Difference in patient's acceptance of early versus late initiation of psychosocial support in breast cancer.
The present study was performed to assess the difference in acceptance of psychosocial counseling and resulting benefits between patients with breast cancer with early or late onset. In a prospective randomized controlled study conducted over 6 months, 41 women with a new diagnosis of early breast cancer (group 1) and 43 patients with advanced breast cancer (group 2) received individually tailored psychosocial support and were compared against controls. This therapy was free of charge, and the duration of support was determined by the patients' wishes and needs. Among the patients with new onset of disease acceptance of the psychosocial counseling was high, and these patients experienced significant improvements in their quality of life. In contrast, acceptance of psychosocial counseling was low in the advanced breast cancer group and the therapy did not improve quality of life over the observation period of 6 months. Early psychosocial support in patients with breast cancer meets with a high acceptance rate and improves quality of life.


A randomized controlled trial of Mindfulness-Based Cognitive Therapy (MBCT) versus treatment-as-usual (TAU) for chronic, treatment-resistant depression: study protocol.
Major depression is a common psychiatric disorder, frequently taking a chronic course. Despite provision of evidence-based treatments, including antidepressant medication and psychological treatments like cognitive behavioral therapy or interpersonal therapy, a substantial amount of patients do not recover. Mindfulness-Based Cognitive Therapy (MBCT) has been found to be effective in reducing relapse in recurrent depression, as well as lowering symptom levels in acute depression. The effectiveness of MBCT for chronic, treatment-resistant depression has only be studied in a few pilot trials. A large randomized controlled trial is necessary to examine the effectiveness of MBCT in reducing depressive symptoms in chronic, treatment-resistant depression. A randomized-controlled trial is conducted to compare MBCT with treatment-as-usual (TAU). Patients with chronic, treatment-resistant depression who have received antidepressant medication and cognitive behavioral therapy or interpersonal therapy are included. Assessments take place at baseline and post intervention/TAU-period. The primary outcome are depressive symptoms. Secondary outcomes are: remission rates, quality of life, rumination, mindfulness skills and self-compassion. Patients in the TAU condition are offered to participate in the MBCT after the post TAU-period assessment. From all completers of the MBCT (MBCT condition and patients participating after the TAU-period), follow-up assessments are taken at three and six months after the completion of the MBCT. This trial will result in valuable information about the effectiveness of MBCT in chronic, treatment-resistant depressed patients who previously received antidepressant medication and psychological treatment. trialregister.nl NTR4843, registered 14th October 2014.


In vivo imaging rhodopsin distribution in the photoreceptors with nano-second pulsed scanning laser ophthalmoscopy.
Rhodopsin is a biomarker for the function of rod photoreceptors, the dysfunction of which is related to many blinding diseases like retinitis pigmentosa and age-related macular degeneration. Imaging rhodopsin quantitatively may provide a powerful clinical tool for diagnosis of these diseases. To map rhodopsin distribution accurately in the retina, absorption by rhodopsin intermediates need to be minimized. We developed nano-second pulsed scanning laser ophthalmoscopy (SLO) to image rhodopsin distribution in the retina. The system takes advantage of the light-induced shift of rhodopsin absorption spectra, which in turn affects the fundus spectral reflection before and after photo-bleaching. By imaging the retina twice, one in the dark-adapted state and the other one in the light-adapted state, the rhodopsin absorption change can be calculated from the differential image, which is a function of the rhodopsin concentration in the rod photoreceptors. The system was successfully applied to in vivo imaging of rat retina in different bleaching conditions to verify its feasibility. Our studies showed that the differential image between the dark- and light-adapted states represents rhodopsin distribution in the retina. We also conducted a dynamic bleaching experiment to prove the importance of reducing light absorption of rhodopsin intermediates. The preliminary results showed that our nano-second pulsed-light SLO is promising in imaging the functional biomarker of the rod photoreceptors. By using nanosecond pulsed laser, in which one laser pulse generates one pixel of the image, the absorption of rhodopsin intermediates can be reduced.


Hypertension in diabetes as related to nephropathy. Early blood pressure changes.
We measured the blood pressure under standardized conditions in three groups of patients with type I (insulin-dependent) diabetes: group 1, patients with Albustix-negative urine and normal urinary albumin excretion rate below 20 micrograms/min; group 2, patients with Albustix-negative urine and elevated urinary albumin excretion rate 20 to 200 micrograms/min; and group 3, patients with Albustix-positive urine at the time of diagnosis of diabetic nephropathy, that is, proteinuria greater than 0.5 g/24 hr on four consecutive visits with an interval of more than 1 month. We also studied blood pressure data at the time of diagnosis of diabetes in patients with type I diabetes who later died with severe nephropathy (n = 84), and in those who survived their disease for more than 40 years (n = 256). Patients subsequently developing diabetic nephropathy could not be identified on the basis of systolic and/or diastolic blood pressure during the first 2 to 10 years of diabetes. Our study also demonstrated that the blood pressure in group 3 (147/93 mm Hg) was significantly higher than that in group 2 (135/86 mm Hg), which again was higher than that in group 1 (128/79 mm Hg). We concluded that arterial hypertension is an early feature in the developing of diabetic nephropathy, with blood pressure rising before the presence of clinical proteinuria.


Recent advances in iodine mediated electrochemical oxidative cross-coupling.
Electrochemical oxidative cross-coupling with hydrogen evolution has become an environmentally friendly and efficient way to form new bonds. Direct electrosynthesis by anodic oxidation has been developed for the synthesis of complex molecules. However, in some cases, redox catalysts were needed to avoid over-oxidation and to achieve better reaction selectivity. Recently, the use of iodine as a mediator to achieve indirect electrochemical reactions has drawn increasing attention. This review article gives an overview of the recent development of iodine mediated electrochemical oxidative coupling reactions.


Quality of reporting of observational longitudinal research.
Observational longitudinal research is particularly useful for assessing etiology and prognosis and for providing evidence for clinical decision making. However, there are no structured reporting requirements for studies of this design to assist authors, editors, and readers. The authors developed and tested a checklist of criteria related to threats to the internal and external validity of observational longitudinal studies. The checklist criteria concerned recruitment, data collection, biases, and data analysis and descriptive issues relevant to study rationale, study population, and generalizability. Two raters independently assessed 49 randomly selected articles describing stroke research published from 1999 to 2003 in six journals: American Journal of Epidemiology, Journal of Epidemiology and Community Health, Stroke, Annals of Neurology, Archives of Physical Medicine and Rehabilitation, and American Journal of Physical Medicine and Rehabilitation. On average, 17 of the 33 checklist criteria were reported. Criteria describing the study design were better reported than those related to internal validity. No relation was found between study type (etiologic or prognostic) or word count and quality of reporting. A flow diagram for summarizing participant flow through a study was developed. Editors and authors should consider using a checklist and flow diagram when reporting on observational longitudinal research.


Polyploidy as a chromosomal component of stochastic noise: variable scalar multiples of the diploid chromosome complement in the invertebrate species Girardia schubarti from Brazil.
Chromosome stoichiometry, a form of genetic plasticity, specifically refers to variation in the standard diploid genomic composition of an individual or species. In the present work, freshwater planarians (Girardia schubarti) were analyzed to recognize variations in chromosomal stoichiometry especially of complete ploidal change between specimens, within specimens and between cells within specimens and any relations they might have with selected components of phenotypic plasticity. Homoploid polyploids for the group reached rational scalar multiples (e.g. tetraploids) or irrational scalar multiples (e.g. triploids). Karyotypic mosaics emerged where individual cells presented polyploid multiples in arithmetic and geometric progressions. Ploidal multiplicity, a chromosomal component of stochastic noise, had positive phenotypic effects (increased dimensions) on morphologic criteria of body length, body width and dorsal surface reflecting a significant genotypic plasticity (GP) and robust phenotypic plasticity (PP). Variable but significant association of genotypic plasticity with robust phenotypic variance suggests kinetics of phenotypic homeostasis that is species-specific permitting phenotypic adaptability to environmental variables by means of GP. That association is diminished, deactivated or lost in more advanced and more complex organisms.


Mercury intoxication and arterial hypertension: report of two patients and review of the literature.
Two children in the same household with symptomatic arterial hypertension simulating pheochromocytoma were found to be intoxicated with elemental mercury. The first child was a 4-year-old boy who presented with new-onset seizures, rash, and painful extremities, who was found to have a blood pressure of 171/123 mm Hg. An extensive investigation ensued. Elevated catecholamines were demonstrated in plasma and urine; studies did not confirm pheochromocytoma. Mercury levels were elevated. These findings prompted an evaluation of the family. A foster sister had similar findings of rash and hypertension. Both had been exposed to elemental mercury in the home. The family was temporarily relocated and chelation therapy was started. A Medline search for mercury intoxication with hypertension found 6 reports of patients ranging from 11 months to 17 years old. All patients showed symptoms of acrodynia. Because of the clinical presentation and the finding of elevated catecholamines, most of the patients were first studied for possible pheochromocytoma. Subsequently, elevated levels of mercury were found. Three children had contact with elemental mercury from a broken thermometer, 2 had played with metallic mercury and 1 had poorly protected occupational exposure. All responded to chelation therapy. Severe systemic arterial hypertension in infants and children is usually secondary to an underlying disease process. The most frequent causes of hypertension in this group include renal parenchymal disease, obstructive uropathy, and chronic pyelonephritis associated with reflux and renal artery stenosis. Less frequent causes include adrenal tumors, pheochromocytomas, neurofibromas, and a number of familial forms of hypertension. Other causes include therapeutic and recreational drugs, notably sympathomimetics and cocaine, and rarely, heavy metals. In children with severe hypertension and elevated catecholamines, the physician should consider mercury intoxication as well as pheochromocytoma. The health hazards of heavy metals need to be reinforced to the medical profession and the general public.


