnerable to injury when dissecting the tissue between them (the interneural tissue). This prospective non-randomized study, conducted on 125 female patients, who underwent axillary lymphadenectomy for breast cancer has evaluated the importance of dissection of the Interneural tissue during axillary dissection in breast cancer surgery by reviewing the lymph node yield and metastasis rate. The interneural tissue was excised separately after a routine axillary dissection. Lymph nodes were found in the interneural tissue of 70 out of 125 patients (56%). The average number of interneural lymph nodes recovered per specimen was 1.3. The interneural tissue lymph nodes were positive for metastasis in 10 (8%) patients. There was no incidence of isolated metastasis in the internerve tissue nodes. There is a significant incidence of lymph nodes (56%) and axillary node metastases (8%) in the tissue lying between the long thoracic and thoracodorsal nerves. Therefore, meticulous dissection and excision of this interneural tissue is strongly recommended to optimize decision making regarding adjuvant treatment and outcome.


Characterization of the DNA copy-number genome in the blood of cutaneous T-cell lymphoma patients.
Cutaneous T-cell lymphoma (CTCL) is a heterogeneous non-Hodgkin's lymphoma that may variably involve the skin, lymph nodes, and peripheral blood. Malignant burden ranges from cutaneous patches and plaques with little evidence of blood involvement to erythroderma often in association with frank leukemia, as in Sézary syndrome. Toward a better understanding of the pathogenesis of this CD4+ T-cell malignancy, we conducted a high-resolution genomic analysis combining DNA (23 samples) and mRNA (12 samples) data of peripheral blood isolates from CTCL patients across a spectrum of stages. Strikingly, even patients with limited involvement, e.g., normal CD4 counts, contained significant copy-number alterations. Defining genomic characteristics of CTCL blood involvement included gains on 8q and 17q, and deletions on 17p and chromosome 10. A consensus analysis of 108 leukemic CTCL samples demonstrated global similarities among patients with varied blood involvement, narrowing 38 of 62 loci. Toward an annotated framework for in vitro testing, we also characterized genomic alterations in five CTCL cell lines (HH, HUT78, PNO, SeAx, and Sez4), revealing intact core features of leukemic CTCL. Together, these studies produce the most comprehensive view of the leukemic CTCL genome to date, with implications for pathogenesis, molecular classification, and potential future therapeutic developments.


Brain atrophy and lesion load in a large population of patients with multiple sclerosis.
To measure white matter (WM) and gray matter (GM) atrophy and lesion load in a large population of patients with multiple sclerosis (MS) using a fully automated, operator-independent, multiparametric segmentation method. The study population consisted of 597 patients with MS and 104 control subjects. The MRI parameters were abnormal WM fraction (AWM-f), global WM-f (gWM-f), and GM fraction (GM-f). Significant differences between patients with MS and control subjects included higher AWM-f and reduced gWM-f and GM-f. MRI data showed significant differences between patients with relapsing-remitting and secondary progressive forms of MS. Significant correlations between MRI parameters and between MRI and clinical data were found. Patients with multiple sclerosis have significant atrophy of both white matter (WM) and gray matter (GM); secondary progressive patients have significantly more atrophy of both WM and GM than do relapsing-remitting patients and a significantly higher lesion load (abnormal WM fraction); lesion load is related to both WM and even more to GM atrophy; lesion load and WM and GM atrophy are significantly related to Expanded Disability Status Scale score and age at onset (suggesting that the younger the age at disease onset, the worse the lesion load and brain atrophy); and GM atrophy is the most significant MRI variable in determining the final disability.


