[A case of bronchiolitis obliterans secondary to human metapneumovirus bronchiolitis].
Human metapneumovirus (hMPV), formerly classified in Paramyxoviridae family is now moved into Pneumoviridae, which was described as a novel family. It causes upper and lower respiratory tract infections (LRTIs) usually in children younger than five years old. The recent epidemiological studies indicated that hMPV is the second most frequently detected virus in LRTIs of young children, following the respiratory syncytial virus (RSV). Bronchiolitis obliterans (BO) is a chronic obstructive lung disease characterized by fibrosis of the distal respiratory airways. It is usually a result of an inflammatory process triggered by a LRTI related to adenovirus, RSV, Mycoplasma pneumoniae, measles virus, Legionella pneumophila, influenza virus or Bordetella pertussis as a causative agent. In this report, a case of hMPV bronchiolitis complicated with BO has been reported to point out the complications and severity of the clinical progress belongs to this virus. A three-month-old female patient has admitted to our pediatric intensive care unit with the diagnosis of acute bronchiolitis and respiratory failure. She was born at term, weighing 2950 gram and had been hospitalized in newborn intensive care unit for 11 days with the diagnosis of transient tachypnea of the newborn and neonatal sepsis. On auscultation, there were bilateral crepitant rales, wheezing and prolonged expirium. Her oxygen saturation was 97-98% while respiratory support was given with a non-rebreathing reservoir mask. Complete blood count, procalcitonin and C-reactive protein levels were in normal ranges. The chest radiography yielded right middle lobe atalectasia, left paracardiac infiltration and bilateral air trapping. A nasopharyngeal swab sample was analyzed by a commercial multiplex real-time reverse transcriptase-polymerase chain reaction (Thermo Fisher Scientific®, USA) developed for the detection of 15 respiratory viruses. Her sample yielded positive result for only hMPV. On the 4th day of hospitalization, the patient was intubated because of respiratory failure and carbon dioxide retention. She was extubated on the 19th day but could not tolerate. In the thorax computed tomography (CT), bilateral hyperinflation, patchy infiltration, mosaic perfusion and atelectasis especially bilateral posterior areas were detected. Bronchoscopy was normal except mild bronchomalacia in right middle lobe bronchus. The patient was diagnosed as BO secondary to hMPV bronchiolitis, according to the clinical, virological, bronchoscopic and thorax CT results. On the 76th day of admission, she was discharged with respiratory support with home ventilation via a tracheostomy cannula and medical treatments of oral metilprednisolone, nebulized salbutamol and budesonide. In conclusion, hMPV should not be undervalued especially in infants with severe LRTI that can be complicated with BO.


Autophagy, apoptosis, mitoptosis and necrosis: interdependence between those pathways and effects on cancer.
Cell death is a fundamental ingredient of life. Thus, not surprisingly more than one form of cell death exists. Several excellent reviews on various forms of cell death have already been published but manuscripts describing interconnection and interdependence between such processes are uncommon. Here, what follows is a brief introduction on all three classical forms of cell death, followed by a more detailed insight into the role of p53, the master regulator of apoptosis, and other forms of cell death. While discussing p53 and also the role of caspases in cell death forms, we offer insight into the interplay between autophagy and apoptosis, or necrosis, where autophagy may initially serve pro-survival functions. The review moves further to present some details about less researched forms of programmed cell death, namely necroptosis, necrosis and mitoptosis. These "mixed" forms of cell death allow us to highlight the interconnected nature of cell death forms, particularly apoptosis and necrosis. The interdependence between apoptosis, autophagy and necrosis, and their significance for cancer development and treatment are also analyzed in further parts of the review. In the concluding parts, the afore-mentioned issues will be put in perspective for the development of novel anti-cancer therapies.


Safety, immunogenicity, and tolerability of three influenza vaccines in older adults: results of a randomized, controlled comparison.
To determine if newer influenza vaccines can safely improve seroprotection rates of older adults, we compared three licensed trivalent inactivated vaccines (TIVs) in a randomized, controlled trial with evaluator blinding. Participants were non-frail adults ≥ 65 y old, annually TIV-immunized. Study vaccines included intradermal (IDV), MF59-adjuvanted (ADV) and subunit (TIV) formulations of equal potency and strain composition. Blood was obtained before vaccination (V1) and 21 (V2) and 180 d (V3) afterward and tested by hemagglutination inhibition (HAI) assay. Safety diaries were completed daily by participants and specific tolerability questions were posed regarding injections and symptoms. In total, 911 participants were immunized and 887 (97.4%) completed V3. Groups had similar demographics. General symptom rates post-vaccination were similar among groups. Rates of injection site redness after IDV/ADV/TIV were 75%/13%/13% and rates of pain were 29%/38%/20%, respectively, but each vaccine was well tolerated, with symptoms causing little bother. Baseline antibody titers did not differ significantly among groups but B/Brisbane titers were too high for meaningful response assessments. At V2, seroprotection rates (HAI titer ≥ 40) were highest after ADV, the rate advantage over IDV and TIV being significant at 11.8% and 11.4% for H3N2 and 10.2% and 12.5% for H1N1, respectively. At day 180, seroprotection rates had declined ~25% and no longer differed significantly among groups. While IDV and TIV were also well tolerated, ADV induced modestly higher antibody titers in seniors to influenza A strains at 3 weeks but not 6 mo post-vaccination. Immune responses to IDV and TIV were similar in this population.


Peripheral calcium-permeable AMPA receptors regulate chronic inflammatory pain in mice.
α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type (AMPA-type) glutamate receptors (AMPARs) play an important role in plasticity at central synapses. Although there is anatomical evidence for AMPAR expression in the peripheral nervous system, the functional role of such receptors in vivo is not clear. To address this issue, we generated mice specifically lacking either of the key AMPAR subunits, GluA1 or GluA2, in peripheral, pain-sensing neurons (nociceptors), while preserving expression of these subunits in the central nervous system. Nociceptor-specific deletion of GluA1 led to disruption of calcium permeability and reduced capsaicin-evoked activation of nociceptors. Deletion of GluA1, but not GluA2, led to reduced mechanical hypersensitivity and sensitization in models of chronic inflammatory pain and arthritis. Further analysis revealed that GluA1-containing AMPARs regulated the responses of nociceptors to painful stimuli in inflamed tissues and controlled the excitatory drive from the periphery into the spinal cord. Consequently, peripherally applied AMPAR antagonists alleviated inflammatory pain by specifically blocking calcium-permeable AMPARs, without affecting physiological pain or eliciting central side effects. These findings indicate an important pathophysiological role for calcium-permeable AMPARs in nociceptors and may have therapeutic implications for the treatment chronic inflammatory pain states.


Global Physiology and Pathophysiology of Cough: Part 1: Cough Phenomenology - CHEST Guideline and Expert Panel Report.
The purpose of this state-of-the-art review is to update the American College of Chest Physicians 2006 guideline on global physiology and pathophysiology of cough. A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 and using prespecified search terms. We describe the basic phenomenology of cough patterns, behaviors, and morphological features. We update the understanding of mechanical and physiological characteristics of cough, adding a contemporary view of the types of cough and their associated behaviors and sensations. New information about acoustic characteristics is presented, and recent insights into cough triggers and the patient cough hypersensitivity phenotype are explored. Lastly, because the clinical assessment of patients largely focuses on the duration rather than morphological features of cough, we review the morphological features of cough that can be measured in the clinic. This is the first of a two-part update to the American College of Chest Physicians 2006 cough guideline; it provides a more global consideration of cough phenomenology, beyond simply the mechanical aspects of a cough. A greater understanding of the typical features of cough, and their variations, may allow a more informed interpretation of cough measurements and the clinical relevance for patients.


Evaluating the effectiveness of multidisciplinary low-vision rehabilitation.
To objectively evaluate the changes in vision-specific quality of life (QoL) after multidisciplinary low-vision rehabilitation at the Royal Society for the Blind Low-Vision Clinic. The standard care model at the Royal Society for the Blind Low-Vision Clinic is optical management at the initial assessment, with subsequent referral to multidisciplinary services as required. Participants completed the Impact of Vision Impairment Questionnaire (IVI) and Veterans Affairs Low-Vision Visual Functioning Questionnaire (VA LV VFQ-48) before initial assessment, at 30 days (to assess the outcome of optical management) and at 3 months follow-up (to assess the outcome of multidisciplinary services). Seventy-one participants completed the study. Using the VA LV VFQ-48, an improvement (p < 0.05) was seen at 30 days follow-up in overall visual ability, and the reading, visual information, and visual motor subscores. However, at 3 months follow-up, all subscores were not significantly different from pre-rehabilitation levels. In contrast, for the IVI, there was no improvement in both the overall score and the mobility subscale at 30 days follow-up, but a significant improvement at 3 months follow-up. Greater improvements in visual function were seen for those with low vision (<20/60-20/200) compared with those with blindness, those aged >85 years compared with those aged 80 to 85 and <80 years, and those without glaucoma (visual motor subscore). The VA LV VFQ-48 and IVI demonstrated improvements in QoL after low-vision rehabilitation. The timing of the observed changes varied between the two questionnaires, reflecting the different content of these instruments and the timing of delivery of multidisciplinary services, but also suggests that continued rehabilitation may be warranted to maintain a patient's QoL.


Determining the feasibility and preliminary efficacy of a stroke instructional and educational DVD in a multinational context: a randomized controlled pilot study.
To assess the feasibility of conducting a randomized controlled trial of an instructional and educational stroke DVD and determine the feasibility and preliminary efficacy of this intervention in a multinational context. Non-funded, pilot randomized controlled trial of intervention versus usual care. International, multicentre, community-based. Community-living adults up to three years post stroke with moderate to severe disability and their nominated informal caregivers. Intervention patients viewed and practised rehabilitation techniques demonstrated in the DVD over six weeks. Trial feasibility by number of active recruitment sites, recruitment efficiency, randomization and follow-up. Intervention feasibility by patient and caregiver impressions. Preliminary efficacy by the quality of life - 5-level EuroQol-5D (EQ-5D) health status measure, General Health Questionnaire and Centre for Epidemiological Studies-Depression at two months. In total, 14 recruitment sites were established across eight countries. Recruitment was achieved at nine (64%) sites. Over 16 months, 66 participants were recruited (mean (SD) age = 63.5 (12.47) years) and randomized to intervention ( n = 34) and control ( n = 32) groups. In total, 54 (82%) completed a follow-up assessment. Patient and/or caregiver comments about the benefits and barriers to accessing the intervention were mixed. There were no significant between-group differences in outcomes at two months ( P > 0.05). Conducting a multinational trial of a stroke DVD requires full funding. The intervention was acceptable to some patients and their caregivers, yet a generalized education approach did not fully meet their needs and/or expectations. A more individualized method may be required to meet peoples' changing needs during stroke recovery.