A large-scale model of the functioning brain.
A central challenge for cognitive and systems neuroscience is to relate the incredibly complex behavior of animals to the equally complex activity of their brains. Recently described, large-scale neural models have not bridged this gap between neural activity and biological function. In this work, we present a 2.5-million-neuron model of the brain (called "Spaun") that bridges this gap by exhibiting many different behaviors. The model is presented only with visual image sequences, and it draws all of its responses with a physically modeled arm. Although simplified, the model captures many aspects of neuroanatomy, neurophysiology, and psychological behavior, which we demonstrate via eight diverse tasks.


Mowing Frequency and Plant Growth Regulator Effects on Dollar Spot Severity and on Duration of Dollar Spot Control by Fungicides.
Management of dollar spot (incited by Sclerotinia homoeocarpa) on golf course fairways is increasingly challenging. The objectives of this study were to determine the influence of mowing frequency and plant growth regulators (PGRs) on dollar spot severity and on the residual efficacy of fungicides for control of dollar spot. Two 4-month-long studies were conducted on 'Putter' creeping bentgrass (Agrostis stolonifera) maintained as a fairway at the University of Connecticut. Treatments were arranged in a three-by-three-by-five factorial that assessed the influence of mowing frequency (2, 4, or 6 days week-1) and PGRs (paclobutrazol, trinexapac-ethyl, or none) on dollar spot control by five fungicide treatments (boscalid, chlorothalonil, iprodione, propiconazole, or none). Turf was mowed in the afternoon hours to minimize the confounding effect of mowing frequency on leaf wetness duration. Treatments were initiated in the late spring of 2007 and 2008, and each fungicide treatment was reapplied only when dollar spot exceeded a threshold of five infection centers plot-1. In the absence of fungicides, dollar spot severity was reduced by 63 to 90% in plots treated with paclobutrazol and by 13 to 55% in plots treated with trinexapac-ethyl. Dollar spot severity was 23 to 50% lower in plots mown 2 days week-1 compared with those mown 6 days week-1. In cases where a significant interaction was observed between mowing frequency and PGRs, dollar spot was reduced on most rating dates in plots treated with trinexapacethyl that were mown 2 days week-1 compared with those mown 6 days week-1. Survival analysis of days until threshold was met revealed that duration of control of fungicides in plots receiving paclobutrazol were 28 to 84% longer compared with plots not receiving PGR. Duration of control by fungicides was generally similar between plots treated with trinexapac-ethyl and no PGR. In general, mowing frequency did not influence duration of control. Results from this study indicate that paclobutrazol could be used to increase the treatment interval of fungicides and that mowing frequency in the absence of dew is likely to have little influence on fungicide residual efficacy. When used without fungicides, PGRs and less frequent mowing may reduce dollar spot in situations where fungicide use is limited.


Transmission and microevolution of USA300 MRSA in U.S. households: evidence from whole-genome sequencing.
Methicillin-resistant Staphylococcus aureus (MRSA) USA300 is a successful S. aureus clone in the United States and a common cause of skin and soft tissue infections (SSTIs). We performed whole-genome sequencing (WGS) of 146 USA300 MRSA isolates from SSTIs and colonization cultures obtained from an investigation conducted from 2008 to 2010 in Chicago and Los Angeles households that included an index case with an S. aureus SSTI. Identifying unique single nucleotide polymorphisms (SNPs) and analyzing whole-genome phylogeny, we characterized isolates to understand transmission dynamics, genetic relatedness, and microevolution of USA300 MRSA within the households. We also compared the 146 USA300 MRSA isolates from our study with the previously published genome sequences of the USA300 MRSA isolates from San Diego (n = 35) and New York City (n = 277). We found little genetic variation within the USA300 MRSA household isolates from Los Angeles (mean number of SNPs ± standard deviation, 17.6 ± 35; π nucleotide diversity, 3.1 × 10(-5)) or from Chicago (mean number of SNPs ± standard deviation, 12 ± 19; π nucleotide diversity, 3.1 × 10(-5)). The isolates within a household clustered into closely related monophyletic groups, suggesting the introduction into and transmission within each household of a single common USA300 ancestral strain. From a Bayesian evolutionary reconstruction, we inferred that USA300 persisted within households for 2.33 to 8.35 years prior to sampling. We also noted that fluoroquinolone-resistant USA300 clones emerged around 1995 and were more widespread in Los Angeles and New York City than in Chicago. Our findings strongly suggest that unique USA300 MRSA isolates are transmitted within households that contain an individual with an SSTI. Decolonization of household members may be a critical component of prevention programs to control USA300 MRSA spread in the United States. USA300, a virulent and easily transmissible strain of methicillin-resistant Staphylococcus aureus (MRSA), is the predominant community-associated MRSA clone in the United States. It most commonly causes skin infections but also causes necrotizing pneumonia and endocarditis. Strategies to limit the spread of MRSA in the community can only be effective if we understand the most common sources of transmission and the microevolutionary processes that provide a fitness advantage to MRSA. We performed a whole-genome sequence comparison of 146 USA300 MRSA isolates from Chicago and Los Angeles. We show that households represent a frequent site of transmission and a long-term reservoir of USA300 strains; individuals within households transmit the same USA300 strain among themselves. Our study also reveals that a large proportion of the USA300 isolates sequenced are resistant to fluoroquinolone antibiotics. The significance of this study is that if households serve as long-term reservoirs of USA300, household MRSA eradication programs may result in a uniquely effective control method.


Rearrangements of immunoglobulin and T cell receptor beta and gamma genes are associated with terminal deoxynucleotidyl transferase expression in acute myeloid leukemia.
The cell origin of the rare terminal deoxynucleotidyl transferase (TdT)-positive acute myeloid leukemias (AML) was investigated at the molecular level, by examining the configuration of the Ig H (Igh) and L (Ig kappa, Ig lambda) chain gene regions, and of the T cell receptor (TCR) beta and T cell rearranging (TRG) gamma loci. In 8 of the 10 TdT+ AML analyzed (classified as myeloid according to morphological and cytochemical criteria, and to the reactivity with one or more antimyeloid mAbs), a rearrangement of the Igh chain gene was found. In TdT- AML, evidence of an Igh gene reorganization was instead observed only in 2 of the 42 patients studied. Furthermore, evidence of TCR-beta and/or TRG-gamma gene rearrangement was observed in four AML, all of which belonged to the Igh-rearranged TdT+ group. In three cases (one TdT+ and two TdT-), the Ig kappa L chain gene was also in a rearranged position. These findings demonstrate a highly significant correlation between TdT expression and DNA rearrangements at the Igh and TCR chain gene regions and support the view that this enzyme plays an important role in the V-(D)-J recombination machinery. Overall, the genomic configuration, i.e., JH gene rearrangement sometimes coupled to a kappa L chain and TCR gene reorganization, similar to that found in non-T-ALL, suggests that in most cases of TdT+ AML, the neoplastic clone, despite the expression of myeloid-related features, is characterized by cells molecularly committed along the B cell lineage.


Phylogenetic characterization of six full-length HIV-1 subtype C molecular clones from three patients: identification of rare subtype C strains containing two NF-κB motifs in the long terminal repeat.
Molecular surveillance is the backbone of HIV-1 vaccinology. Full-length HIV-1 sequences are useful tools that can provide a better understanding of the epidemiology in a given region. A limited number of full-length HIV-1 sequences are available from India, where >95% of the HIV infections are due to HIV-1 subtype C (HIV-1C), which is distinct from the prototype African HIV-1C. In this study, we sequenced six full-length clones isolated from three patients. Extensive phylogenetic analyses of the full-length viral sequences using bioinformatic tools identified a separate cluster of Indian strains, thus confirming the distinct phylogenetic identity of the Indian HIV-1C. Notably, the long terminal repeat (LTR) of two of the six molecular clones contained only two NF-κB binding sites. The sequences also displayed features characteristic of HIV-1C including a Tat dicysteine motif, a shortened Rev open reading frame, and a predicted CCR5 coreceptor tropism for gp120 of three of the proviral sequences.


Association of dietary habits with symptoms of temporomandibular disorders in Bangladeshi adolescents.
The prevalences of signs and symptoms of temporomandibular disorder (TMD) in Bangladeshi adolescents and their associations with intake of various hard food items were investigated. A group of 1200 randomly selected high school students aged 12-17 years from three communities (rural, semi-urban and urban) completed a questionnaire on dietary habits and presence of TMD symptoms and were examined clinically. In bivariate analysis, no significant relationship was observed between TMD symptoms and eating of hard foods. However, in logistic regression analysis, clicking showed a significant correlation with consumption of hard vegetable and fruits more than three times per week (P < 0.05). A statistically significant correlation was also observed between consumption of all hard food items (at least one item in each of the four categories of hard food) more than 12 times per week and pain in the temporomandibular joint (TMJ) (P < 0.05). A positive association was found between pain in the TMJ and older age (15-17 years) (P < 0.001). The prevalence of pain in the TMJ was significantly higher in males (P < 0.01). Prevalences of clicking and pain in the TMJ were significantly higher in subjects living in a rural area than in subjects living in an urban area (P < 0.01 and P < 0.01, respectively). Subjects having one or more decayed, missing and filled teeth (DMFT) showed significantly higher prevalences of clicking (P < 0.01) and restricted mouth opening (P < 0.01). The results suggest that prevalence of TMD symptoms are related to prolonged consumption of hard food items.