Influence of media composition on the production of alkaline α-amylase from Bacillus subtilis CB-18.
Starch, a homopolysaccharide is an important and an abundant food reserve and energy source. Starches are processed to yield different products which find many industrial applications. Alpha-amylases hydrolyze starch by cleaving α-1,4-glucosidic bonds and have been used in food, textile and pharmaceutical industries [Sun et al. 2010]. Enzymatic conversion of starch with amylase presents an economically superior alternative to the conventional method of starch gelatinization. Alkaline α-amylase has an important position in the global enzyme market as a constituent of detergent. In this paper, we screened soil bacteria and an isolate, alkalophilic Bacillus subtilis CB-18 was found to produce an alkaline α-amylase in different media. MATERIAL AND METHODS. Screening of the isolates for amylolytic activity was carried out by growing bacteria isolated from the soil in starch agar plates and subsequently staining the plates with iodine solution to reveal zones of hydrolysis of starch. The selected isolate, Bacillus subtlis CB-18 was grown in different media at alkaline pH to evaluate the influence of media composition on alkaline α-amylase production. Enzyme assay was carried out by growing the culture in a broth medium and obtaining cell - free culture supernatant after centrifugation at 2515 × g for 15 minutes Amylase activity was determined by incubating 0.5 ml of crude enzyme solution in 0.1M Tris/HCl buffer (pH 8.5) with 0.5 ml of 1% soluble starch solution. The reaction was terminated by the addition of DNS reagent and reducing sugar produced from the amylolytic reaction was determined. Bacillus subtilis CB-18 used for this work was selected because it produced 7 mm zone diameter on starch agar plate. This organism was cultured in different alkaline broth media containing 2% soluble starch as inducer carbohydrate for α-amylase production. Among the carbon sources used for enzyme production, sorbitol was the best to stimulate enzyme production with α-amylase activity of 758 U/mL after 48 h. Peptone was the best nitrogen source for enzyme production with α-amylase activity of 680 U/mL after 48 h. Metal ions including Ca (2+), Mn(2+) and Mg(2+) stimulated enzyme production while Hg(2+) and Ag(+) repressed enzyme production. The best enzyme yields were observed in basal media containing agro-based substrates. This work reports the production of alkaline α-amylase by Bacillus subtlis CB-18 in different media. Enzyme production was highest when agro-based media were used to formulate the media.


High yields of lethal mutations in somatic mammalian cells that survive ionizing radiation.
When mammalian cells are irradiated in vitro, the component cells of a normal-appearing survivor colony or clone are commonly thought to have proliferative capacity equivalent to that of the unirradiated cells. We have found, however, that cells appearing in survivor colonies may carry heritable lethal defects which come to light, perhaps only after numerous successful divisions, in the form of plating efficiencies that are reduced below those of unirradiated cells in a dose-dependent manner. We regard these heritable defects as signs of the induction of lethal mutations, which, like non-lethal mutations, may require many generations before they are expressed. This effect has been noted in two very dissimilar mammalian cell lines, one a primary culture from adult tissue, the other an immortal cell line. We suggest that induction of lethal mutations may occur also in somatic cells in vivo; this would account for the well-known observation that previously irradiated but apparently healed tissue is subsequently proved to be extraordinarily sensitive to subsequent exposure to irradiation or cytotoxic drugs. The results of our experiments in vitro suggest that current methods of estimating mutation or transformation yields may yield underestimates. If lethal mutations are induced also in vivo, interpretations of the results of fractionation experiments on normal tissues may have to be reconsidered.


Explaining the geographic spread of emerging epidemics: a framework for comparing viral phylogenies and environmental landscape data.
Phylogenetic analysis is now an important tool in the study of viral outbreaks. It can reconstruct epidemic history when surveillance epidemiology data are sparse, and can indicate transmission linkages among infections that may not otherwise be evident. However, a remaining challenge is to develop an analytical framework that can test hypotheses about the effect of environmental variables on pathogen spatial spread. Recent phylogeographic approaches can reconstruct the history of virus dispersal from sampled viral genomes and infer the locations of ancestral infections. Such methods provide a unique source of spatio-temporal information, and are exploited here. We present and apply a new statistical framework that combines genomic and geographic data to test the impact of environmental variables on the mode and tempo of pathogen dispersal during emerging epidemics. First, the spatial history of an emerging pathogen is estimated using standard phylogeographic methods. The inferred dispersal path for each phylogenetic lineage is then assigned a "weight" using environmental data (e.g. altitude, land cover). Next, tests measure the association between each environmental variable and lineage movement. A randomisation procedure is used to assess statistical confidence and we validate this approach using simulated data. We apply our new framework to a set of gene sequences from an epidemic of rabies virus in North American raccoons. We test the impact of six different environmental variables on this epidemic and demonstrate that elevation is associated with a slower rabies spread in a natural population. This study shows that it is possible to integrate genomic and environmental data in order to test hypotheses concerning the mode and tempo of virus dispersal during emerging epidemics.