RNA polymerase mutants found through adaptive evolution reprogram Escherichia coli for optimal growth in minimal media.
Specific small deletions within the rpoC gene encoding the β'-subunit of RNA polymerase (RNAP) are found repeatedly after adaptation of Escherichia coli K-12 MG1655 to growth in minimal media. Here we present a multiscale analysis of these mutations. At the physiological level, the mutants grow 60% faster than the parent strain and convert the carbon source 15-35% more efficiently to biomass, but grow about 30% slower than the parent strain in rich medium. At the molecular level, the kinetic parameters of the mutated RNAP were found to be altered, resulting in a 4- to 30-fold decrease in open complex longevity at an rRNA promoter and a ∼10-fold decrease in transcriptional pausing, with consequent increase in transcript elongation rate. At a genome-scale, systems biology level, gene expression changes between the parent strain and adapted RNAP mutants reveal large-scale systematic transcriptional changes that influence specific cellular processes, including strong down-regulation of motility, acid resistance, fimbria, and curlin genes. RNAP genome-binding maps reveal redistribution of RNAP that may facilitate relief of a metabolic bottleneck to growth. These findings suggest that reprogramming the kinetic parameters of RNAP through specific mutations allows regulatory adaptation for optimal growth in new environments.


Ligand-induced changes in the location of actin, myosin, 95K (alpha-actinin), and 120K protein in amebae of Dictyostelium discoideum.
In this study we investigated concanavalin A (Con A) induced changes in the locations of actin, myosin, 120K, and 95K (alpha-actinin) to determine the extent to which actin and myosin are reorganized during capping and the roles that 120K and 95K might play in this reorganization. We observed the location of each protein by indirect immunofluorescence using affinity purified antibodies. Four morphological states were distinguished in vegetative Dictyostelium amebae: ameboid cells before Con A binding, patched cells, capped cells, and ameboid cells with caps. The location of each protein was distinct in ameboid cells both before and after capping Actin and 120K were found in the cell cortex usually associated with surface projections, and myosin and 95K were diffusely distributed. Myosin was excluded from surface projections in ameboid cells. During patching, all four proteins were localized below Con A patches. During capping, actin, myosin, and 95K protein moved with the Con A patches into the cap whereas 120K protein was excluded from the cap. During the late stages of cap formation actin and myosin were progressively lost from the cap, and 120K became concentrated in new actin-filled projections that formed away from the cap. However, 95K remained tightly associated with the cap. Poisoning cells with sodium azide inhibited capping but not patching of ligand. In azide-poisoned cells, myosin and 95K did not co-patch with Con A, whereas copatching of 120K and actin with Con A occurred as usual. Our results support the hypothesis that capping is an actomyosin-mediated motile event that involves a sliding interaction between actin filaments, which are anchored through the membrane to ligand patches, and myosin in the cortex. They are also consistent with a role for 120K in the formation of surface projections by promoting growth and/or cross-linking of actin filaments within projections, and with a role for 95K in regulating actomyosin-mediated contractility, earlier proposals based on the in vitro properties of these two proteins (Condeelis, J., M. Vahey, J. M. Carboni, J. DeMey, S. Ogihara, 1984, J. Cell Biol., 99:119s-126s).


Zinc-deficiency induced changes in the distribution of rat white blood cells.
Zinc is known to play an important role for immune-functions. However, the effects of zinc-deficiency on the immune response system from the point of view of the distribution changes of the number of total white blood cells (WBCs) are still primarily unknown. Therefore, the effects of zinc-deficiency on the number of total WBCs, neutrophil, eosinophil, basophil, monocyte and lymphocytes (T lymphocyte, B lymphocyte and NK cell) were studied in rats. The weaned male rats were randomly divided into the zinc deficient diet (ZDD: 0.7 mg zinc/kg diet) group and the control diet (CON: 34.8 mg zinc/kg diet) group, and were pair-fed for 4 wk. The number of lymphocyte subsets, visceral organ weights, serum zinc, corticosterone and IL-6 concentrations were also determined. Zinc-deficiency increased duration-dependently the number of total white blood cells, granulocytes (neutrophil, eosinophil and basophil) and monocytes in 2-4 wk without changing the number of lymphocytes, T lymphocytes, B lymphocytes or NK cells. The relative weights of thymus and adrenals were 0.63 times (p<0.01) lower and 1.60 times (p<0.001) higher in ZDD group than in CON group, respectively. Zinc-deficiency increased serum corticosterone concentration to 1.48 times (p<0.05) without changing serum IL-6 concentration, as compared with those of CON group. From these results, zinc-deficiency increases markedly the number of granulocytes and monocytes without changing the number of lymphocytes, T lymphocytes, B lymphocytes or NK cells. These results also suggest that zinc-deficiency induces stress responses and the responses may have in part participated in increased actions of the number of granulocytes and monocytes during zinc-deficiency, and induce thymus atrophy and adrenal hypertrophy.


Medical legal and ethical questions in palliative medicine and euthanasia.
The increasing importance of legal and ethical questions in palliative medicine and euthanasia due to the increased technical possibilities for extending life will be considered. In palliative medicine, the choice of the best therapy will be discussed, especially in the case of oncological diseases. Here, consideration of the prospects of success, for example, in chemotherapy, is faced with partly serious side-effects. The requirements of palliative medicine that the patient has to be fully informed of the fatal prognosis of his disease is equally debated as the optimum pain therapy. In this respect, the modification of the Narcotics Act of 1 February 1993 is also under discussion. In the field of euthanasia, the technical development of life extension versus dying has raised considerable legal and ethical problems regarding termination of therapy. Additionally, fiscal considerations are of increasing relevance. The common development of the legal and ethical discussion, for example, with regard to the publicity of the work of the so-called 'Gesellschaft für humanes Sterben', the public discussion leading up to a hearing of the 'Bundestag' regarding active euthanasia leads to a realization of the subject. The proposals for an active termination of life by discontinuing therapy for adults and also for malformed newborns are discussed. A dispute concerning the new legal regulation of active euthanasia in the Netherlands of February 1993 is also discussed. There, around 2% of all deaths per year result from active termination of life and also cases where persons are not able to consent. This also has enormous consequences for the position of the physician.(ABSTRACT TRUNCATED AT 250 WORDS)


Lysogeny and bacteriocinogeny in Xenorhabdus nematophilus and other Xenorhabdus spp.
Induction by mitomycin or high-temperature treatment resulted in the production of bacteriocins and phages in both phases of Xenorhabdus nematophilus A24, indicating lysogeny. Phage DNA purified from X. nematophilus A24 hybridized to several fragments of DraI-digested A24 chromosomal DNA, confirming that the phage genome was incorporated into the bacterial chromosome. Bacteriocins and phages were detected in cultures of most other Xenorhabdus spp. after mitomycin or high-temperature treatment. Xenorhabdus luminescens K80 was not lysed by these treatments, and no phages were seen associated with this strain. However, bacteriocins were detected in limited quantities in all Xenorhabdus cultures, including X. luminescens K80, without any induction. X. nematophilus A24 bacteriocins were antagonistic for other Xenorhabdus species but not for A24 or other strains of X. nematophilus.


Racial differences in the development of impulsivity and sensation seeking from childhood into adolescence and their relation to alcohol use.
Pronounced differences in drinking behavior exist between African Americans and European Americans. Disinhibited personality characteristics are widely studied risk factors for alcohol use outcomes. Longitudinal studies of children have not examined racial differences in these characteristics and in their rates of change or whether these changes differentially relate to adolescent alcohol use. Latent growth curve modeling was performed on 7 annual waves of data on 447 African American and European American 8- and 10-year-old children followed into adolescence as part of the Tween to Teen Project. Both mother and child data were examined. European Americans had higher initial levels of (β = 0.22, p < 0.001) and greater growth in sensation seeking (β = 0.16, p < 0.05) compared with African Americans. However, African American children had higher initial levels of impulsivity compared with European American children (β = -0.27 and -0.16, p < 0.01). Higher initial levels of sensation seeking (β = 0.18, p < 0.01) and greater growth in both sensation seeking (β = 0.24, p < 0.01) and impulsivity (β = 0.30 to 0.34, p < 0.01) related to subsequent frequency of alcohol use. The association between race and alcohol use was partially mediated by initial levels of sensation seeking (β = 0.04, p < 0.05; 95% CI: 0.004 to 0.078). Additionally, sharper increases in sensation seeking predicted greater levels of subsequent alcohol use for European Americans (β = 0.33, p < 0.001) but not for African Americans (β = -0.15, ns). This study revealed different developmental courses and important racial differences for sensation seeking and impulsivity. Findings highlight the possibility that sensation seeking at least partly drives early alcohol use for European American but not for African American adolescents.


Aromatic peptide amphiphiles: significance of the Fmoc moiety.
Aromatic peptide amphiphile hydrogelators commonly utilise the fluorenyl-9-methoxycarbonyl moiety as an N-terminal capping group. Material properties and spectroscopic techniques show the influence of alternative linkers between the fluorenyl moiety and the peptide. This study establishes whether methoxycarbonyl is an optimal or mainly convenient linker, for this class of self-assembling systems.