Towards the development of a fully protective Plasmodium falciparum antimalarial vaccine.
If ever there were a truism then it would be that a completely protective Plasmodium falciparum malaria vaccine is desperately needed. Our institute has devoted all its efforts during the last 30 years to developing a fully protective, minimal subunit-based, multiepitope, multistage (targeting sporozoite and merozoite proteins), chemically synthesized antimalarial vaccine, given that peptides with high binding activity to their corresponding host cells (liver cells or red blood cells) form the springboard for vaccine design. However, such conserved high activity binding peptides have to be specifically modified to render them into highly immunogenic and protection-inducing peptides since they are immunologically silent. These modifications, analyzed at the 3D structural level by (1)H-NMR, allow them a better fit into the MHC II-peptide-T-cell receptor complex to induce an appropriate immune response, providing a rational and logical approach (analyzed at the single atom level) for vaccine development, particularly in the field of malaria.


Mining poly-regions in DNA.
We study the problem of mining poly-regions in DNA. A poly-region is defined as a bursty DNA area, i.e., area of elevated frequency of a DNA pattern. We introduce a general formulation that covers a range of meaningful types of poly-regions and develop three efficient detection methods. The first applies recursive segmentation and is entropy-based. The second uses a set of sliding windows that summarize each sequence segment using several statistics. Finally, the third employs a technique based on majority vote. The proposed algorithms are tested on DNA sequences of four different organisms in terms of recall and runtime.


Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse models of bone marrow transplantation.
Allogeneic blood or BM transplantation (BMT) is the most commonly applied form of adoptive cellular therapy for cancer. In this context, the ability of donor T cells to respond to recipient antigens is coopted to generate graft-versus-tumor (GVT) responses. The major reason for treatment failure is tumor recurrence, which is linked to the eventual loss of functional, host-specific CTLs. In this study, we have explored the role of recipient antigen expression by nonhematopoietic cells in the failure to sustain effective CTL immunity. Using clinically relevant models, we found that nonhematopoietic antigen severely disrupts the formation of donor CD8+ T cell memory at 2 distinct levels that operate in the early and late phases of the response. First, initial and direct encounters between donor CD8+ T cells and nonhematopoietic cells blocked the programming of memory precursors essential for establishing recall immunity. Second, surviving CD8+ T cells became functionally exhausted with heightened expression of the coinhibitory receptor programmed death-1 (PD-1). These 2 factors acted together to induce even more profound failure in long-term immunosurveillance. Crucially, the functions of exhausted CD8+ T cells could be partially restored by late in vivo blockade of the interaction between PD-1 and its ligand, PD-L1, without induction of graft-versus-host disease, suggestive of a potential clinical strategy to prevent or treat relapse following allogeneic BMT.


Differences in the protective capabilities of bicycle helmets in real-world and standard-specified impact scenarios.
The purpose of this study was to investigate relative differences in impact attenuation capabilities of bicycle helmets under real-world impact conditions and safety standard-specified conditions using a standard rig. A Consumer Product Safety Commission (CPSC) test rig was used to impact 10 helmet models of varied design. Impact configurations included 2 locations and 2 velocities. A frontal rim location (inferior to the standard-defined test area) and a temporal location were selected to reflect common cyclist impacts. An impact velocity of 3.4 m/s, an average normal impact velocity in cyclist accidents, was selected, as well as the CPSC standard velocity of 6.2 m/s. Four samples per helmet model were subjected to each of the 4 impact configurations once (randomized test order per sample), resulting in 160 drop tests. Peak linear acceleration (PLA) and head injury criterion (HIC)-based Abbreviated Injury Scale (AIS) ≥ 4 brain injury risk were determined and compared across helmets and impact configurations using analysis of variance. Other impact characteristics such as duration, effective liner stiffness, and energy dissipated were also calculated from acceleration data. Helmet performance varied significantly between models. PLA ranged from 78 to 169 g at 3.4 m/s (0-2% AIS ≥ 4 brain injury risk) and 165-432 g (10-100% risk) at 6.2 m/s. Temporal impacts resulted in higher PLAs than frontal impacts, likely due to increased effective liner stiffness. However, 2 helmets exceeded the CPSC pass-fail threshold (300 g) at the frontal rim location, producing >70% risk. Force-displacement curves suggest that bottoming-out occurred in these impacts. Aside from bottoming-out cases, helmets that performed worse in one impact configuration tended to perform worse in others, with non-road-style helmets among the worst. The 10 bicycle helmets tested produced considerable differences in their protective capabilities under both real-world and standard-specified conditions on the CPSC rig. Risk of severe brain injury varied widely between helmets at the standard impact velocity, whereas the common, lower severity impacts produced PLAs associated with concussion. Helmets of a nonroad style generally performed worse across configuration. The temporal location produced higher risks for most helmets, although some helmets were found to offer inadequate protection at the helmet rim. Because this is a commonly impacted location in cyclist accidents, there may be benefit to expanding the testable area in standards to include the rim. Results from this study demonstrate the value in testing nonstandard conditions and can be used to inform standards testing and helmet design.


Human brain mechanisms of pain perception and regulation in health and disease.
The perception of pain due to an acute injury or in clinical pain states undergoes substantial processing at supraspinal levels. Supraspinal, brain mechanisms are increasingly recognized as playing a major role in the representation and modulation of pain experience. These neural mechanisms may then contribute to interindividual variations and disabilities associated with chronic pain conditions. To systematically review the literature regarding how activity in diverse brain regions creates and modulates the experience of acute and chronic pain states, emphasizing the contribution of various imaging techniques to emerging concepts. MEDLINE and PRE-MEDLINE searches were performed to identify all English-language articles that examine human brain activity during pain, using hemodynamic (PET, fMRI), neuroelectrical (EEG, MEG) and neurochemical methods (MRS, receptor binding and neurotransmitter modulation), from January 1, 1988 to March 1, 2003. Additional studies were identified through bibliographies. Studies were selected based on consensus across all four authors. The criteria included well-designed experimental procedures, as well as landmark studies that have significantly advanced the field. Sixty-eight hemodynamic studies of experimental pain in normal subjects, 30 in clinical pain conditions, and 30 using neuroelectrical methods met selection criteria and were used in a meta-analysis. Another 24 articles were identified where brain neurochemistry of pain was examined. Technical issues that may explain differences between studies across laboratories are expounded. The evidence for and the respective incidences of brain areas constituting the brain network for acute pain are presented. The main components of this network are: primary and secondary somatosensory, insular, anterior cingulate, and prefrontal cortices (S1, S2, IC, ACC, PFC) and thalamus (Th). Evidence for somatotopic organization, based on 10 studies, and psychological modulation, based on 20 studies, is discussed, as well as the temporal sequence of the afferent volley to the cortex, based on neuroelectrical studies. A meta-analysis highlights important methodological differences in identifying the brain network underlying acute pain perception. It also shows that the brain network for acute pain perception in normal subjects is at least partially distinct from that seen in chronic clinical pain conditions and that chronic pain engages brain regions critical for cognitive/emotional assessments, implying that this component of pain may be a distinctive feature between chronic and acute pain. The neurochemical studies highlight the role of opiate and catecholamine transmitters and receptors in pain states, and in the modulation of pain with environmental and genetic influences. The nociceptive system is now recognized as a sensory system in its own right, from primary afferents to multiple brain areas. Pain experience is strongly modulated by interactions of ascending and descending pathways. Understanding these modulatory mechanisms in health and in disease is critical for developing fully effective therapies for the treatment of clinical pain conditions.


Improving the identification accuracy of senior witnesses: do prelineup questions and sequential testing help?
Eyewitness research has identified sequential lineup testing as a way of reducing false lineup choices while maintaining accurate identifications. The authors examined the usefulness of this procedure for reducing false choices in older adults. Young and senior witnesses viewed a crime video and were later presented with target present orabsent lineups in a simultaneous or sequential format. In addition, some participants received prelineup questions about their memory for a perpetrator's face and about their confidence in their ability to identify the culprit or to correctly reject the lineup. The sequential lineup reduced false choosing rates among young and older adults in target-absent conditions. In target-present conditions, sequential testing significantly reduced the correct identification rate in both age groups.