The role of proteomics in assessing beta-cell dysfunction and death in type 1 diabetes.
Introduction: Type 1 diabetes (T1D) is characterized by autoimmune-induced dysfunction and destruction of the pancreatic beta cells. Unfortunately, this process is poorly understood, and the current best treatment for type 1 diabetes is the administration of exogenous insulin. To better understand these mechanisms and to develop new therapies, there is an urgent need for biomarkers that can reliably predict disease stage. Areas covered: Mass spectrometry (MS)-based proteomics and complementary techniques play an important role in understanding the autoimmune response, inflammation and beta-cell death. MS is also a leading technology for the identification of biomarkers. This, and the technical difficulties and new technologies that provide opportunities to characterize small amounts of sample in great depth and to analyze large sample cohorts will be discussed in this review. Expert opinion: Understanding disease mechanisms and the discovery of disease-associated biomarkers are highly interconnected goals. Ideal biomarkers would be molecules specific to the different stages of the disease process that are released from beta cells to the bloodstream. However, such molecules are likely to be present in trace amounts in the blood due to the small number of pancreatic beta cells in the human body and the heterogeneity of the target organ and disease process.


Effects of co-trimoxazole, erythromycin, amoxycillin, tetracycline and chloroquine on sperm function in vitro.
This in-vitro study was designed to investigate the effects of commonly prescribed antibiotics on sperm movement characteristics, viability and the ability of spermatozoa to undergo the acrosome reaction. Spermatozoa were obtained by swim-up from normozoospermic semen and cultured for 24 h with increasing concentrations of co-trimoxazole, erythromycin, amoxycillin, tetracycline and chloroquine. Tetracycline at concentrations as low as 2.5 microg/ml led to a significant dose-dependent inhibition in percent rapid-moving spermatozoa, mean path velocity (VAP), straight-line velocity (VSL) and curvilinear velocity (VCL), but at 50 microg/ml tetracycline all spermatozoa were static. Erythromycin had significant effects on rapid movement, VAP, VSL and VCL only at concentrations >100 microg/ml. In contrast, percent rapid-moving spermatozoa was significantly enhanced at low concentrations of chloroquine (5 microg/ml), but significantly inhibited by higher concentrations. Co-trimoxazole did not adversely affect percent rapid-moving spermatozoa below 500 microg/ml, at which concentration movement was decreased by 34%. The mean lateral head displacement (ALH) was significantly enhanced by 5 microg/ml co-trimoxazole and reduced at 1 mg/ml erythromycin. The effects of these drugs were mostly irreversible. Amoxycillin had no effect on sperm movement characteristics over the dose range used, though it inhibited viability at high doses. Viability was significantly reduced at concentrations of all drugs which affect rapid sperm movement; these concentrations of drugs did not appear to affect the ability of spermatozoa to undergo the acrosome reaction. The results from this study, when combined with known effects on spermatogenesis, should facilitate the choice of drugs for the treatment of both genitourinary and unrelated infections in men who are attempting to conceive.