Weighing up the possibilities: Controlling translation by ubiquitylation and sumoylation.
Regulation of protein synthesis is of fundamental importance to cells. It has a critical role in the control of gene expression, and consequently cell growth and proliferation. The importance of this control is supported by the fact that protein synthesis is frequently upregulated in tumor cells. The major point at which regulation occurs is the initiation stage. Initiation of translation involves the interaction of several proteins to form the eIF4F complex, the recognition of the mRNA by this complex, and the subsequent recruitment of the 40S ribosomal subunit to the mRNA. This results in the formation of the 48S complex that then scans the mRNA for the start codon, engages the methionyl-tRNA and eventually forms the mature 80S ribosome which is elongation-competent. Formation of the 48S complex is regulated by the availability of individual initiation factors and through specific protein-protein interactions. Both of these events can be regulated by post-translational modification by ubiquitin or Ubls (ubiquitin-like modifiers) such as SUMO or ISG15. We provide here a summary of translation initiation factors that are modified by ubiquitin or Ubls and, where they have been studied in detail, describe the role of these modifications and their effects on regulating protein synthesis.


Influence of affective significance on different levels of processing using pupil dilation in an analogical reasoning task.
The present study investigates the interaction of cognition and emotion in decision making, using an analogical reasoning task. In this task, two word pairs were presented simultaneously. Each word pair could be characterized by an associative conceptual relation (object, actor, or location relation) as well as an emotional relation (negative, neutral, or positive valence). Both types of relations were equally task-relevant: Participants had to identify both types of relations, to compare them, and to decide whether or not the word pairs were analogous, i.e., corresponding in both conceptual and emotional relations. Behavioral data showed that emotional relations were identified preferentially and faster than conceptual relations. Pupil dilations reflected the descending difficulty of the conditions and were greatest in amplitude when both conceptual and emotional correspondence was shown, intermediate when only one type of relation (either the emotional or the conceptual) corresponded, and least when neither correspondence existed. Additionally, a negative valence of the word material slowed down response times and increased pupil dilation relative to positive and neutral items. In summary, pupil and response time data together support recent (neurobiological) models concerning the interaction of emotion and cognition by showing that affective significance leads to a processing advantage at a cognitively lower level of information processing (here, identification or retrieval of relations from long-term memory) but can also distract people from higher level cognitive processes (here, from the controlled comparison of retrieved relations).


Hamstrings stiffness and landing biomechanics linked to anterior cruciate ligament loading.
Greater hamstrings stiffness is associated with less anterior tibial translation during controlled perturbations. However, it is unclear how hamstrings stiffness influences anterior cruciate ligament (ACL) loading mechanisms during dynamic tasks. To evaluate the influence of hamstrings stiffness on landing biomechanics related to ACL injury. Cross-sectional study. Research laboratory. A total of 36 healthy, physically active volunteers (18 men, 18 women; age = 23 ± 3 years, height = 1.8 ± 0.1 m, mass = 73.1 ± 16.6 kg). Hamstrings stiffness was quantified via the damped oscillatory technique. Three-dimensional lower extremity kinematics and kinetics were captured during a double-legged jump-landing task via a 3-dimensional motion-capture system interfaced with a force plate. Landing biomechanics were compared between groups displaying high and low hamstrings stiffness via independent-samples t tests. Hamstrings stiffness was normalized to body mass (N/m·kg(-1)). Peak knee-flexion and -valgus angles, vertical and posterior ground reaction forces, anterior tibial shear force, internal knee-extension and -varus moments, and knee-flexion angles at the instants of each peak kinetic variable were identified during the landing task. Forces were normalized to body weight, whereas moments were normalized to the product of weight and height. Internal knee-varus moment was 3.6 times smaller in the high-stiffness group (t22 = 2.221, P = .02). A trend in the data also indicated that peak anterior tibial shear force was 1.1 times smaller in the high-stiffness group (t22 = 1.537, P = .07). The high-stiffness group also demonstrated greater knee flexion at the instants of peak anterior tibial shear force and internal knee-extension and -varus moments (t22 range = 1.729-2.224, P < .05). Greater hamstrings stiffness was associated with landing biomechanics consistent with less ACL loading and injury risk. Musculotendinous stiffness is a modifiable characteristic; thus exercises that enhance hamstrings stiffness may be important additions to ACL injury-prevention programs.


A dynamic conceptual model of care planning.
This article presents a conceptual model of the care planning process developed to identify the hypothetical links between structural, process and outcome factors important to the quality of the process. Based on existing literature, it was hypothesized that a thorough assessment of patients' health needs is an important prerequisite when making a rigorous diagnosis and preparing plans for various care interventions. Other important variables that are assumed to influence the quality of the process are the care culture and professional knowledge. The conceptual model was developed as a system dynamics causal loop diagram as a first essential step towards a computed model. System dynamics offers the potential to describe processes in a nonlinear, dynamic way and is suitable for exploring, comprehending, learning and communicating complex ideas about care processes.


Assessment of volumetric noise and resolution performance for linear and nonlinear CT reconstruction methods.
For nonlinear iterative image reconstructions (IR), the computed tomography (CT) noise and resolution properties can depend on the specific imaging conditions, such as lesion contrast and image noise level. Therefore, it is imperative to develop a reliable method to measure the noise and resolution properties under clinically relevant conditions. This study aimed to develop a robust methodology to measure the three-dimensional CT noise and resolution properties under such conditions and to provide guidelines to achieve desirable levels of accuracy and precision. The methodology was developed based on a previously reported CT image quality phantom. In this methodology, CT noise properties are measured in the uniform region of the phantom in terms of a task-based 3D noise-power spectrum (NPStask). The in-plane resolution properties are measured in terms of the task transfer function (TTF) by applying a radial edge technique to the rod inserts in the phantom. The z-direction resolution properties are measured from a supplemental phantom, also in terms of the TTF. To account for the possible nonlinearity of IR, the NPStask is measured with respect to the noise magnitude, and the TTF with respect to noise magnitude and edge contrast. To determine the accuracy and precision of the methodology, images of known noise and resolution properties were simulated. The NPStask and TTF were measured on the simulated images and compared to the truth, with criteria established to achieve NPStask and TTF measurements with <10% error. To demonstrate the utility of this methodology, measurements were performed on a commercial CT system using five dose levels, two slice thicknesses, and three reconstruction algorithms (filtered backprojection, FBP; iterative reconstruction in imaging space, IRIS; and sinogram affirmed iterative reconstruction with strengths of 5, SAFIRE5). To achieve NPStask measurements with <10% error, the number of regions of interest needed to be greater than 65. To achieve TTF measurements with <10% error, the contrast-to-noise ratio of the edge needed to be ≥15, achievable by averaging multiple slices across the same edge. The NPStask measured on a commercial CT system showed IR's reduced noise (IRIS, 30% and SAFIRE5, 55%) and "waxier" texture (peak frequencies: FBP, 0.25 mm(-1); IRIS, 0.23 mm(-1); and SAFIRE5, 0.16 mm(-1)). The TTF measured within the axial plane showed improved in-plane resolution with SAFIRE5 at the TTF 50% frequency, f50 (FBP, 0.36-0.41 mm(-1); SAFIRE5, 0.37-0.46 mm(-1)). The TTF measured along the axial direction showed improved z-direction resolution with thinner slice thickness (f50: 0.6 mm, 0.35-0.79 mm(-1); 1.5 mm, 0.22-0.3 mm(-1)) and with SAFIRE5 (f50: FBP, 0.35-0.52 mm(-1); SAFIRE5, 0.42-0.79 mm(-1)). Both in-plane and z-direction resolution of SAFIRE5 showed strong dependency on contrast, reflecting SAFIRE5's nonlinearity. A methodology was developed to measure three-dimensional CT noise and resolution properties for iterative reconstruction, especially at challenging measurement conditions with low contrast and high image noise. The methodology also demonstrated its utility for evaluating commercial CT systems.


Application of a high-speed breeding technology to apple (Malus × domestica) based on transgenic early flowering plants and marker-assisted selection.
Breeding of apple (Malus × domestica) remains a slow process because of protracted generation cycles. Shortening the juvenile phase to achieve the introgression of traits from wild species into prebreeding material within a reasonable time frame is a great challenge. In this study, we evaluated early flowering transgenic apple lines overexpressing the BpMADS4 gene of silver birch with regard to tree morphology in glasshouse conditions. Based on the results obtained, line T1190 was selected for further analysis and application to fast breeding. The DNA sequences flanking the T-DNA were isolated and the T-DNA integration site was mapped on linkage group 4. The inheritance and correctness of the T-DNA integration were confirmed after meiosis. A crossbred breeding programme was initiated by crossing T1190 with the fire blight-resistant wild species Malus fusca. Transgenic early flowering F(1) seedlings were selected and backcrossed with 'Regia' and 98/6-10 in order to introgress the apple scab Rvi2, Rvi4 and powdery mildew Pl-1, Pl-2 resistance genes and the fire blight resistance quantitative trait locus FB-F7 present in 'Regia'. Three transgenic BC'1 seedlings pyramiding Rvi2, Rvi4 and FB-F7, as well as three other BC'1 seedlings combining Pl-1 and Pl-2, were identified. Thus, the first transgenic early flowering-based apple breeding programme combined with marker-assisted selection was established.


Applicability of 3T body MRI in assessment of nonfocal bone marrow involvement of hematopoietic neoplasia in dogs.
The utility of whole body magnetic resonance imaging (MRI) in detecting bone marrow infiltration in dogs with cancer has not been investigated. To assess the feasibility of 3T body MRI for bone marrow assessment in dogs with hematopoietic neoplasia. Seven dogs with B-cell lymphoma, 3 dogs with myelodysplastic syndrome (MDS), and 2 clinically normal dogs. A prospective study of dogs with hematopoetic cancer was conducted using T1W, T2W, In-Phase, Out-of-Phase and STIR pulse sequences of the body excluding the head prior to bone marrow sampling. The relative signal intensity of a midlumbar vertebral body and a midshaft femoral bone marrow was compared by visual and point region of interest analysis to regional skeletal muscle. Similarity of femoral diaphyseal and vertebral body marrow signal intensity to that of skeletal muscle on the Out-of-Phase sequence was useful in distinguishing the 3 dogs with hypercellular marrow because of MDS from the 7 dogs with B-cell lymphoma and from the 2 clinically normal dogs. 1/7 dogs with lymphoma had proven bone marrow involvement but normal cellularity and less than 5% abnormal cells. Unaffected midfemoral marrow had greater signal intensity than skeletal muscle and unaffected vertebral marrow had less signal intensity than skeletal muscle on the Out-of-Phase sequence. 3T, Out-of-Phase MR pulse sequence was useful in distinguishing diffuse bone marrow infiltrate (MDS) from minimally or unaffected marrow using skeletal muscle for signal intensity comparison on whole body MRI.