Myeloid cells contribute to tumor lymphangiogenesis.
The formation of new blood vessels (angiogenesis) and lymphatic vessels (lymphangiogenesis) promotes tumor outgrowth and metastasis. Previously, it has been demonstrated that bone marrow-derived cells (BMDC) can contribute to tumor angiogenesis. However, the role of BMDC in lymphangiogenesis has largely remained elusive. Here, we demonstrate by bone marrow transplantation/reconstitution and genetic lineage-tracing experiments that BMDC integrate into tumor-associated lymphatic vessels in the Rip1Tag2 mouse model of insulinoma and in the TRAMP-C1 prostate cancer transplantation model, and that the integrated BMDC originate from the myelomonocytic lineage. Conversely, pharmacological depletion of tumor-associated macrophages reduces lymphangiogenesis. No cell fusion events are detected by genetic tracing experiments. Rather, the phenotypical conversion of myeloid cells into lymphatic endothelial cells and their integration into lymphatic structures is recapitulated in two in vitro tube formation assays and is dependent on fibroblast growth factor-mediated signaling. Together, the results reveal that myeloid cells can contribute to tumor-associated lymphatic vessels, thus extending the findings on the previously reported role of hematopoietic cells in lymphatic vessel formation.


Interplay between myogenic pacemakers and enteric neurons determine distinct motor patterns in the rat colon.
Waxing and waning of slow waves amplitude has been recently associated with a segmentation motor pattern in the murine small intestine. The 'wax and wane' phenomenon in this area of the gastrointestinal tract seems to be the result of modulation of slow waves by a second pacemaker of a lower frequency displayed by the interstitial cells of Cajal near the deep muscular plexus (ICC-DMP). In the rat colon, smooth muscle cyclic depolarizations causing low-frequency (LF) contractions (0.9 ± 0.1 cpm) occur together with slow wave activity associated to high-frequency (HF) contractions (14 ± 0.3 cpm; ripples). In the present manuscript, we demonstrate the presence of 'wax and wane' in rat colonic slow waves. Depolarization from the 'wax' to the 'wane' was 7.6 ± 1.2 mV, i.e., smooth muscle cells went from a resting membrane potential (RMP) of -50.0 mV to a RMP of -42.4 mV. The amplitude of the slow wave decreased from 14.0 ± 2.2 mV to 3.4 ± 0.7 mV. The wax and wane phenomenon occurred at 0.9 ± 0.1 cpm, coinciding with the frequency of cyclic depolarizations. Therefore, we hypothesized that the 'wax and wane' of slow waves in the rat colon could be the result of their interaction with the LF pacemaker. We describe three different myogenic motor patterns that depend on the level of smooth muscle and ICC excitation: (i) LF propulsive contractions, (ii) regular slow waves causing ripples, and (iii) a wax and wane pattern that may lead to segmentation. Different intra- and extra-luminal inputs probably determine the dominating motor pattern in each area through the enteric nervous system.


Patterns of recurrence and long-term survival after curative resection of localized fibrous tumors of the pleura.
Localized fibrous tumors of the pleura (LFTPs) are uncommon thoracic neoplasms with variable malignant potential that were previously classified as benign presentation of mesothelioma. We investigate the clinical presentation, recurrence patterns, and long-term survival of patients undergoing curative resection of LFTPs. Thirty-four patients underwent resection of LFTPs in the present study. There were 20 women and 14 men with a median age of 59 years (range, 35-81 years). The malignant potential of the tumor was estimated through histologic assessment of the degree of cellularity, mitotic activity, and nuclear pleomorphism. Patients' clinical outcomes were correlated to pathologic findings. Seventeen patients (50%) were symptomatic, and 7 tumors (21%) were considered malignant by histologic characteristics. Ipsilateral pleural recurrence remote to the original tumor site occurred in 6 of these patients with malignant microscopic characteristics at a mean of 9 months after resection. Repeated resection was accomplished in 3 of these patients (range, 3-8 repeat operations). There have been no recurrences among the other 27 patients with benign histologic features, and 31 patients remain alive at a median follow-up of 34.5 months. Histologic characteristics are helpful in estimating the risk of recurrence among patients with LFTPs. Close surveillance is recommended for patients with malignant histologic characteristics. Local recurrence is common without evidence of systemic spread among such patients. Surgical resection is definitive therapy; however, patients with tumors with histologic atypia require close postoperative observation because of the frequency of locoregional recurrence.


Autophagy and autophagy-related proteins in the immune system.
Autophagy is an intracellular bulk degradation system that is highly conserved in eukaryotes. The discovery of autophagy-related ('ATG') proteins in the 1990s greatly advanced the mechanistic understanding of autophagy and clarified the fact that autophagy serves important roles in various biological processes. In addition, studies have revealed other roles for the autophagic machinery beyond autophagy. In this Review, we introduce advances in the knowledge of the roles of autophagy and its components in immunity, including innate immunity, inflammatory responses and adaptive immunity.


Prevalence of multimorbidity according to the deprivation level among the elderly in the Basque Country.
Multimorbidity is clearly a major challenge for healthcare systems. However, currently, its magnitude and impact on healthcare expenditures is still not well known. The objective of this paper is to present an overview of the prevalence of multimorbidity by deprivation level in the elderly population of the Basque Country. We conducted a cross-sectional analysis that included all the inhabitants of the Basque Country aged 65 years and over (N = 452,698). This was based on data from primary care electronic medical records, hospital admissions, and outpatient care databases, for a 4-year period. The health problems of the patients were identified from their diagnoses and prescriptions. Multimorbidity was defined as the presence of two or more chronic diseases out of a list of 47 of the most important and common chronic conditions consistent with the literature. In addition, we explored socio-economic and demographic variables such as age, sex, and deprivation level. Multimorbidity was found in 66.13% of the population aged 65 and over and increases with age until 80 years. The prevalence of multimorbidity was higher in deprived (69.94%) than better-off (60.22%) areas. This pattern of differences between the most and least disadvantaged areas was observed in all age groups and more marked in female (70.96-59.78%) than in male (68.54-60.86%) populations. In almost all diseases studied (43 out of 47), 90% of patients had been diagnosed with at least one other illness. It was also frequent the coexistence of mental and physical health problems in the same person and the presence of multiple physical diseases is higher in patients with mental disease than in the rest of population (74.97% vs. 58.14%). Multimorbidity is very common among people over 65 years old in the Basque Country, particularly in unfavourable socioeconomic environments. Given the ageing population, multimorbidity and its consequences should be taken into account in healthcare policy, organization of care and medical research. Administrative health databases are readily available sources of a range of information that can be useful for such purposes.


Infectious complications in patients receiving mobilization chemotherapy for autologous peripheral blood stem cell collection.
The purpose of this retrospective study was to evaluate infectious complications in patients receiving mobilization chemotherapy for stem cell collection prior to autologous peripheral blood stem cell transplantation. An additional goal was to evaluate risk factors associated with the development of infectious complications. At the Medical College of Georgia BMT center, 54 patients were administered mobilization chemotherapy for the purpose of collecting stem cells between June, 1997, and May, 2002. All patients received Filgrastim in addition to chemotherapy, and 50 of 54 patients received prophylactic acyclovir, fluconazole, and ciprofloxacin until neutrophil recovery. The median duration to neutrophil recovery was 11 days. Fourteen of 54 (26%) patients developed fever/infections during the mobilization phase. One patient developed both a catheter-related infection and Clostridium difficile colitis, increasing the total number of infectious episodes to 15. Twelve patients had a documented site of infection whereas 2 patients had neutropenic fever with no identifiable source. Eight of the 15 (55%) infections were Gram-positive catheter infections. All the patients were treated successfully with antibiotics. No systemic fungal infections were identified and none of the patients died from complications related to mobilization chemotherapy. Logistic regression was applied for univariate and multivariate analysis and showed that age, sex, diagnosis, neutrophil recovery, disease status, use of salvage chemotherapy, and mobilization regimen used did not affect the infection rate. In our series of 54 patients, 14 patients developed fever/infections during mobilization. Although there is a substantial risk of infectious complications among patients who receive mobilization chemotherapy, it is not clear that prophylactic antibiotics decrease infectious complications. Because the vast majority of infections are Gram-positive catheter infections, it appears reasonable to employ Gram-positive prophylaxis. Controlled studies should be conducted to define the optimum mobilization regimens as well as the optimum combination of prophylactic antibiotics.


Multifractal zone plates.
We present multifractal zone plates (MFZPs) as what is to our knowledge a new family of diffractive lenses whose structure is based on the combination of fractal zone plates (FZPs) of different orders. The typical result is a composite of two FZPs with the central one having a first-order focal length f surrounded by outer zones with a third-order focal length f. The focusing properties of different members of this family are examined and compared with conventional composite Fresnel zone plates. It is shown that MFZPs improve the axial resolution and also give better performance under polychromatic illumination.


[Second transplantation for graft failure after allogeneic hematopoietic stem cell transplantation--a retrospective survey by Kanto Study Group for Cell Therapy].
We retrospectively surveyed patients who received a second transplantation for graft failure (GF) after allogeneic hematopoietic stem cell transplantation (SCT) in hospitals participating in the Kanto Study Group for Cell Therapy. A second SCT was performed in 21 of 45 patients with primary GF and in 13 of 15 with secondary GF. The median time between the first and second SCT was 49 days (range, 18-1204 days). The diagnosis included 28 patients with hematologic malignancies and 6 with aplastic anemia. Non-myeloablative or reduced-intensity conditioning was performed in 30 patients. Cord blood was frequently used as the source of stem cells followed by related donor peripheral blood, and unrelated bone marrow. Engraftment was achieved in 23 patients (68%). Conditioning regimen including total body or total lymphoid irradiation, was significantly associated with a higher engraftment rate. Overall survival at 5 years in all patients who underwent second SCT was 34%. Prognostic factors for better survival after second SCT were a time to second SCT longer than 90 days, the performance status at second SCT with 0 or 1, and the administration of tacrolimus for GVHD prophylaxis. The major cause of death after second SCT was infection. Although the outcome of a second SCT for graft failure remains poor, these findings suggest that the selection of patients as well as transplant methods, such as conditioning and GVHD prophylaxis, may contribute to survival.