IL-6 induces PI 3-kinase and nitric oxide-dependent protection and preserves mitochondrial function in cardiomyocytes.
Interleukin-6 (IL-6) is a pro-inflammatory cytokine which is a prognostic marker associated with left ventricular contractile dysfunction and heart failure. On the other hand, IL-6 activates signalling pathways which mediate delayed ischemic preconditioning. We have therefore studied the cellular mechanisms of IL-6-induced cardioprotection. Inducible nitric oxide synthase (iNOS) expression, cardiomyocyte calcium handling, mitochondrial energetics, and the activation of protective signalling pathways in response to IL-6 were studied in a model of simulated ischemia/reperfusion (sI/R) in isolated neonatal rat ventricular cardiomyocytes. Reperfusion after sI/R induced a rise in cytosolic [Ca2+], a loss of cell morphology and integrity, and a transient increase in mitochondrial potential (Deltapsi m), followed by mitochondrial swelling and collapse of Deltapsi m. Pre-treatment of cardiomyocytes with 10 ng/ml IL-6 for 6 h, 24 h prior to sI/R prevented the secondary rise in cytosolic [Ca2+] and induced expression of iNOS and NO-dependent protection against sI/R injury. The protection against sI/R was concomitant with a NO-dependent reduction in the amplitude of cytosolic Ca2+ transients. IL-6 induced an increase in inner mitochondrial membrane polarisation and increased mitochondrial Ca2+ loading (rhod-2 fluorescence) at baseline, but prevented the reperfusion-induced changes in mitochondrial function. IL-6 pre-treatment also resulted in activation of the phosphatidylinositol (PI) 3-kinase/Akt pathway, and both iNOS induction and IL-6-dependent protection were blocked by the PI 3-kinase inhibitor wortmannin. IL-6 induces a PI 3-kinase and NO-dependent protection of cardiomyocytes, which is associated with alterations in mitochondrial Ca2+ handling, inhibition of reperfusion-induced mitochondrial depolarisation, swelling and loss of structural integrity, and suppression of cytosolic Ca2+ transients.


Explosive avian radiations and multi-directional dispersal across Wallacea: evidence from the Campephagidae and other Crown Corvida (Aves).
The systematic relationships among avian families within Crown Corvida have been poorly studied so far and as such been of limited use for biogeographic interpretations. The group has its origin in Australia and is thought to have colonized Africa and the New World via Asia beginning some 35 Mya when terranes of Australian origin approached Asian landmasses. Recent detailed tectonic mapping of the origin of land masses in the region around Wallace's line have revealed a particularly complex movement of terranes over the last 20-30 Myr. Thus the biogeographic dispersal pattern of Crown Corvida is a particularly exciting case for linking vicariance and dispersal events with Earth history. Here we examine phylogenetic affinities among 72 taxa covering a broad range of genera in the basal radiations within Crown Corvida with an emphasis on Campephagidae and Pachycephalidae. Bayesian analyses of nuclear DNA sequence data identified the family Campephagidae as monophyletic but the large genus Coracina is not. Within the family Pachycephalidae the genera Pachycephala and Colluricincla are paraphyletic with respect to each other. The resulting phylogeny suggests that patterns of dispersal across Wallace's line are complex and began at least 25 Mya. We find evidence of explosive radiations and multi-directional dispersal within the last 10 Myr, and three independent long distance ocean dispersal events between Wallacea and Africa at 10-15 Mya. Furthermore, the study reveals that in the Campephagidae a complex series of dispersal events rather than vicariance is the most likely explanation for the current biogeographic pattern in the region.