A Comparison of Hugging Frequency and Its Association with Momentary Mood Before and During COVID-19 Using Ecological Momentary Assessment.
The COVID-19 pandemic has necessitated a drastic decrease in human social interactions including social touch. One of the most prevalent forms of touch is hugging. Hugging has been demonstrated to benefit both physical and mental well-being. In the present study, we used an ecological momentary assessment approach to assess the relationship between hugging and momentary mood in two independent cohorts sampled prior or during the pandemic. We found that the frequency of hugging was significantly reduced during the pandemic. Using multilevel modeling, we found a significant positive association between momentary mood and daily hugs. This effect was moderated by the cohort, as individuals during the pandemic showed a stronger positive association compared to the cohort sampled prior to the pandemic. While we have to stress that our results are correlational in nature, they potentially indicate that social touch is more beneficial in times of social distancing.


EFNS guidelines on diagnosis and treatment of primary dystonias.
to provide a revised version of earlier guidelines published in 2006. primary dystonias are chronic and often disabling conditions with a widespread spectrum mainly in young people. primary dystonias are classified as pure dystonia, dystonia plus or paroxysmal dystonia syndromes. Assessment should be performed using a validated rating scale for dystonia. Genetic testing may be performed after establishing the clinical diagnosis. DYT1 testing is recommended for patients with primary dystonia with limb onset before age 30, and in those with an affected relative with early-onset dystonia. DYT6 testing is recommended in early-onset or familial cases with cranio-cervical dystonia or after exclusion of DYT1. Individuals with early-onset myoclonus should be tested for mutations in the DYT11 gene. If direct sequencing of the DYT11 gene is negative, additional gene dosage is required to improve the proportion of mutations detected. A levodopa trial is warranted in every patient with early-onset primary dystonia without an alternative diagnosis. In patients with idiopathic dystonia, neurophysiological tests can help with describing the pathophysiological mechanisms underlying the disorder. botulinum toxin (BoNT) type A is the first-line treatment for primary cranial (excluding oromandibular) or cervical dystonia; it is also effective on writing dystonia. BoNT/B is not inferior to BoNT/A in cervical dystonia. Pallidal deep brain stimulation (DBS) is considered a good option, particularly for primary generalized or cervical dystonia, after medication or BoNT have failed. DBS is less effective in secondary dystonia. This treatment requires a specialized expertise and a multidisciplinary team.


New data on the morphology of some Far-Eastern species of Rhabdochona (Nematoda: Rhabdochonidae), as revealed by SEM observations.
Specimens of the nematode genus Rhabdochona Railliet, 1916 (Rhabdochonidae) were collected during helminthological examination of four species of cyprinid fishes in two rivers of the Amur River basin in the Russian Far East (Primorsky Region) in June 2011. Detailed light microscopical (LM) and scanning electron microscopical (SEM) examinations (the latter used for the first time for the reported nematode species) of the available material revealed the presence of three inadequately described nominal species of this genus: R. (Rhabdochona) denudata (Dujardin, 1845) from the spotted steed Hemibarbus maculatus Bleeker (Gobioninae), and R. (Rhabdochona) longispicula Belous in Roytman, 1963 and R. (Globochonoides) coronacauda Belous, 1965 from Culter alburnus Basilewsky (Cultrinae) in the Ilistaya River. Detailed morphological study of these worms, especially SEM examination, made it possible to reveal some previously unreported morphological features (e.g., the presence of sublabia or the character of ventral precloacal ridges) and to confirm other taxonomically important characters such as the shape of deirids, number of anterior prostomal teeth, number and situation of lateral preanal and postanal papillae or the detailed structure of the crown-like formation on the female tail tip in R. coronacauda. Unidentifiable Rhabdochona (Rhabdochona) gravid females were recorded from the humpback Chanodichthys dabryi (Bleeker) (Cultrinae) in the Ilistaya River and from the Amur minnow Rhynchocypris lagowskii (Dybowski) (Leuciscinae) in the Komissarovka River.


Analyzing the control of mosquito-borne diseases by a dominant lethal genetic system.
Motivated by the failure of current methods to control dengue fever, we formulate a mathematical model to assess the impact on the spread of a mosquito-borne viral disease of a strategy that releases adult male insects homozygous for a dominant, repressible, lethal genetic trait. A dynamic model for the female adult mosquito population, which incorporates the competition for female mating between released mosquitoes and wild mosquitoes, density-dependent competition during the larval stage, and realization of the lethal trait either before or after the larval stage, is embedded into a susceptible-exposed-infectious-susceptible human-vector epidemic model for the spread of the disease. For the special case in which the number of released mosquitoes is maintained in a fixed proportion to the number of adult female mosquitoes at each point in time, we derive mathematical formulas for the disease eradication condition and the approximate number of released mosquitoes necessary for eradication. Numerical results using data for dengue fever suggest that the proportional policy outperforms a release policy in which the released mosquito population is held constant, and that eradication in approximately 1 year is feasible for affected human populations on the order of 10(5) to 10(6), although the logistical considerations are daunting. We also construct a policy that achieves an exponential decay in the female mosquito population; this policy releases approximately the same number of mosquitoes as the proportional policy but achieves eradication nearly twice as fast.


Restoration by insulin of impaired prostaglandin E1/I2 receptor activity of platelets in acute ischemic heart disease.
Treatment of normal platelet-rich plasma with a physiological amount of insulin (100 microunits/ml, optimum concentration) for 3 hours at 23 degrees C stimulated the binding of prostaglandin E1 by more than twofold (3,940 +/- 250 sites/10(8) platelets) compared with the nontreated, control platelet-rich plasma (1,590 +/- 265 sites/10(8) platelets). After platelet-rich plasma from patients with acute ischemic heart disease (n = 43), whose platelets showed impaired prostaglandin E1/I2 receptor activity (850 +/- 100 sites/10(8) platelets), was incubated with insulin (optimum amounts varied from 100 to 200 microunits/ml), the binding of the prostanoid was restored to normal levels (1,790 +/- 140 sites/10(8) platelets) in 75% of the cases. Twenty-five percent of the patients did not respond to the stimulatory effect of insulin. The increased binding of the prostanoid to the insulin-treated platelets also resulted in increased cyclic AMP levels both in normal subjects (44.14 +/- 3.1 pmol/10(8) [insulin-treated] platelets versus 16.35 +/- 2.91 pmol/10(8) [control] platelets) and in patients with acute ischemic heart disease (23.87 +/- 4.1 pmol/10(8) [insulin-treated] platelets versus 7.70 +/- 2.0 pmol/10(8) [control] platelets) by the prostanoid (1.0 microM). The treatment of platelet-rich plasma with the hormone decreased the minimum inhibitory concentration of the prostanoid from 34 +/- 14 to 15 +/- 9 nM (p less than 0.001) in the case of normal volunteers and from 49 +/- 15 to 32 +/- 11 nM (p = 0.002) in the case of "responder" patients. Insulin did not produce any effect on the inhibition of platelet aggregation by the prostaglandin in "nonresponder" patients. In the follow-up study, although the stimulatory effects of insulin on platelets from responder patients were improved to normal levels, the platelets from the nonresponder patients remained persistently unresponsive to the effect of the hormone.


Permanent neonatal diabetes mellitus caused by a novel homozygous (T168A) glucokinase (GCK) mutation: initial response to oral sulphonylurea therapy.
To evaluate the clinical response to sulphonylurea treatment in a child with a homozygous T168A GCK (glucokinase) mutation, causing permanent neonatal diabetes mellitus (PNDM). Oral glibenclamide was given for 3 months. Pancreatic beta cell function was assessed by a glucagon stimulation test. Mutant and wild-type (WT) GCK were characterized. Sulphonylurea treatment resulted in a 12-fold increase in basal and stimulated C-peptide levels. HbA1c levels were reduced from 9.4% to 8.1% on a reduced insulin dose (0.85 to 0.60 U/kg/day). Mutant T168A-GST-GCK showed reduced kinetic activity (0.02 fold) compared to WT. Sulphonylureas can close the adenosine triphosphate (ATP)-sensitive potassium channel and elicit insulin secretion, but the ATP generated from metabolism is insufficient to fully restore insulin secretory capacity. Nonetheless, sulphonylurea treatment should be tried in patients with GCK-PNDM, particularly those with mutations resulting in less severe kinetic defects, in whom improved glycemic control may be obtained with lower doses of insulin.


Influences of variation in total energy intake and dietary composition on regulation of fat cell lipolysis in ideal-weight subjects.
Weight-maintaining fat-rich, "prudent," carbohydrate-rich, as well as energy-restricted diets (300 kcal/d) were fed in succession for 7 d to 12 healthy males of ideal body weight under metabolic ward conditions. At the end of each period isolated fat cells were prepared from subcutaneous abdominal adipose tissue and incubated in vitro in the absence or presence of adenosine deaminase, either alone or in combination with various lipolytic or antilipolytic hormones and agents. Variations in total energy intake and dietary composition had characteristic and specific effects on fat cell lipolysis in vitro. High carbohydrate and prudent diets resulted in low rates of nonstimulated glycerol release and impaired insulin action in the presence of adenosine deaminase (320 mU/ml). High-fat and energy restricted diets were characterized by high rates of nonstimulated glycerol release. Sensitivity of antilipolysis to insulin and prostaglandin E2 was 10 to 200 times lower respectively on energy-restricted than on fat-rich diets. The effects of alpha 2- and beta-adrenergic catecholamines and of N6-phenylisopropyladenosine were not affected by the preceding diets.


Effect of Neurocognitive Training for Children With ADHD at Improving Academic Engagement in Two Learning Settings.
Objective: This preliminary study investigated effectiveness of neurocognitive training on academic engagement (AET) for children with ADHD. The training approach targeted working memory, inhibitory control, and attention/relaxation (via brain electrical activity). Method: A reversal design with a 2-week follow-up was used to assess the effectiveness of the treatment on two children with diagnosed ADHD in two learning settings. Direct observation was used to collect academic-related behavior. Results: Improvements in on-task expected behavior (ONT-EX) and general AET, as well as reductions in off-task motor activity (OFF-MA) and off-task passive behavior (OFF-PB) were observed for both students over baselines and across the settings. Moreover, differences in behavioral change were found between participants and settings. Conclusion: These findings support using the treatment for improving academic performance of children with ADHD. Future studies may investigate influences of contextual differences, nontreatment variables, or adult's feedback during the training session on treatment effectiveness.