Hippuric acid in 24-hour urine collections is a potential biomarker for fruit and vegetable consumption in healthy children and adolescents.
An objective noninvasive biomarker for fruit and vegetable (FV) consumption would help to more reliably characterize the relationship between FV intake and health status in observational studies. Because increases in urinary hippuric acid (HA) were observed after consumption of several FV varieties, we aimed to investigate whether 24-h urinary HA may represent a potential biomarker for FV consumption in children and adolescents. The association of FV and juice (FVJ) intake calculated from 3-d weighed dietary records with 24-h urinary HA excretion was analyzed in 240 healthy children and adolescents and compared with associations of the established biomarkers urinary nitrogen (uN) and urinary potassium (uK) with protein and potassium intake, respectively. Spearman correlation coefficients (r) and cross-classifications were calculated for all diet-biomarker associations. Potential confounders for the HA-FVJ association were examined in linear regression models. In children, correlations of HA with FVJ (r = 0.62), uN with protein (r = 0.64), and potassium intake with uK (r = 0.65) were comparable. In adolescents, the HA-FVJ association was weaker (r = 0.41) compared with the biomarkers uN (r = 0.60) and uK (r = 0.58) (all P < 0.0001). Cross-classification into the same/adjacent quartile by dietary and urinary data were >85% for all analyzed comparisons except for a 75% classification agreement between HA and FVJ in adolescents. Unadjusted and adjusted linear regression models indicated significant (P < 0.0001) HA-FVJ associations in both age groups. FVJ explained more of the variability in HA excretion in children (R(2) = 0.38) than in adolescents (R(2) = 0.22). Our findings in children showing HA-FVJ associations comparable to those for well-established biomarkers with their respective dietary intakes suggest that HA may represent a useful biomarker for FVJ.


Permeability of root dentin to epinephrine released from gingival retraction cord.
The permeation of racemic epinephrine across roots of human molar crown segments was studied in vitro. Permeation was measured in the presence of cementum, with cementum removed (dentin exposed), and with and without dentin smear layers. Epinephrine was initially detected at 10 minutes and reached a steady state in 70 minutes. Epinephrine flux (the product of concentration and the flow rate per unit of dentin surface area) significantly increased when both the cementum and dentin smear layers were removed. The T1/2 (half-time in minutes necessary to reach steady-state diffusion) was zero with intact cementum and increased to approximately 40 minutes in dentin with and without smear layers. This study suggests that the permeation of epinephrine across root surfaces is prevented by the presence of cementum and retarded by the presence of dentin smear layers. Also, the data suggest that root dentin is another source of absorption when epinephrine-impregnated retraction cord is applied to the gingival sulcus.


Consumption of nutrients and insulin resistance suppress markers of bone turnover in subjects with abdominal obesity.
Abdominal obesity and type 2 diabetes are associated with insulin resistance and low bone turnover along with an increased fracture risk. The mode of action is poorly understood. The bone resorption marker, C-terminal telopeptide type 1 collagen (CTX), and to a lesser extent, the bone formation marker, Procollagen type 1 N-terminal propeptide (P1NP) appear to be inhibited by food consumption. The link between food consumption, insulin resistance and bone turnover remains to be clarified. Primarily we aimed to compare the postprandial CTX, P1NP and PTH responses by two frequently applied methods in assessing metabolic health; oral glucose tolerance test (OGTT) and mixed meal tolerance test. Secondly, we explored the effect of insulin resistance on bone marker responses. We enrolled 64 subjects with abdominal obesity. Following 10 h of fasting, subjects initially underwent a standard OGTT (300 kcal) and approximately one week later a mixed meal tolerance test (1130 kcal). Circulating CTX, P1NP and PTH were assessed on both days at time = 0, after 30 min and after 90 min for comparison of the two interventions. We analyzed glucose and insulin levels for the assessment of insulin resistance. Additionally, we measured plasma calcium levels along with the gut hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like-peptide 2 (GLP-2) in an attempt to identify possible mediators of the postprandial bone response. CTX, P1NP and PTH were suppressed by OGTT and the mixed meal; the latter induced a more pronounced suppression after 90 min. Calcium levels were similar between OGTT and meal. GIP and GLP-2 levels increased after both interventions, although only the meal induced a sustained increase after 90 min. Fasting P1NP was inversely associated with insulin resistance. The meal-induced suppression of P1NP (but not CTX or PTH) was inversely associated with level of insulin resistance. The acute postprandial suppression of bone turnover markers is extended after ingestion of a mixed meal compared to an OGTT. The response appears to be independent of gender and prompted by a reduction in PTH. The study additionally indicates a possible link between the development of insulin resistance and low bone turnover - which may be of key essence in the development of the fragile bone structure and increased fracture risk demonstrated in subjects with abdominal obesity and T2D.


Vascular surgery within general surgery: an analysis of workload 1989-2005.
There is considerable debate as to whether vascular surgery should be a subspecialty separate from general surgery. This study examines the changing relationship between general and vascular surgery in a district general surgical unit over 16 years. A detailed survey of referrals, admissions and operations to one unit was carried out over 3 months in 2003. This was compared with similar surveys in 1989, 1990 and 1995. In addition a 3-month audit of operations performed was carried out in 2005 following a decision by the Primary Care Trust (PCT) to reduce varicose vein referrals. There was a significant increase in the number of varicose vein and arterial referrals 1989-2003 (P = 0.0001 and P < 0.0001, respectively). This was reflected in increased number of vascular admissions (P < 0.0001). In 1989, 14% of the arterial cases were admitted as emergencies. This figure rose to 52% in 2003 (P < 0.0001). There was a significant increase in the number of arterial operations performed between 1989 and 1995; however, from 1995 to 2003 this number fell P < 0.0001). The number of varicose vein procedures increased significantly 1989-2003 (P < 0.0001), with a significant fall after the PCT decision (P < 0.0001). However, the number of operations carried out in 2005 increased slightly with the proportion of general surgical cases, mostly hernia repairs and laparoscopic cholecystectomies, increasing. With increasing specialisation comes the risk that reduction in any aspect of a particular specialty may result in that unit becoming unsustainable. In vascular surgery this will inevitably lead to centralisation of services. In a large district general hospital having two general surgeons with a vascular interest, the general surgical component has maintained the workload of the unit following reduction in varicose vein referrals.


Atypical manifestations and poor outcome of herpes simplex encephalitis in the immunocompromised.
To characterize clinical features, neuroimaging, and outcomes of herpes simplex encephalitis (HSE) in immunocompromised individuals. We performed a retrospective case control review of patients diagnosed with HSE. Adult patients were dichotomized into immunocompromised (n = 14) and immunocompetent groups (n = 15). Fewer immunocompromised patients presented with prodromal symptoms and focal deficits. While the majority of CSF profiles in the immunocompromised patients were mononuclear cells predominant, 3 had polymorphonuclear predominance and another 3 had normal profiles. MRI showed widespread cortical involvement, with brainstem or cerebellar involvement in some. Two immunocompromised patients had recurrent HSE. The immunosuppressed state was associated with a decrease in Karnofsky Performance Status Scale (KPSS) score of 23.1 (p = 0.018). Every 1-day delay in initiation of acyclovir was associated with a decrease in KPSS of 10.2 (p = 0.002), and every 10 cell/mm(3) increase of CSF leukocytosis was associated with an increase in KPSS of 0.7 (p = 0.009). Mortality rate was 6 times higher in the immunocompromised patients. Immunocompromised states may predispose to HSE with atypical clinical and neuroradiologic features. Immunocompromised individuals with HSE have significantly worse outcomes and mortality. Early diagnosis and treatment is associated with improved outcome. The findings are particularly important in light of the increasing use of potent immunosuppressive and immunomodulatory therapies.


Harmine promotes periodontal ligament cell-induced tissue regeneration.
to investigate whether harmine has a promotive effect on human periodontal ligament cells (hPDLCs)-induced tissue regeneration. Various concentrations of harmine on hPDLCs proliferation were tested. Osteogenic and cementogenic characteristics were examined in hPDLC/rhBMP-2 and hPDLC/harmine by alizarin red S staining, real-time PCR, and Western blotting assay. The activity of harmine was investigated in an ectopic transplantation nude mouse model. We determined that 10 μM of harmine was the threshold concentration. hPDLC/harmine showed similar mineralized nodule formation in alizarin S staining compared to hPDLC/rhBMP-2. In real-time PCR, the highest gene expression level was observed for Runx2 in hPDLC/harmine at all time points. The level of CEMP-1 in hPDLC/harmine was higher at 7 days than hPDLCs alone. Thicker band of Runx2 in hPDLC/harmine was observed than in hPDLC/rhBMP-2 at 7 days by Western blotting. The band for CEMP-1 in hPDLC/harmine was thicker than hPDLCs alone at both 7 and 14 days. In ectopic transplantation, hPDLCs with harmine showed a comparable amount of mineralized tissue formation compared to rhBMP-2. hPDLCs with harmine or rhBMP-2 formed both bone and cementum-like tissue with Sharpey's fiber-like collagen insertion. Harmine can be a potential candidate for promoting hPDLCs-induced tissue regeneration.