Obesity and survival among a cohort of breast cancer patients is partially mediated by tumor characteristics.
Obesity exerts adverse effects on breast cancer survival, but the means have not been fully elucidated. We evaluated obesity as a contributor to breast cancer survival according to tumor molecular subtypes in a population-based case-cohort study using data from the Surveillance Epidemiology and End Results (SEER) program. We determined whether obese women were more likely to be diagnosed with poor prognosis tumor characteristics and quantified the contribution of obesity to survival. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated via Cox multivariate models. The effect of obesity on survival was evaluated among 859 incident breast cancers (subcohort; 15% random sample; median survival 7.8 years) and 697 deaths from breast cancer (cases; 100% sample). Obese women had a 1.7- and 1.8-fold increased risk of stage III/IV disease and grade 3/4 tumors, respectively. Obese women with Luminal A- and Luminal B-like breast cancer were 1.8 (95% CI 1.3-2.5) and 2.2 (95% CI 0.9-5.0) times more likely to die from their cancer compared to normal weight women. In mediation analyses, the proportion of excess mortality attributable to tumor characteristics was 36.1% overall and 41% and 38% for Luminal A- and Luminal B-like disease, respectively. Obesity was not associated with breast cancer-specific mortality among women who had Her2-overexpressing or triple-negative tumors. Obesity may influence hormone-positive breast cancer-specific mortality in part through fostering poor prognosis tumors. When tumor biology is considered as part of the causal pathway, the public health impact of obesity on breast cancer survival may be greater than previously estimated.


Bacterial vaginosis diagnosed by analysis of first-void-urine specimens.
Bacterial vaginosis (BV) is traditionally diagnosed using vaginal samples. The aim of this study was to investigate whether BV can be diagnosed from first-void urine (FVU). Self-collected vaginal smears, vaginal swabs, and FVU were obtained from 176 women. BV was diagnosed by Nugent's criteria. The FVU and vaginal swabs were analyzed by quantitative PCRs (qPCRs) for selected vaginal bacteria (Atopobium vaginae, Prevotella spp., Gardnerella vaginalis, bacterial vaginosis-associated bacterium 2, Eggerthella-like bacterium, "Leptotrichia amnionii," Megasphaera type 1), and all had an area under the receiver operating characteristic (ROC) curve of >85%, suggesting good prediction of BV according to the Nugent score. All seven bacteria in FVU were significantly associated with BV in univariate analysis. An accurate diagnosis of BV from urine was obtained in this population by a combination of qPCRs for Megasphaera type 1 and Prevotella spp. The same two bacteria remained significantly associated with BV in a multivariate model after adjusting for the other five species. There was no statistically significant difference between the sensitivities and specificities of BV diagnosis by molecular methods performed on swabs and FVU samples. A linear regression analysis showed good agreement between bacterial loads from swabs and FVU, but Prevotella spp. could be detected in high numbers in a few FVU samples without being present in swabs. This method will allow diagnosis of BV in studies where only urine has been collected and where detection of BV is considered relevant.


What is the minimum number of specialist anaesthetists needed in low-income and middle-income countries?
The number of specialist anaesthetists in most low-income and middle-income countries is below what is needed to provide a safe quality anaesthesia service. There are no estimates of the optimal number; therefore, we estimated the minimum density of specialist anaesthetists to achieve a reasonable standard of healthcare as indicated by the maternal mortality ratio (MMR). Utilising existing country-level data of the number of physician anaesthesia providers (PAPs), MMR and Human Development Index (HDI), we developed best-fit curves to describe the relationship between MMR and PAPs, controlling for HDI. The aim was to use this relationship to estimate the number of PAPs associated with achieving the median MMR. We estimated that, in order to achieve a reasonable standard of healthcare, as indicated by the global median MMR, countries should aim to have at least four PAPs per 100 000 population. Existing data show that currently 80 countries have fewer than this number. Four PAPs per 100 000 population is a modest target, but there is a need to increase training of doctors in many countries in order to train more specialist anaesthetists. It is important that this target is considered during the development of national workforce plans, even if a stepwise approach to workforce planning is chosen.


Epithelial barriers, compartmentation, and cancer.
Epithelial cells, and the tight junctions between them, form a polarized barrier between luminal and serosal fluid compartments and segregate luminal growth factors from their basal-lateral receptors. Breakdown of this barrier should allow access of growth factors in the luminal fluid to their receptors on the basal-lateral cell membranes, as recently demonstrated for heregulin and erbB receptors in airway epithelia. It should also allow luminal growth factors to access the stroma. This property may have adaptive value for epithelial tissues in general, as an elegant response to injury, but may also promote cancer formation in premalignant epithelial tissues in which the tight junctions have become chronically leaky to growth factors.