Suboptimal Adherence to Combination Antiretroviral Therapy Is Associated With Higher Levels of Inflammation Despite HIV Suppression.
Human immunodeficiency virus (HIV)-infected individuals exhibit residual inflammation regardless of virologic suppression. We evaluated whether suboptimal adherence to combination antiretroviral therapy (cART) is associated with greater residual inflammation than optimal adherence, despite virologic suppression. Longitudinal self-reported cART adherence data and serum concentrations of 24 biomarkers of inflammation and immune activation were measured at the same study visit in HIV RNA-suppressed (<50 copies/mL) HIV-infected men in the Multicenter AIDS Cohort Study from 1998 to 2009. Associations between dichotomized 6-month (<100% vs 100%) and categorized 4-day (<85%, 85%-99%, and 100%) cART adherence with biomarker concentrations were evaluated. A total of 912 men provided 2816 person-visits with documented plasma HIV RNA suppression. In adjusted models, person-visits at which <100% cART 6-month adherence was reported had higher concentrations of interleukin 2, 6, and 10, interferon γ, tumor necrosis factor α, and C-reactive protein than person-visits at which 100% cART adherence (P < .05) was reported. These same differences were observed in person-visits reporting <85% versus 100% 4-day cART adherence, but not in visits reporting 85%-99% versus 100% cART adherence. After adjustment for multiple comparisons, tumor necrosis factor α remained significantly higher (11% increase; P < .001) in person-visits at which <100% adherence was reported. Higher concentrations of inflammatory biomarkers were observed among HIV RNA-suppressed men who reported <100% cART adherence than among more adherent men. Residual HIV replication (ie, below the limit of detection), more likely among men with suboptimal adherence, is a plausible mechanism. Whether improving cART adherence could affect residual inflammation and associated morbidity and mortality rates should be investigated.


An institutional strategy to increase minority recruitment to therapeutic trials.
Participation in therapeutic clinical trials rarely reflects the race and ethnic composition of the patient population. To meet National Institutes of Health-mandated goals, strategies to increase participation are required. We present a framework for institutional enhancement of minority clinical trial accrual. We implemented structural changes on four levels to induce and sustain minority accrual to clinical trials: (1) leadership support; (2) center-wide policy change; (3) infrastructural process control, data analysis, and reporting; and (4) follow-up with clinical investigators. A Protocol Review and Monitoring Committee reviews studies and monitors accrual, and the Program for the Elimination Cancer Disparities leads efforts for proportional accrual, supporting the system through data tracking, Web tools, and feedback to investigators. Following implementation in 2005, minority accrual to therapeutic trials increased from 12.0 % in 2005 to 14.0 % in 2010. The "rolling average" minority cancer incidence at the institution during this timeframe was 17.5 %. In addition to therapeutic trial accrual rates, we note significant increase in the number of minorities participating in all trials (therapeutic and nontherapeutic) from 2005 to 2010 (346-552, 60 % increase, p < 0.05) compared to a 52 % increase for Caucasians. Implementing a system to aid investigators in planning and establishing targets for accrual, while requiring this component as a part of annual protocol review and monitoring of accrual, offers a successful strategy that can be replicated in other cancer centers, an approach that may extend to other clinical and translational research centers.


Identify temporal trend of air temperature and its impact on forest stream flow in Lower Mississippi River Alluvial Valley using wavelet analysis.
Characterization of stream flow is essential to water resource management, water supply planning, environmental protection, and ecological restoration; while air temperature variation due to climate change can exacerbate stream flow and add instability to the flow. In this study, the wavelet analysis technique was employed to identify temporal trend of air temperature and its impact upon forest stream flows in Lower Mississippi River Alluvial Valley (LMRAV). Four surface water monitoring stations, which locate near the headwater areas with very few land use disturbances and the long-term data records (60-90 years) in the LMRAV, were selected to obtain stream discharge and air temperature data. The wavelet analysis showed that air temperature had an increasing temporal trend around its mean value during the past several decades in the LMRAV, whereas stream flow had a decreasing temporal trend around its average value at the same time period in the same region. Results of this study demonstrated that the climate in the LMRAV did get warmer as time elapsed and the streams were drier as a result of warmer air temperature. This study further revealed that the best way to estimate the temporal trends of air temperature and stream flow was to perform the wavelet transformation around their mean values.


Inotuzumab ozogamicin: a CD22 mAb-drug conjugate for adult relapsed or refractory B-cell precursor acute lymphoblastic leukemia.
Despite improved rates of remission and cure in newly diagnosed adult acute lymphoblastic leukemia (ALL), the prognosis for patients with relapsed or refractory disease remains poor and the 5-year overall survival rate after relapse is under 10%. A recent paradigm shift has focused on the promise of targeted immunotherapy rather than standard chemotherapy, as ALL blast cells express a variety of antigens, and monoclonal antibodies may be developed to identify and destroy the leukemic cells. Inotuzumab ozogamicin is a CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin. CD22 expression is detected on leukemic blasts in over 90% of patients with ALL. Based on promising results from preclinical studies, inotuzumab ozogamicin was tested in Phase 1/2 and Phase 3 clinical trials and it demonstrated improved complete remission rates, progression-free survival and overall survival in relapsed or refractory adult ALL compared to standard therapy. Ongoing studies are evaluating the value of inotuzumab ozogamicin when given in combination with chemotherapy as part of upfront treatment. This review discusses the drug's biochemical properties and mechanism of action, preclinical research outcomes, clinical trial results, adverse events and toxicities, drug approval and ongoing investigations.


Democratising deep learning for microscopy with ZeroCostDL4Mic.
Deep Learning (DL) methods are powerful analytical tools for microscopy and can outperform conventional image processing pipelines. Despite the enthusiasm and innovations fuelled by DL technology, the need to access powerful and compatible resources to train DL networks leads to an accessibility barrier that novice users often find difficult to overcome. Here, we present ZeroCostDL4Mic, an entry-level platform simplifying DL access by leveraging the free, cloud-based computational resources of Google Colab. ZeroCostDL4Mic allows researchers with no coding expertise to train and apply key DL networks to perform tasks including segmentation (using U-Net and StarDist), object detection (using YOLOv2), denoising (using CARE and Noise2Void), super-resolution microscopy (using Deep-STORM), and image-to-image translation (using Label-free prediction - fnet, pix2pix and CycleGAN). Importantly, we provide suitable quantitative tools for each network to evaluate model performance, allowing model optimisation. We demonstrate the application of the platform to study multiple biological processes.


Thermal decomposition of perfluorinated carboxylic acids: Kinetic model and theoretical requirements for PFAS incineration.
Thermal decomposition of high-fluorine content PFAS streams for the disposal of old generations of concentrates of firefighting foams, exhausted ion-exchanged resins and granular activated carbon, constitutes the preferred method for destruction of these materials. This contribution studies the thermal transformation of perfluoropentanoic acid (C4F9C(O)OH, PFPA), as a model PFAS species, in gas-phase reactions over broad ranges of temperature and residence time, which characterise incinerators and cement kilns. Our focus is only on gas-phase reactions, to formulate a gas-phase submodel that, in future, could be used in comprehensive simulation of thermal destruction of PFAS; such comprehensive models will need to comprise fluorine mineralisation on flyash and in clinker material. Our submodel consists of 56 reactions and 45 species, and includes new pathways that cover the initial decomposition channels of PFPA, including those that lead to the formation of the n-C4F9 radical, the abstraction of hydroxyl H by O/H radicals, the fragmentation of the n-C4F9 radical, reactions between HF and perfluoropentanoic acid, as well as between HF and heptafluorobutanoyl fluoride (C3F7COF), and the cyclisation reactions. The model illustrates the formation of a wide spectrum of small CnFm and CnHFm compounds in the temperature window of 800-1500 K, 2 and 25 s residence time in a plug flow reactor, providing theoretical estimates for the operating conditions of PFAS thermal destruction systems. The initiation reactions involve the loss of HF and formation of the transition α-lactone species that converts to C3F7COF, with C4F9C(O)OH completely decomposed at 1020 K for 2 s residence time. At 1500 K, we predict the emission of ꞉CF2 (biradical difluorocarbene), HF, CO2, CO, CF4, C2F6, and C2F4, but at < 1400 K, we note the formation of 1H-nonafluorobutane (C4HF9), phosgene (COF2), and heptafluorobutanoyl fluoride (C3F7COF), with 1-C4F8, 2-C4F8 and C3HF7 persisting to 1500 K. We demonstrate that, the gas-phase pyrolysis processes by themselves convert PFAS to HF and short-chain fluorocarbons, with similar product distribution for short (2 s) and long (25 s) residence times, as long as the treatment temperature exceeds 1500 K. These residence times reflect those encountered in incinerators and cement kilns, respectively. Thermokinetic and mechanistic insights revealed herein shall assist to innovate PFAS thermal disposal technologies, and, from a fundamental perspective, to accelerate research progress in modelling of gas/solid reactions that mineralise PFAS-derived fluorine.


Successful treatment of metastatic retinoblastoma.
In the past, patients with metastatic retinoblastoma have had a poor prognosis when treated with conventional modalities. In the current study, the authors evaluated the use of combined intensive conventional chemotherapy, high dose chemotherapy with autologous stem cell rescue (ASCR), and radiation therapy. Four patients with metastatic retinoblastoma were treated. All had orbital and bone marrow metastases. In addition, three patients had bone metastases and two patients had liver metastases. None had central nervous system disease. Patients received intensive conventional chemotherapy that included vincristine, cyclophosphamide, etoposide, and either cisplatin or carboplatin. Stem cells were harvested after bone marrow disease was no longer detectable. High dose chemotherapy with carboplatin (500 mg/m(2)/day x 3 days or area under the curve = 7 via the Calvert formula) and thiotepa (300 mg/m(2)/day x 3 days) with (n = 3 patients) or without (n = 1 patient) etoposide (250 mg/m(2)/day x 3 days) was administered with ASCR. Sites that originally harbored bulky disease were irradiated after recovery from the high dose chemotherapy. The therapy was associated with substantial acute hematopoietic and mucosal toxicities. At last follow-up, all four patients had survived event free from 46-80 months after the diagnosis of metastatic disease. The treatment strategy described in the current study is effective for patients with metastatic retinoblastoma that does not involve the central nervous system. However, a multicenter trial should be considered to evaluate it in a larger group of patients.