Psychosocial profiles of patients with burning mouth syndrome.
Burning mouth syndrome (BMS) is estimated to affect 1 to 5% of the adult population, with women experiencing symptoms more frequently than men. The purpose of this study was to examine the psychosocial profiles of BMS patients to determine whether psychologic factors are related to pain reports. Based on previous literature, it was hypothesized that patients with BMS would be characterized by clinical elevations on standardized psychologic assessment instruments that included the Revised Symptom Checklist (SCL-90R) and the Multidimensional Pain Inventory (MPI). Thirty-three BMS patients completed the McGill Pain Questionnaire, MPI, and SCL-90R during their initial clinical evaluation session. The SCL-90R and MPI data were then summarized and presented in standardized format (T-scores) to enable meaningful comparisons with larger population samples that included both a chronic pain population and a normal nonclinical sample. The T-score for the overall pain severity on the MPI was 40.8 (SD 12.8). For the entire BMS sample, there was no evidence for significant clinical elevations on any of the SCL-90R subscales, including depression, anxiety, and somatization. Moreover, patients reported significantly fewer disruptions in normal activities as a result of their oral burning pain than did a large sample of chronic pain patients. These findings indicate that, as a group, this sample of BMS patients did not report significant psychologic distress. There were, however, individual cases (7 of 33, or 21%) where psychometric data indicated a likelihood of psychologic distress, and further evaluation by a competent health professional would be warranted for those individuals.


Optimization of probe geometry for diffuse optical brain imaging based on measurement density and distribution.
Optode geometry plays an important role in achieving both good spatial resolution and spatial uniformity of detection in diffuse-optical-imaging-based brain activation studies. The quality of reconstructed images for six optode geometries were studied and compared using a laboratory tissue phantom model that contained an embedded object at two separate locations. The number of overlapping measurements per pixel (i.e., the measurement density) and their spatial distributions were quantified for all six geometries and were correlated with the quality of the resulting reconstructed images. The latter were expressed by the area ratio (AR) and contrast-to-noise ratio (CNR) between reconstructed and actual objects. Our results revealed clearly that AR and CNR depended on the measurement density asymptotically, having an optimal point for measurement density beyond which more overlapping measurements would not significantly improve the quality of reconstructed images. Optimization of probe geometry based on our method demonstrated that a practical compromise can be attained between DOI spatial resolution and measurement density.


Socioeconomic and partner status in chronic heart failure: Relationship to exercise capacity, quality of life, and clinical outcomes.
Prognosis in patients with heart failure (HF) is commonly assessed based on clinical characteristics. The association between partner status and socioeconomic status (SES) and outcomes in chronic HF requires further study. We performed a post hoc analysis of HF-ACTION, which randomized 2,331 HF patients with ejection fraction ≤35% to usual care ± aerobic exercise training. We examined baseline quality of life and functional capacity and outcomes (all-cause mortality/hospitalization) by partner status and SES using adjusted Cox models and explored an interaction with exercise training. Outcomes were examined based on partner status, education level, annual income, and employment. Having a partner, education beyond high school, an income >$25,000, and being employed were associated with better baseline functional capacity and quality of life. Over a median follow-up of 2.5 years, higher education, higher income, being employed, and having a partner were associated with lower all-cause mortality/hospitalization. After multivariable adjustment, lower mortality was seen associated with having a partner (hazard ratio 0.91, 95% CI 0.81-1.03, P=.15) and more than a high school education (hazard ratio 0.91, CI 0.80-1.02, P=.12), although these associations were not statistically significant. There was no interaction between any of these variables and exercise training on outcomes (all P>.5). Having a partner and higher SES were associated with greater functional capacity and quality of life at baseline but were not independent predictors of long-term clinical outcomes in patients with chronic HF. These findings provide information that may be considered as potential variables impacting outcomes.


Reliability and validity of the Leuven Perceptual Organization Screening Test (L-POST).
Neuropsychological tests of visual perception mostly assess high-level processes like object recognition. Object recognition, however, relies on distinct mid-level processes of perceptual organization that are only implicitly tested in classical tests. Furthermore, the psychometric properties of the existing instruments are limited. To fill this gap, the Leuven perceptual organization screening test (L-POST) was developed, in which a wide range of mid-level phenomena are measured in 15 subtests. In this study, we evaluated reliability and validity of the L-POST. Performance on the test is evaluated relative to a norm sample of more than 1,500 healthy control participants. Cronbach's alpha of the norm sample and test-retest correlations for 20 patients provide evidence for adequate reliability of L-POST performance. The convergent and discriminant validity of the test was assessed in 40 brain-damaged patients, whose performance on the L-POST was compared with standard clinical tests of visual perception and other measures of cognitive function. The L-POST showed high sensitivity to visual dysfunction and decreased performance was specific to visual problems. In conclusion, the L-POST is a reliable and valid screening test for perceptual organization. It offers a useful online tool for researchers and clinicians to get a broader overview of the mid-level processes that are preserved or disrupted in a given patient.


Growth kinetics of human cytomegalovirus are altered in monocyte-derived macrophages.
Stimulation of monocytes/macrophages with activated nonadherent cells allows productive nonlytic growth of human cytomegalovirus (HCMV), but the viral replication cycle is delayed relative to replication of HCMV in human fibroblasts. Analysis of infected monocyte-derived macrophage (MDM) mRNA for major immediate-early (MIE 86, 72, and 55) and late (pp65 and gB) gene expression by reverse transcription PCR indicates that transcription peaks at 3 and 7 days postinfection (dpi), respectively. In contrast, in human fibroblast controls, mRNA for MIE and late gene expression peaked at 5 and 48 h postinfection, respectively. Consistent with reverse transcription PCR experiments, double-label antibody experiments first detected MIE antigen expression at 12 h postinfection, peaking at 3 dpi, and late (pp65 or gB) antigen expression at 5 dpi, peaking at 7 dpi. MIE antigen was not detected between 3 and 7 dpi but reappeared and was coexpressed with pp65 in enlarged MDM nuclei at 7 dpi. After 7 dpi, macrophages with numerous vacuoles containing large amounts of pp65 and gB were observed in culture. These vacuoles were frequently seen at cellular contact points, suggesting that cell-to-cell transfer of virus was the major mode of viral transmission. Consistent with this observation, infectious virus was recovered from MDM cellular lysates but not culture supernatant. The delayed growth and compartmentalization of HCMV in macrophages may allow the cell to accommodate the viral replication cycle without cell lysis. In addition, the macrophage may function as a vehicle for cell-to-cell transmission of HCMV.


Occurrence of anti-Neospora caninum antibodies in dogs in rural areas in Minas Gerais, Brazil.
The aim of this study was to determine the frequency of anti-Neospora caninum antibodies and risk factors associated with seropositivity in 240 dogs from rural areas of the Lavras, Belo Horizonte and Nanuque regions, state of Minas Gerais, Brazil. The indirect fluorescence antibody test (IFAT) with a cutoff of 50 was used to assess the frequency of seropositive dogs. The risk factor analysis was performed using the Chi-square test (χ2) and multiple logistic regression. The frequency of seropositivity for N. caninum was 15% of the dogs (36/240). Presence of dogs without defined breed (p = 0.018; OR = 5.9) and presence of cattle on the farm (p = 0.053, OR = 4.3) were associated with N. caninum seropositivity. Dogs in the Nanuque region had higher seropositivity for N. caninum (29.9%) than did those in the Lavras (6.2%) and Belo Horizonte (2.2%) regions (p < 0.05). The presence of seropositive dogs in rural areas of Minas Gerais demonstrates the potential risk of horizontal transmission of N. caninum to cattle, especially from dogs without defined breed, which were four times more likely to be seropositive than purebred dogs were.


Post-operative nausea and vomiting in bariatric surgery patients: an observational study.
The risk of post-operative nausea and vomiting (PONV) in patients undergoing bariatric surgery is unclear. The aim of the study was to investigate the risk of PONV and the use and effectiveness of PONV prophylaxis. This prospective observational study included 74 patients undergoing bariatric surgery with total intravenous anaesthesia. Patients were given PONV prophylaxis based on published guidelines and a simplified PONV risk score. Perioperative data were collected and a questionnaire was used at 2, 4, 6, 24, 48 and 72 h after the operation to evaluate PONV. Data are presented as risk (%) with the 95% confidence interval. Sixty five per cent (54-75) of the patients experienced PONV in the first 24 post-operative hours and the risk increased with the number of risk factors for PONV. PONV occurred in 78% (66-87) of women and 26% (12-49) of men during the first 24 h. In relation to the guidelines, one patient received suboptimal PONV prophylaxis, 23% received optimal prophylaxis and 76% supra-optimal prophylaxis. The risk of PONV was 82% (59-94) with optimal prophylaxis and 59% (46-71) with supra-optimal prophylaxis. Of all patients, 34% (24-45) experienced severe PONV in the first 24 h that limited their activity. The incidence of PONV in bariatric surgery patients was high despite a PONV prophylaxis regime following current guidelines. These results cast doubt as to the effectiveness of the usual PONV prophylaxis in this patient group and point to the need for further investigation of PONV prophylaxis and treatment in bariatric surgery patients.