Albinism in childhood: a flash VEP and ERG study.
Flash visual evoked potentials (F. VEPs) and electroretinograms (ERGs) were recorded in a total of 20 young children with albinism (age range 5 months to 11 years, mean 4 years). All recordings were made without sedation. There were 13 oculocutaneous cases (one with Hermansky-Pudlak syndrome) and seven ocular albinos. Monocular flash stimulation commonly elicited an asymmetrical occipital VEP distribution with a well lateralised component at around 80 ms which was of opposite polarity in a comparison of VEPs from each eye. None of the normally pigmented matched controls or obligate female carriers showed this anomalous distribution. The albino electroretinogram, compared with controls, recorded under fully darkened conditions had a significantly larger a wave and significantly shorter latencies for both a and b waves. The accentuated ERG and asymmetrical VEP recorded in infants and young children with albinism permits distinction of these patients from those with congenital cone dysfunction and idiopathic nystagmus, with whom they may be confused by a clinical examination only.


Polythiophene derivative on quartz resonators for miRNA capture and assay.
A novel approach for miRNA assay using a cationic polythiophene derivative, poly[3-(3'-N,N,N-triethylamino-1'-propyloxy)-4-methyl-2,5-thiophene hydrobromide] (PT), immobilized on a quartz resonator is proposed. The cationic PT enables capturing of all RNA sequences in the sample matrix via electrostatic interactions, resulting in the formation of PT-RNA duplex structures on quartz resonators. Biotinylated peptide nucleic acid (b-PNA) sequences are subsequently utilized for the RNA assay, upon monitoring the PT-RNA-b-PNA triplex formation. Signal amplification is achieved by anchoring avidin coated nanoparticles to b-PNA in order to yield responses at clinically relevant concentration regimes. Unlike conventional nucleic acid assay methodologies that usually quantify a specific sequence of RNA, the proposed approach enables the assay of any RNA sequence in the sample matrix upon hybridization with a PNA sequence complementary to the RNA of interest. As an illustration, successful detection of mir21, (a miRNA sequence associated with lung cancer) is demonstrated with a limit of detection of 400 pM. Furthermore, precise quantification of mir21 in plasma samples is demonstrated without requiring PCR and sophisticated instrumentation.


Signal Normalization Reduces Image Appearance Disparity Among Multiple Optical Coherence Tomography Devices.
To assess the effect of the previously reported optical coherence tomography (OCT) signal normalization method on reducing the discrepancies in image appearance among spectral-domain OCT (SD-OCT) devices. Healthy eyes and eyes with various retinal pathologies were scanned at the macular region using similar volumetric scan patterns with at least two out of three SD-OCT devices at the same visit (Cirrus HD-OCT, Zeiss, Dublin, CA; RTVue, Optovue, Fremont, CA; and Spectralis, Heidelberg Engineering, Heidelberg, Germany). All the images were processed with the signal normalization. A set of images formed a questionnaire with 24 pairs of cross-sectional images from each eye with any combination of the three SD-OCT devices either both pre- or postsignal normalization. Observers were asked to evaluate the similarity of the two displayed images based on the image appearance. The effects on reducing the differences in image appearance before and after processing were analyzed. Twenty-nine researchers familiar with OCT images participated in the survey. Image similarity was significantly improved after signal normalization for all three combinations (P ≤ 0.009) as Cirrus and RTVue combination became the most similar pair, followed by Cirrus and Spectralis, and RTVue and Spectralis. The signal normalization successfully minimized the disparities in the image appearance among multiple SD-OCT devices, allowing clinical interpretation and comparison of OCT images regardless of the device differences. The signal normalization would enable direct OCT images comparisons without concerning about device differences and broaden OCT usage by enabling long-term follow-ups and data sharing.