Removal of metals from aqueous solutions using dried Cladophora parriaudii of varying biochemical composition.
Macroalgal biosorption has shown promise for the removal of metal ions from wastewaters, whose presence can pose a threat to the aquatic environment. There is a wealth of literature published on macroalgal biosorption, the common thread being that the biosorbent material was collected from the field, under undefined conditions. These studies offer little insight into the impact of prior cultivation or biomass production practices upon the biosorbent material, its adsorptive physico-chemical properties and its subsequent capacity for metal removal. The present study sought to investigate the influence of changes in macroalgal cultivation, specifically nutrient regime, upon biomass properties and the resultant adsorption performance. The macroalga Cladophora parriaudii was cultivated under six different nutrient regimes; 2:1 and 12:1 N:P molar ratios, with nitrogen supplied either as ammonium (NH4+), nitrate (NO3-), or urea (CO(NH2)2). These nutrient regimes were designed to produce biomass of varying biochemical and cell surface profiles. After cultivation, the biomass was rinsed, dried, biochemically analysed and then used for the removal of four individual metals from solution. Metal removal varied considerably between treatments and across initial metal concentrations, with removal values of 46-85%, 9-80%, 8-71%, and 49-94% achieved for Al, Cu, Mn, and Pb, respectively, with initial metal concentrations varying between 0 and 150 mg L-1. The observed variation in metal removal can only be attributed to differences in biochemistry and cell surface properties of the biosorbent induced by nutrient regime, as all other variables were constant. This study demonstrates that prior cultivation conditions influence the biochemistry of a biosorbent material, namely macroalgae Cladophora parriaudii, which has an impact upon metal removal. This aspect should be given due consideration for future biosorption research and when reviewing already published literature.


Extrathyroid extension of well-differentiated papillary thyroid microcarcinoma on US.
Extrathyroidal extension is an important factor to determine the extent of thyroid surgery. The aim of the present study was to evaluate the usefulness of high-resolution ultrasound (US) for predicting the extrathyroidal extension of papillary thyroid microcarcinoma (PTMC). This study included a total of 221 PTMCs in 181 patients. PTMC was defined as thyroid papillary carcinoma equal or less than 1 cm in size. The US findings, such as contact and disruption of thyroid capsule, were evaluated to predict the extrathyroidal extension of thyroid carcinoma. We calculated the diagnostic accuracy and odds ratio for each US finding. Of the 221 PTMCs, extrathyroidal extension was present in 89 (40.3%) based on pathologic results. The mean size was not significantly different between PTMCs with and without extrathyroidal extension (p = 0.527). When the degree of contact was high, extrathyroidal extension of the thyroid cancer was high (p < 0.0001). Considering the odds ratio, Az value, and positive predictive value of each US finding, more than 25% contact with the adjacent capsule is the most accurate measurement for predicting extrathyroidal extension. This study suggests that the presence and degree of contact between a PTMC and the adjacent capsule as found on preoperative US can provide an useful predictive information about an extrathyroidal extension.


The calcium channel blocker nitrendipine blocks sodium channels in neonatal rat cardiac myocytes.
The dihydropyridine calcium channel blocker, nitrendipine, was studied for its effects on the sodium current of single cultured ventricular cells from neonatal rats. The patch-clamp method of recording whole cell currents was used, and sodium currents were isolated by suppressing potassium and calcium currents. Potassium currents were blocked by replacing potassium with cesium in the internal and external solutions and by adding tetraethylammonium chloride and 4-aminopyridine in the external solution; calcium current was blocked by replacing calcium with cobalt in the external solution. At low frequencies (0.1 Hz), nitrendipine reduced sodium currents without any significant change in the current-voltage relation. The block was dose dependent, and assuming a single occupancy model with complete block, had a half-maximum value of 3 X 10(-6) M at a holding potential of -80 mV where half the sodium channels are activatable. This value is within the range of the Kd's that have been reported for low-affinity dihydropyridine-binding sites found in cardiac sarcolemmal vesicles. In the presence of nitrendipine, the inactivation curve was shifted to hyperpolarized potentials. The block was greater with pulse intervals shorter than 1000 msec, and repriming was prolonged in the presence of the drug. These effects are similar to those of local anesthetics of the tertiary amine class, such as lidocaine. The block was relieved by the dihydropyridine agonist Bay K8644. The results are interpreted as indicating that dihydropyridines react with sodium channels.


Alterations of sucrose preference after Roux-en-Y gastric bypass.
Roux-en-Y gastric bypass (gastric bypass) patients reportedly have changes in perception and consumption of sweet-tasting foods. This study aimed to further investigate alterations in sweet food intake in rats and sucrose detection in humans after gastric bypass. Wistar rats were randomized to gastric bypass or sham-operations and preference for sucrose (sweet), sodium chloride (salty), citric acid (sour) and quinine hydrochloride (bitter) was assessed with standard two-bottle intake tests (vs. water). Intestinal T1R2 and T1R3 expression and plasma levels of glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) were measured. Furthermore, obese patients and normal weight controls were tested for sucrose taste detection thresholds pre- and postoperatively. Visual analogue scales measuring hedonic perception were used to determine the sucrose concentration considered by patients and controls as "just about right" pre- and postoperatively. Gastric bypass reduced the sucrose intake relative to water in rats (p<0.001). Preoperative sucrose exposure reduced this effect. Preference or aversion for compounds representative of other taste qualities in naïve rats remained unaffected. Intestinal T1R2 and T1R3 expression was significantly decreased in the alimentary limb while plasma levels of GLP-1 and PYY were elevated after bypass in rats (p=0.01). Bypass patients showed increased taste sensitivity to low sucrose concentrations compared with controls (p<0.05), but both groups considered the same sucrose concentration as "just about right" postoperatively. In conclusion, gastric bypass reduces sucrose intake relative to water in sucrose-naïve rats, but preoperative sucrose experience attenuates this effect. Changes in sucrose taste detection do not predict hedonic taste ratings of sucrose in bypass patients which remain unchanged. Thus, factors other than the unconditional affective value of the taste may also play a role in determining food preferences after gastric bypass.


Crystallographic B-factors highlight energetic frustration in aldolase folding.
Kinetic simulations of the folding and unfolding of the mammalian TIM barrel protein aldolase were conducted to determine if a minimalist monomeric Gō model, using the native structure to determine attractive energies in the protein chain, could capture the experimentally determined folding pathway. The folding order, that is, the order in which different secondary structures fold, between the Gō model simulations and that from hydrogen-deuterium exchange experiments, did not agree. To explain this discrepancy, two alternate variant of the basic Gō model were simulated: (1) a monomer Gō model with native contact energies weighted by a statistical potential (SP model) and (2) a monomer Gō model with native contact energies inversely weighted by crystallographic B factors (B model). The B model demonstrated the best agreement between simulation and experiments. The success of the B model is attributed to the ability of B factors to highlight local energetic frustration in the aldolase structure which results in weaker native contacts in these frustrated regions. The predictive success of the B model also reveals the potential use of B factor information for energetic weighting in general protein modeling.


Celiac disease, collagenous sprue and microscopic colitis in IBD. Observations from a population-based cohort of IBD (ICURE).
Inflammatory bowel disease (IBD), microscopic colitis and celiac disease are all diseases with worldwide distribution and increased incidence has been reported from many areas. There is a shortage of studies investigating the occurrence of these diseases in the same individual and whether those affected demonstrate any particular phenotype. The aim of the study was to describe the concomitant incidence of microscopic colitis and celiac disease in a population-based IBD cohort. All 790 individuals in a prospective population-based cohort included 2005-09 from Uppsala region, Sweden, were reviewed regarding the appearance of microscopic or celiac disease before or after IBD diagnosis. Fifty percent (396/790) of the patients had been examined for the possibility of celiac disease. Seventeen patients with celiac disease were found, representing 2.2% of the cohort. Patients with celiac disease were younger compared to the non-celiac patients and those with colitis had more often an extensive inflammation of the colon. Seventy-one percent (12/17) were women. The majority of the patients were diagnosed with celiac disease before IBD. Five patients with IBD had an earlier diagnosis of microscopic colitis or developed it after the IBD diagnosis. One teenager developed collagenous sprue, misinterpreted as a severe relapse of ulcerative colitis (UC) resulting in colectomy. The risk for celiac disease seems not to be increased in IBD, but those affected by both diseases seem to be predominantly women with extensive UC. There is a potential association between microscopic colitis and IBD.


Musings on privacy issues in health research involving disaggregate geographic data about individuals.
This paper offers a state-of-the-art overview of the intertwined privacy, confidentiality, and security issues that are commonly encountered in health research involving disaggregate geographic data about individuals. Key definitions are provided, along with some examples of actual and potential security and confidentiality breaches and related incidents that captured mainstream media and public interest in recent months and years. The paper then goes on to present a brief survey of the research literature on location privacy/confidentiality concerns and on privacy-preserving solutions in conventional health research and beyond, touching on the emerging privacy issues associated with online consumer geoinformatics and location-based services. The 'missing ring' (in many treatments of the topic) of data security is also discussed. Personal information and privacy legislations in two countries, Canada and the UK, are covered, as well as some examples of recent research projects and events about the subject. Select highlights from a June 2009 URISA (Urban and Regional Information Systems Association) workshop entitled 'Protecting Privacy and Confidentiality of Geographic Data in Health Research' are then presented. The paper concludes by briefly charting the complexity of the domain and the many challenges associated with it, and proposing a novel, 'one stop shop' case-based reasoning framework to streamline the provision of clear and individualised guidance for the design and approval of new research projects (involving geographical identifiers about individuals), including crisp recommendations on which specific privacy-preserving solutions and approaches would be suitable in each case.