A systematic review of attachment and psychosis: measurement, construct validity and outcomes.
This review sought to identify, summarise and critically evaluate studies that investigated attachment amongst individuals with psychosis. The following computerised databases searched were CINAHL<1980 to December 2012; EMBASE<1980 to December 2012; Ovid MEDLINE (R)<1980 to December 2012; PsychINFO<1980 to December 2012; and Google Scholar<1980 to December 2012. We identified 22 papers describing 21 studies comprising 1453 participants, with a mean age of 35.0 years (range of 12-71 years), of whom 68.4% (n=994) were male. Of our sample, 1112 (76.5%) had a diagnosis of schizophrenia. We found small to moderate associations between greater attachment insecurity (as reflected in anxiety and avoidance) and poorer engagement with services, more interpersonal problems, more avoidant coping strategies, more negative appraisals of parenting experiences and more severe trauma. We also found small to modest associations between attachment insecurity and more positive and negative symptoms and greater affective symptom problems. Attachment theory may be useful as a means of understanding the developmental and interpersonal basis of recovery and adaptation in the context of psychosis. However, further research comprising more representative samples in their first episode and using prospective designs is required.


Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing.
Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10-7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.


Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs.
Subcellular regulation of protein synthesis requires the correct localization of messenger RNAs (mRNAs) within the cell. In this study, we investigate whether the axonal localization of neuronal mRNAs is regulated by extracellular stimuli. By profiling axonal levels of 50 mRNAs detected in regenerating adult sensory axons, we show that neurotrophins can increase and decrease levels of axonal mRNAs. Neurotrophins (nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3) regulate axonal mRNA levels and use distinct downstream signals to localize individual mRNAs. However, myelin-associated glycoprotein and semaphorin 3A regulate axonal levels of different mRNAs and elicit the opposite effect on axonal mRNA levels from those observed with neurotrophins. The axonal mRNAs accumulate at or are depleted from points of ligand stimulation along the axons. The translation product of a chimeric green fluorescent protein-beta-actin mRNA showed similar accumulation or depletion adjacent to stimuli that increase or decrease axonal levels of endogenous beta-actin mRNA. Thus, extracellular ligands can regulate protein generation within subcellular regions by specifically altering the localized levels of particular mRNAs.


ESPRIT: estimating species richness using large collections of 16S rRNA pyrosequences.
Recent metagenomics studies of environmental samples suggested that microbial communities are much more diverse than previously reported, and deep sequencing will significantly increase the estimate of total species diversity. Massively parallel pyrosequencing technology enables ultra-deep sequencing of complex microbial populations rapidly and inexpensively. However, computational methods for analyzing large collections of 16S ribosomal sequences are limited. We proposed a new algorithm, referred to as ESPRIT, which addresses several computational issues with prior methods. We developed two versions of ESPRIT, one for personal computers (PCs) and one for computer clusters (CCs). The PC version is used for small- and medium-scale data sets and can process several tens of thousands of sequences within a few minutes, while the CC version is for large-scale problems and is able to analyze several hundreds of thousands of reads within one day. Large-scale experiments are presented that clearly demonstrate the effectiveness of the newly proposed algorithm. The source code and user guide are freely available at http://www.biotech.ufl.edu/people/sun/esprit.html.


The Role of Prosocialness and Trust in the Consumption of Water as a Limited Resource.
This research analyzes the role of prosocialness and trust in the use of water as a limited resource under situations of competition or cooperation. For this purpose, 107 participants played the role of farmers and made decisions about irrigating their fields in the web-based multiplayer game Irrigania. Before the simulation exercise, participants' prosocialness and trust levels were evaluated and they were randomly assigned to an experimental condition (competition or cooperation). Repeated measures analysis, using the 10 fields and the experimental conditions as factors, showed that, in the cooperation condition, farmers and their villages used a less selfish strategy to cultivate their fields, which produced greater benefits. Under competition, benefits to farmers and their villages were reduced over time. Mediational analysis shows that the selfish irrigation strategy fully mediated the relationship between prosocialness and accumulated profits; prosocial individuals choose less selfish irrigation strategies and, in turn, accumulated more benefit. Moreover, moderation analysis shows that trust moderated the link between prosocialness and water use strategy by strengthening the negative effect of prosocialness on selection of selfish strategies. The implications of these results highlight the importance of promoting the necessary trust to develop prosocial strategies in collectives; therefore, the efficacy of interventions, such as the creation of cooperative educational contexts or organization of collective actions with groups affected by water scarcity, are discussed.


Effect of medicolegal liability on patterns of general and family practice in Canada.
As part of the Federal/Provincial/Territorial Review on Liability and Compensation Issues in Health Care, in 1988 we surveyed Canadian general practitioners and family physicians to determine the effect of liability concerns on their practices in the previous 5 years. Questionnaires were sent to a random, stratified national sample of 1295 physicians, with a response rate of 64.6%. However, a high proportion of the returned questionnaires were ineligible because the physicians were not in general or family practice, were not involved in direct patient care, or had died or moved; thus, the corrected response rate was 50.8%. The newsletter of the Canadian Medical Protective Association was the source of information on liability most frequently cited (by 88.1% of the physicians) and most influential (to 62.4%). Only 15.5% of the physicians cited personal involvement with medicolegal issues as a source of information; the rate was higher for Ontario physicians and those in urban areas generally. A total of 74.6% of the respondents had altered their style of practice in the previous 5 years, and 56.3% reported changes in the scope of their practice. Concern about litigation was the most important reason for changing style of practice and reducing or eliminating administration of anesthesia, whereas lifestyle and other issues along with liability concerns most influenced decisions to reduce obstetric care and emergency department work. Our findings suggest that physicians' perceptions of liability issues have had a profound influence on primary care practice in Canada in the past several years.


Results of a Search for Sub-GeV Dark Matter Using 2013 LUX Data.
The scattering of dark matter (DM) particles with sub-GeV masses off nuclei is difficult to detect using liquid xenon-based DM search instruments because the energy transfer during nuclear recoils is smaller than the typical detector threshold. However, the tree-level DM-nucleus scattering diagram can be accompanied by simultaneous emission of a bremsstrahlung photon or a so-called "Migdal" electron. These provide an electron recoil component to the experimental signature at higher energies than the corresponding nuclear recoil. The presence of this signature allows liquid xenon detectors to use both the scintillation and the ionization signals in the analysis where the nuclear recoil signal would not be otherwise visible. We report constraints on spin-independent DM-nucleon scattering for DM particles with masses of 0.4-5 GeV/c^{2} using 1.4×10^{4} kg day of search exposure from the 2013 data from the Large Underground Xenon (LUX) experiment for four different classes of mediators. This analysis extends the reach of liquid xenon-based DM search instruments to lower DM masses than has been achieved previously.


Coordination of vasomotor responses by the endothelium.
Increases in the diameter of small resistance arteries and arterioles occur secondary to processes that can be dependent or independent of changes in membrane potential. Hyperpolarization reduces the opening of voltage-gated calcium channels and thereby the stimulus for contraction of these resistance vessels. The stimulus for smooth muscle cell (SMC) hyperpolarization can occur directly via opening K(+)-channels expressed within those cells, but can also occur in response to stimulation of endothelial cells (ECs). This endothelium-dependent hyperpolarization (EDH) of smooth muscle often occurs in response to agonists that stimulate a rise in the Ca(2+) concentration of ECs, which in turn can open Ca(2+)-activated K-channels to hyperpolarize the ECs, and if present, patent gap junctions connecting ECs to SMCs (myoendothelial gap junctions) can potentially enable direct electrical coupling. There is also evidence to suggest a diffusible factor or factors hyperpolarizes SMCs (EDHF pathways). Furthermore, whether evoked in ECs or SMCs, hyperpolarization can spread a considerable distance to neighboring cells via gap junctions, causing remote dilatation termed ;spreading' or ;conducted' dilatation. This process is endothelium-dependent and likely relies on both homo- and heterocellular gap junctions. This review will focus on the cross-talk between ECs and SMCs that coordinates the spread of hyperpolarization and thus modulates smooth muscle tone.


The hiiragi gene encodes a poly(A) polymerase, which controls the formation of the wing margin in Drosophila melanogaster.
The hiiragi (hrg) gene plays a key role in the development of the wing margin in Drosophila melanogaster. A mutation in the hrg gene resulted in a decrease in the level of the hrg transcript and was associated with a notched wing phenotype. We report here that the hrg gene encodes a poly(A) polymerase (PAP). The bovine cDNA for PAP type II reversed the phenotype due to mutation of the hrg gene, suggesting that hrg might encode a functional homolog of PAP. A mutation that reduced the enzymatic activity of Hrg failed to reverse the phenotype of hrg mutants, suggesting that the enzymatic activity of Hrg was required to rescue the wing phenotype. The levels of expression of wingless and cut at the presumptive wing margins were reduced in the late third-instar larvae of hrg mutants. These results suggest that the product of hrg is required for the normal expression of a series of genes in this region. Our results provide the first evidence that a PAP in Drosophila plays a key role in the early development of the wing margin, acting to regulate the specific expression of a series of genes via, perhaps, control of the processing of the 3' ends of transcripts.