Robotic versus thoracoscopic lung resection: A systematic review and meta-analysis.
Robotic video-assisted surgery (RVATS) has been reported to be equally effective to video-assisted surgery (VATS) in lung resection (pneumonectomy, lobectomy, and segmentectomy). Operation time, mortality, drainage duration, and length of hospitalization of patients undergoing either RVATS or VATS are compared in this meta-analysis. A systematic research for articles meeting our inclusion criteria was performed using the PubMed database. Articles published from January 2011 to January 2016 were included. We used results of reported mortality, operation time, drainage duration, and hospitalization length for performing this meta-analysis. Mean difference and logarithmic odds ratio were used as summary statistics. Ten studies eligible were included into this analysis (5 studies for operation time, 3 studies for chest in tube days, 4 studies for length of hospitalization, and 6 studies for mortality). We were able to include 3375 subjects for RVATS and 58,683 subjects for VATS. Patients were mainly treated for lung cancer, metastatic foci, and benign lesions. We could not detect any difference between operation time; however, we found 2 trends showing that drainage duration and length of hospitalization are shorter for following RVATS than for following VATS. Mortality also is lower in patients undergoing RVATS. Therefore, we conclude that RVATS is a suitable minimal-invasive procedure for lung resection and suitable alternative to VATS. RVATS is as time-efficient as VATS and shows a trend to reduced hospital stay and drainage duration. More and better studies are required to provide reliable, unbiased evidence regarding the relative benefits of both methods.


Economic costs, health-related quality of life outcomes and cost-utility of a physical and psychological group intervention targeted at older adults with neurogenic claudication.
Emerging evidence suggests that structured and progressive exercise underpinned by a cognitive behavioural approach can improve functional outcomes in patients with neurogenic claudication (NC). However, evidence surrounding its economic benefits is lacking. To estimate the economic costs, health-related quality of life outcomes and cost-effectiveness of a physical and psychological group intervention (BOOST programme) versus best practice advice (BPA) in older adults with NC. An economic evaluation was conducted based on data from a pragmatic, multicentre, superiority, randomised controlled trial. The base-case economic evaluation took the form of an intention-to-treat analysis conducted from a UK National Health Service (NHS) and personal social services (PSS) perspective and separately from a societal perspective. Costs (£ 2018-2019 prices) were collected prospectively over a 12 month follow-up period. A bivariate regression of costs and quality-adjusted life-years (QALYs), with multiple imputation of missing data, was conducted to estimate the incremental cost per QALY gained and the incremental net monetary benefit (INMB) of the BOOST programme in comparison to BPA. Sensitivity and pre-specified subgroup analyses explored uncertainty and heterogeneity in cost-effectiveness estimates. Participants (N = 435) were randomised to the BOOST programme (n = 292) or BPA (n = 143). Mean (standard error [SE]) NHS and PSS costs over 12 months were £1,974 (£118) in the BOOST arm versus £1,827 (£169) in the BPA arm (p = 0.474). Mean (SE) QALY estimates were 0.620 (0.009) versus 0.599 (0.006), respectively (p = 0.093). The probability that the BOOST programme is cost-effective ranged between 67 and 83% (NHS and PSS perspective) and 79-89% (societal perspective) at cost-effectiveness thresholds between £15,000 and £30,000 per QALY gained. INMBs ranged between £145 and £464 at similar cost-effectiveness thresholds. The cost-effectiveness results remained robust to sensitivity analyses. The BOOST programme resulted in modest QALY gains over the 12 month follow-up period. Future studies with longer intervention and follow-up periods are needed to address uncertainty around the health-related quality of life impacts and cost-effectiveness of such programmes. Trial registration This study has been registered in the International Standard Randomised Controlled Trial Number registry, reference number ISRCTN12698674. Registered on 10 November 2015.