Isolation and characterization of SUA5, a novel gene required for normal growth in Saccharomyces cerevisiae.
We have identified the sua5 locus as a suppressor of an aberrant ATG codon located in the leader region of the cyc1 gene. The sua5-1 allele enhances the iso-1-cytochrome c steady state level in the cyc1-1019 mutant from 2% to approximately 60% of normal (Cyc+) and also confers a marked slow growth (Slg-) phenotype. Suppression is not a consequence of altered transcription initiation at the cyc1 locus. The SUA5 wild-type gene was isolated and sequenced, revealing an open reading frame (ORF) encoding a potential protein of 46,537 Da. SUA5 transcript analyses were consistent with expression of the predicted ORF and Sua5 antisera detected a protein with an apparent molecular mass of 44 kDa. SUA5 was mapped to chromosome VII, immediately adjacent to the PMR1 gene. Hybridization analysis revealed the presence of a related gene on chromosome XII. Neither the SUA5 DNA sequence nor deduced amino acid sequence showed homology to any sequences in the data banks. Disruption of SUA5 conferred the same Cyc+ and Slg- phenotypes as the sua5-1 suppressor, which is the result of a missense mutation, encoding a Ser107----Phe replacement. In addition, sua5 null mutants lack cytochrome a.a3 and fail to grow on lactate or glycerol medium. These results define SUA5 as a new gene encoding a novel protein that is necessary for normal cell growth.


Aberrant salience network functional connectivity in auditory verbal hallucinations: a first episode psychosis sample.
Auditory verbal hallucinations (AVH) often lead to distress and functional disability, and are frequently associated with psychotic illness. Previously both state and trait magnetic resonance imaging (MRI) studies of AVH have identified activity in brain regions involving auditory processing, language, memory and areas of default mode network (DMN) and salience network (SN). Current evidence is clouded by research mainly in participants on long-term medication, with chronic illness and by choice of seed regions made 'a priori'. Thus, the aim of this study was to elucidate the intrinsic functional connectivity in patients presenting with first episode psychosis (FEP). Resting state functional MRI data were available from 18 FEP patients, 9 of whom also experienced AVH of sufficient duration in the scanner and had symptom capture functional MRI (sc fMRI), together with 18 healthy controls. Symptom capture results were used to accurately identify specific brain regions active during AVH; including the superior temporal cortex, insula, precuneus, posterior cingulate and parahippocampal complex. Using these as seed regions, patients with FEP and AVH showed increased resting sb-FC between parts of the SN and the DMN and between the SN and the cerebellum, but reduced sb-FC between the claustrum and the insula, compared to healthy controls.It is possible that aberrant activity within the DMN and SN complex may be directly linked to impaired salience appraisal of internal activity and AVH generation. Furthermore, decreased intrinsic functional connectivity between the claustrum and the insula may lead to compensatory over activity in parts of the auditory network including areas involved in DMN, auditory processing, language and memory, potentially related to the complex and individual content of AVH when they occur.


Diabetes-Related Topics in an Online Forum for Caregivers of Individuals Living With Alzheimer Disease and Related Dementias: Qualitative Inquiry.
Diabetes and Alzheimer disease and related dementias (ADRD) are the seventh and sixth leading causes of death in the United States, respectively, and they coexist in many older adults. Caring for a loved one with both ADRD and diabetes is challenging and burdensome. This study aims to explore diabetes-related topics in the Alzheimer's Association ALZConnected caregiver forum by family caregivers of persons living with ADRD. User posts on the Alzheimer's Association ALZConnected caregiver forum were extracted. A total of 528 posts related to diabetes were included in the analysis. Of the users who generated the 528 posts, approximately 96.1% (275/286) were relatives of the care recipient with ADRD (eg, child, grandchild, spouse, sibling, or unspecified relative). Two researchers analyzed the data independently using thematic analysis. Any divergence was discussed among the research team, and an agreement was reached with a senior researcher's input as deemed necessary. Thematic analysis revealed 7 key themes. The results showed that comorbidities of ADRD were common topics of discussions among family caregivers. Diabetes management in ADRD challenged family caregivers. Family caregivers might neglect their own health care because of the caring burden, and they reported poor health outcomes and reduced quality of life. The online forum provided a platform for family caregivers to seek support in their attempts to learn more about how to manage the ADRD of their care recipients and seek support for managing their own lives as caregivers. The ALZConnected forum provided a platform for caregivers to seek informational and emotional support for caring for persons living with ADRD and diabetes. The overwhelming burdens with these two health conditions were apparent for both caregivers and care recipients based on discussions from the online forum. Studies are urgently needed to provide practical guidelines and interventions for diabetes management in individuals with diabetes and ADRD. Future studies to explore delivering diabetes management interventions through online communities in caregivers and their care recipients with ADRD and diabetes are warranted.


Additional microsatellite markers for mouse genome mapping.
Mouse sequence information from the EMBL and GenBank databases, published sequences and genomic clones have been analyzed for simple repetitive elements or microsatellites. Each microsatellite has been amplified by the polymerase chain reaction (PCR) as a single locus marker. PCR primers were designed from unique sequence flanking each repeat. Size variation of PCR products less than 750 base pairs (bp) between mouse strains has been determined using ethidium bromide-stained acrylamide or agarose gels. A further 74 newly characterized microsatellites are presented in this paper, bringing to 185 the total we have analyzed. Of these, 157/185 (85%) have more than one allele, 143/178 (80%) vary in length between C57BL/6J and Mus spretus, and 82/168 (49%) vary between DBA/2J and C57BL/6J. Microsatellites provide informative single locus probes for linkage analysis in the construction of a genetic map of the mouse genome.


Globalization and the health of Canadians: 'Having a job is the most important thing'.
Globalization describes processes of greater integration of the world economy through increased flows of goods, services, capital and people. Globalization has undergone significant transformation since the 1970s, entrenching neoliberal economics as the dominant model of global market integration. Although this transformation has generated some health gains, since the 1990s it has also increased health disparities. As part of a larger project examining how contemporary globalization was affecting the health of Canadians, we undertook semi-structured interviews with 147 families living in low-income neighbourhoods in Canada's three largest cities (Montreal, Toronto and Vancouver). Many of the families were recent immigrants, which was another focus of the study. Drawing on research syntheses undertaken by the Globalization Knowledge Network of the World Health Organization's Commission on Social Determinants of Health, we examined respondents' experiences of three globalization-related pathways known to influence health: labour markets (and the rise of precarious employment), housing markets (speculative investments and affordability) and social protection measures (changes in scope and redistributive aspects of social spending and taxation). Interviews took place between April 2009 and November 2011. Families experienced an erosion of labour markets (employment) attributed to outsourcing, discrimination in employment experienced by new immigrants, increased precarious employment, and high levels of stress and poor mental health; costly and poor quality housing, especially for new immigrants; and, despite evidence of declining social protection spending, appreciation for state-provided benefits, notably for new immigrants arriving as refugees. Job insecurity was the greatest worry for respondents and their families. Questions concerning the impact of these experiences on health and living standards produced mixed results, with a majority expressing greater difficulty 'making ends meet,' some experiencing deterioration in health and yet many also reporting improved living standards. We speculate on reasons for these counter-intuitive results. Current trends in the three globalization-related pathways in Canada are likely to worsen the health of families similar to those who participated in our study.


Comparing data accuracy between structured abstracts and full-text journal articles: implications in their use for informing clinical decisions.
The abstract is the most frequently read section of a research article. The use of 'Consensus Abstracts', a clinician-oriented web application formatted for mobile devices to search MEDLINE/PubMed, for informing clinical decisions was proposed recently; however, inaccuracies between abstracts and the full-text article have been shown. Efforts have been made to improve quality. We compared data in 60 recent-structured abstracts and full-text articles from six highly read medical journals. Data inaccuracies were identified and then classified as either clinically significant or not significant. Data inaccuracies were observed in 53.33% of articles ranging from 3.33% to 45% based on the IMRAD format sections. The Results section showed the highest discrepancies (45%) although these were deemed to be mostly not significant clinically except in one. The two most common discrepancies were mismatched numbers or percentages (11.67%) and numerical data or calculations found in structured abstracts but not mentioned in the full text (40%). There was no significant relationship between journals and the presence of discrepancies (Fisher's exact p value =0.3405). Although we found a high percentage of inaccuracy between structured abstracts and full-text articles, these were not significant clinically. The inaccuracies do not seem to affect the conclusion and interpretation overall. Structured abstracts appear to be informative and may be useful to practitioners as a resource for guiding clinical decisions.


Peptidyl inhibition of Spt4-Spt5: Protein-protein inhibitors for targeting the transcriptional pathway related to C9orf72 expansion repeats.
Spt4/Spt5 is an useful target as it is likely a transcription factor that has implications for long non-coding RNA repeats related to frontotemporal dementia (FTD) found in the C9orf72 disease pathology. Inhibitors for Spt4/Spt5 using peptides as a starting point for assays as a means for developing small molecules, which could likely lead to therapeutic development for inhibition for Spt4/Spt5 with CNS characteristics. To elucidate the specific steps of identification and modification of key interacting residues from Spt4/Spt5 complex with further effect prediction, a set of different computational methods was applied. Newly characterized, theoretically derived peptides docked on Spt4/Spt5 models, based on X-ray crystallography sources, allowed us to complete molecular dynamics simulations and docking studies for peptide libraries that give us high confident set of peptides for use to screen for Spt4/Spt5 inhibition. Several peptides with increased specificity to the Spt4/Spt5 interface were found and can be screened in cell-based assays and enzymatic assays for peptide screens that lead to small molecule campaigns. Spt4/Spt5 comprises an attractive target for neurological diseases, and applying these peptides into a screening campaign will promote the goal of therapeutic searches for FTD drug discovery.


Women's preference for a cesarean section: incidence and associated factors.
Few studies have examined women's preferences for birth. The object of this study was to determine the incidence of women's preferred type of birth, and the reasons and factors associated with their preference. Three hundred and ten women between 36 and 40 weeks' gestation were recruited from the antenatal clinic of a major metropolitan teaching hospital and the consulting rooms of six private obstetricians in Brisbane, Australia. Participants completed a questionnaire asking about their preferred type of birth, reasons for their preference, preparation for childbirth, level of anxiety and concerns, and the influence of the primary caregiver. Two hundred and ninety women (93.5%) preferred a spontaneous vaginal birth; 20 women (6.4%) preferred a cesarean section. Of the latter group, most had a current obstetric complication or experienced a previously complicated delivery (p <0.001); 1 woman (0.3%) preferred a cesarean section in the absence of any known current or previous obstetric complication. Women who preferred a cesarean section were more anxious, were generally poorly informed of the risks of this procedure, and/or overestimated the safety of the procedure. Women who preferred a cesarean section were more likely to have experienced this type of birth previously and to have negative feelings about it. To decrease women's preference for a cesarean section, practitioners should reduce the primary cesarean delivery rate and improve the quality of emotional care for women who require a cesarean section. Caregivers should engage in a sensitive discussion of the risks and benefits of various birth options, including a vaginal birth after cesarean, with women who have previously experienced a cesarean birth before they make decisions about mode of delivery in a subsequent pregnancy.


Efficacy of tenofovir and efavirenz in combination with lamivudine or emtricitabine in antiretroviral-naive patients in Europe.
The combination of tenofovir and efavirenz with either lamivudine or emtricitabine (TELE) has proved to be highly effective in clinical trials for first-line treatment of HIV-1 infection. However, limited data are available on its efficacy in routine clinical practice. A multicentre cohort study was performed in therapy-naive patients initiating ART with TELE before July 2009. Efficacy was studied using ITT (missing or switch = failure) and on-treatment (OT) analyses. Genotypic susceptibility scores (GSSs) were determined using the Stanford HIVdb algorithm. Efficacy analysis of 1608 patients showed virological suppression to <50 copies/mL at 48 weeks in 91.5% (OT) and 70.6% (ITT). Almost a quarter of all patients (22.9%) had discontinued TELE at week 48, mainly due to CNS toxicity. Virological failure within 48 weeks was rarely observed (3.3%, n = 53). In multilevel, multivariate analysis, infection with subtype B (P = 0.011), baseline CD4 count <200 cells/mm³ (P < 0.001), GSS <3 (P = 0.002) and use of lamivudine (P < 0.001) were associated with a higher risk of virological failure. After exclusion of patients using co-formulated compounds, virological failure was still more often observed with lamivudine. Following virological failure, three-quarters of patients switched to a PI-based regimen with GSS <3. After 1 year of second-line therapy, viral load was suppressed to <50 copies/mL in 73.5% (OT). In clinical practice, treatment failure on TELE regimens is relatively frequent due to toxicity. Virological failure is rare and more often observed with lamivudine than with emtricitabine. Following virological failure on TELE, PI-based second-line therapy was often successful despite GSS <3.


Hypermetabolic syndrome as a consequence of repeated psychological stress in mice.
Stress is a powerful modulator of neuroendocrine, behavioral, and immunological functions. After 4.5-d repeated combined acoustic and restraint stress as a murine model of chronic psychological stress, severe metabolic dysregulations became detectable in female BALB/c mice. Stress-induced alterations of metabolic processes that were found in a hepatic mRNA expression profiling were verified by in vivo analyses. Repeatedly stressed mice developed a hypermetabolic syndrome with the severe loss of lean body mass, hyperglycemia, dyslipidemia, increased amino acid turnover, and acidosis. This was associated with hypercortisolism, hyperleptinemia, insulin resistance, and hypothyroidism. In contrast, after a single acute stress exposure, changes in expression of metabolic genes were much less pronounced and predominantly confined to gluconeogenesis, probably indicating that metabolic disturbances might be initiated already early but will only manifest in repeatedly stressed mice. Thus, in our murine model, repeated stress caused severe metabolic dysregulations, leading to a drastic reduction of the individual's energy reserves. Under such circumstances stress may further reduce the ability to cope with new stressors such as infection or cancer.


Regulation of vascular endothelial function by procyanidin-rich foods and beverages.
Flavonoid-rich diets are associated with a lower mortality from cardiovascular disease. This has been linked to improvements in endothelial function. However, the specific flavonoids, or biologically active metabolites, conferring these beneficial effects have yet to be fully defined. In this experimental study of the effect of flavonoids on endothelial function cultured endothelial cells have been used as a bioassay with endothelin-1 (ET-1) synthesis being measured an index of the response. Evaluation of the relative effects of extracts of cranberry juice compared to apple, cocoa, red wine, and green tea showed inhibition of ET-1 synthesis was dependent primarily on their oligomeric procyanidin content. Procyanidin-rich extracts of cranberry juice triggered morphological changes in endothelial cells with reorganization of the actin cytoskeleton and increased immunostaining for phosphotyrosine residues. These actions were independent of antioxidant activity. Comparison of the effects of apple procyanidin monomers through heptamer showed a clear structure-activity relationship. Although monomer, dimer, and trimer had little effect on ET-1 synthesis, procyanidin tetramer, pentamer, hexamer, and heptamer produced concentration-dependent decreases with IC(50) values of 5.4, 1.6, 0.9, and 0.7 microM, respectively. Levels of ET-1 mRNA showed a similar pattern of decreases, which were inversely correlated with increased expression of Kruppel-like factor 2 (KLF2), a key endothelial transcription factor with a broad range of antiatherosclerotic actions including suppression of ET-1 synthesis. Future investigations of procyanidin-rich products should assess the role KLF2 induction plays in the beneficial vascular effects of high flavonoid consumption.


Mesenchymal stromal cell treatment of donor kidneys during ex vivo normothermic machine perfusion: A porcine renal autotransplantation study.
Normothermic machine perfusion (NMP) of injured kidneys offers the opportunity for interventions to metabolically active organs prior to transplantation. Mesenchymal stromal cells (MSCs) can exert regenerative and anti-inflammatory effects in ischemia-reperfusion injury. The aims of this study were to evaluate the safety and feasibility of MSC treatment of kidneys during NMP using a porcine autotransplantation model, and examine potential MSC treatment-associated kidney improvements up to 14 days posttransplant. After 75 min of kidney warm ischemia, four experimental groups of n = 7 underwent 14 h of oxygenated hypothermic machine perfusion. In three groups this was followed by 240 min of NMP with infusion of vehicle, 10 million porcine, or 10 million human adipose-derived MSCs. All kidneys were autotransplanted after contralateral nephrectomy. MSC treatment did not affect perfusion hemodynamics during NMP or cause adverse effects at reperfusion, with 100% animal survival. MSCs did not affect plasma creatinine, glomerular filtration rate, neutrophil gelatinase-associated lipocalin concentrations or kidney damage assessed by histology during the 14 days, and MSCs retention was demonstrated in renal cortex. Infusing MSCs during ex vivo NMP of porcine kidneys was safe and feasible. Within the short posttransplant follow-up period, no beneficial effects of ex vivo MSC therapy could be demonstrated.


"Global" visual training and extent of transfer in amblyopic macaque monkeys.
Perceptual learning is gaining acceptance as a potential treatment for amblyopia in adults and children beyond the critical period. Many perceptual learning paradigms result in very specific improvement that does not generalize beyond the training stimulus, closely related stimuli, or visual field location. To be of use in amblyopia, a less specific effect is needed. To address this problem, we designed a more general training paradigm intended to effect improvement in visual sensitivity across tasks and domains. We used a "global" visual stimulus, random dot motion direction discrimination with 6 training conditions, and tested for posttraining improvement on a motion detection task and 3 spatial domain tasks (contrast sensitivity, Vernier acuity, Glass pattern detection). Four amblyopic macaques practiced the motion discrimination with their amblyopic eye for at least 20,000 trials. All showed improvement, defined as a change of at least a factor of 2, on the trained task. In addition, all animals showed improvements in sensitivity on at least some of the transfer test conditions, mainly the motion detection task; transfer to the spatial domain was inconsistent but best at fine spatial scales. However, the improvement on the transfer tasks was largely not retained at long-term follow-up. Our generalized training approach is promising for amblyopia treatment, but sustaining improved performance may require additional intervention.


Identifying priorities for patient-centered outcomes research for serious mental illness.
The purpose of this project was to engage a diverse group of stakeholders (N=38) to help establish priorities to guide patient-centered outcomes research (PCOR) in serious mental illness. Three meetings, two Web-based and one on site, were held to generate and prioritize an initial list of topics. Topics were then sorted and organized into common themes. About 140 topics were identified and sorted into 21 main themes, ranked by priority. Three of the top four themes focused on how research was conducted, particularly the need to develop consensus measurement and outcomes definitions; improving infrastructure for research, longitudinal studies, and new data sets and investigators; and developing PCOR methodology. Stakeholders also identified a need to focus on service delivery, treatment settings, and structure of the delivery of care. Engagement by a broad group of stakeholders in a transparent process resulted in the identification of priority areas for PCOR. Stakeholders clearly indicated a need to fundamentally change how research on serious mental illness is conducted and a critical need for the development of methodology and infrastructure. Most current PCOR has been focused on relatively short-term outcomes, but real world, long-term studies providing guidance for treatment over the lifetime of a serious mental illness are needed.


The Effects of Meditation on Grey Matter Atrophy and Neurodegeneration: A Systematic Review.
The present systematic review is based on the premise that a variety of neurodegenerative diseases are accompanied by grey matter atrophy in the brain and meditation may impact this. Given that age is a major risk factor for many of these progressive and neurodegenerative diseases and that the percentage of the population over the age of 65 is quickly increasing, there is an obvious need for prompt treatment and prevention advances in research. As there is currently no cure for Alzheimer's disease and other neurodegenerative diseases, many are seeking non-pharmacological treatment options in attempts to offset the disease-related cognitive and functional declines. On the basis of a growing body of research suggesting that meditation is effective in increasing grey matter volume in healthy participants, this paper systematically reviewed the literature regarding the effects of meditation on restoring grey matter volume in healthy individuals and those affected by neurodegeneration. This review searched PubMed, CINAHL, and APA PsycNET to identify original studies that included MRI imaging to measure grey matter volume in meditators and post-mindfulness-based intervention participants compared to controls. Thirteen studies were considered eligible for review and involved a wide variety of meditation techniques and included participants with and without cognitive impairment. All studies reported significant increases in grey matter volume in the meditators/intervention group, albeit in assorted regions of the brain. Limited research exists on the mechanisms through which meditation affects disease-related neurodegeneration, but preliminary evidence suggests that it may offset grey matter atrophy.