[Treatment of viral hepatitis in drug addicts].
Management of viral hepatitis in drug uses must follow a multidisciplinary approach within the framework of overall psychosocial, alcohologic, and medical care. Substitution is an important but not indispensable aspect. In patients who have achieved social, psychological and medical stability (possible initiation of antiretroviral treatment), antiviral treatments can be started and followed in the same way as for other patients. Prescriptions should aim at improving the liver disease and avoid progression to cirrhosis and complications. Ribavirin/interferon-alfa appears to be the combination of choice for first line treatment of hepatitis C (while waiting for combinations with protease inhibitors). Anti-HBV vaccination is the treatment of choice for the prevention of hepatitis B and D. Coordination and information sharing between health and social care partners is crucial for the management of these patients.


The newly revised interview for deteriorations in daily living activities in dementia (R-IDDD2): distinguishing initiative from performance at assessment.
Minimal evidence exists on the detailed deficits in complex instrumental activities of daily living (IADLs) in mild dementia. The aim of this study was twofold, to validate a revised questionnaire focusing measuring the initiative and performance of IADLs in mild dementia and to explore the relationship between individual IADLs and patient and carer well-being. A total of 183 carers of people with mild dementia completed a further modified Revised Interview for Deterioration in Daily Living Activities 2 (R-IDDD2), which comprised new activities such as computer use, as well as sub-activities on the performance scale. Carers also completed questionnaires assessing patient quality of life (QoL-AD), carer quality of life (AC-QoL), and burden (GHQ-12). Persons with dementia were significantly poorer initiating than performing cleaning, doing repair work, and preparing a hot or cold meal, whereas being poorer at performing dressing and following current affairs. Using the computer, preparing a hot meal, finance, and medication management were most impaired, whereas more basic activities of dressing, washing oneself, brushing hair or teeth, and preparing a hot drink were most preserved. Poor initiative and performance on nearly all activities were significantly related to reduced carer and patient well-being. The R-IDDD2 offers a platform to comprehensively assess everyday functioning. Deteriorations in initiative and performance need to be targeted separately in interventions, as the former requires effective triggering and the latter structured training and support. Most activities were significantly associated with well-being, particularly patient quality of life so that improving any activity should improve well-being.


Fitness and health of children through sport: the context for action.
A growing body of scientific evidence indicates that the declining levels of physical activity and fitness in children and youth are associated with adverse impacts on their health, including rising levels of obesity, diabetes, heart disease, metabolic syndrome and increased risk of sports injury. In response, a number of governmental and non-governmental organisations have instituted programmes to promote health in children and youth through sports and physical activity. Many of these programmes have achieved success in increasing participation in sports and other forms of physical activity and, by extension, improving the health of these young people. These programmes have also been used successfully to enhance the lives of the young participants by means other than improving physical health.


Competence-induced type VI secretion might foster intestinal colonization by Vibrio cholerae: Intestinal interbacterial killing by competence-induced V. cholerae.
The human pathogen Vibrio cholerae exhibits two distinct lifestyles: one in the aquatic environment where it often associates with chitinous surfaces and the other as the causative agent of the disease cholera. While much of the research on V. cholerae has focused on the host-pathogen interaction, knowledge about the environmental lifestyle of the pathogen remains limited. We recently showed that the polymer chitin, which is extremely abundant in aquatic environments, induces natural competence as a mode of horizontal gene transfer and that this competence regulon also includes the type VI secretion system (T6SS), a molecular killing device. Here, I discuss the putative consequences that chitin-induced T6SS activation could have on intestinal colonization and how the transmission route might influence disease outcome. Moreover, I propose that common infant animal models for cholera might not sufficiently take into account T6SS-mediated interbacterial warfare between V. cholerae and the intestinal microbiota.


Toxicity of cobalt-complexed cyanide to Oncorhynchus mykiss, Daphnia magna, and Ceriodaphnia dubia. Potentiation by ultraviolet radiation and attenuation by dissolved organic carbon and adaptive UV tolerance.
Cobalt cyanide complexes often result when ore is treated with cyanide solutions to extract gold and other metals. These have recently been discovered in low but significant concentrations in effluents from gold leach operations. This study was conducted to determine the potential toxicity of cobalt-cyanide complexes to freshwater organisms and the extent to which ultraviolet radiation (UV) potentiates this toxicity. Tests were also conducted to determine if humic acids or if adaptation to UV influenced sensitivity to the cyanide complexes. Rainbow trout (Oncorhynchus mykiss), Daphnia magna, and Ceriodaphnia dubia were exposed to potassium hexacyanocobaltate in the presence and absence of UV radiation, in the presence and absence of humic acids. Cyano-cobalt exposures were also conducted with C. dubia from cultures adapted to elevated UV. With an LC50 concentration of 0.38 mg/L, cyanocobalt was over a 1000 times more toxic to rainbow trout in the presence of UV at a low, environmentally relevant irradiance level (4 microW/cm2 as UVB) than exposure to this compound in the absence of UV with an LC50 of 112.9 mg/L. Toxicity was immediately apparent, with mortality occurring within an hour of the onset of exposure at the highest concentration. Fish were unaffected by exposure to UV alone. Weak-acid dissociable cyanide concentrations were observed in irradiated aqueous solutions of cyanocobaltate within hours of UV exposure and persisted in the presence of UV for at least 96 hours, whereas negligible concentrations were observed in the absence of UV. The presence of humic acids significantly diminished cyanocobalt toxicity to D. magna and reduced mortality from UV exposure. Humic acids did not significantly influence survival among C. dubia. C. dubia from UV-adapted populations were less sensitive to metallocyanide compounds than organisms from unadapted populations. The results indicate that metallocyanide complexes may pose a hazard to aquatic life through photochemically induced processes. Factors that decrease UV exposure such as dissolved organic carbon or increased pigmentation would diminish toxicity.


Mapping and Modelling the Geographical Distribution and Environmental Limits of Podoconiosis in Ethiopia.
Ethiopia is assumed to have the highest burden of podoconiosis globally, but the geographical distribution and environmental limits and correlates are yet to be fully investigated. In this paper we use data from a nationwide survey to address these issues. Our analyses are based on data arising from the integrated mapping of podoconiosis and lymphatic filariasis (LF) conducted in 2013, supplemented by data from an earlier mapping of LF in western Ethiopia in 2008-2010. The integrated mapping used woreda (district) health offices' reports of podoconiosis and LF to guide selection of survey sites. A suite of environmental and climatic data and boosted regression tree (BRT) modelling was used to investigate environmental limits and predict the probability of podoconiosis occurrence. Data were available for 141,238 individuals from 1,442 communities in 775 districts from all nine regional states and two city administrations of Ethiopia. In 41.9% of surveyed districts no cases of podoconiosis were identified, with all districts in Affar, Dire Dawa, Somali and Gambella regional states lacking the disease. The disease was most common, with lymphoedema positivity rate exceeding 5%, in the central highlands of Ethiopia, in Amhara, Oromia and Southern Nations, Nationalities and Peoples regional states. BRT modelling indicated that the probability of podoconiosis occurrence increased with increasing altitude, precipitation and silt fraction of soil and decreased with population density and clay content. Based on the BRT model, we estimate that in 2010, 34.9 (95% confidence interval [CI]: 20.2-51.7) million people (i.e. 43.8%; 95% CI: 25.3-64.8% of Ethiopia's national population) lived in areas environmentally suitable for the occurrence of podoconiosis. Podoconiosis is more widespread in Ethiopia than previously estimated, but occurs in distinct geographical regions that are tied to identifiable environmental factors. The resultant maps can be used to guide programme planning and implementation and estimate disease burden in Ethiopia. This work provides a framework with which the geographical limits of podoconiosis could be delineated at a continental scale.


Effect of Uric Acid-Lowering Agents on Cardiovascular Outcome in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Clinical Studies.
Several trials have been completed in patients with heart failure (HF) treated with uric acid (UA)-lowering agents with inconsistent results. We aimed to investigate whether lowering UA would have an effect on mortality and cardiovascular (CV) events in patients with HF in a systematic review and meta-analysis. The primary outcome measures were all-cause mortality, CV mortality, CV events, and CV hospitalization in patients with HF. We included 11 studies in our final analysis. Overall, allopurinol treatment was associated with a significant increase in the risk for all-cause mortality (hazard ratio [HR]: 1.24, 95% confidence interval [CI]: 1.04-1.49, P = .02). The trial heterogeneity is high (heterogeneity χ2 = 37.3, I2 = 73%, P < .001). With regard to CV mortality, allopurinol treatment was associated with a 42% increased risk of CV mortality (HR: 1.42, 95% CI: 1.11-1.81, P = .005). There was a trend toward increased CV hospitalization in the same group (HR: 1.21, 95% CI: 0.95-1.53, P = .12). Uric acid-lowering treatments increase all-cause and CV mortality but did not increase CV hospitalization significantly in this study.


Characterisation of natural killer cells and CD56+ T-cells in sarcoidosis patients.
The aim of the current study was to investigate the frequency, phenotype and functional activity of natural killer (NK) cells and CD56+ T-cells in the bronchoalveolar lavage fluid and peripheral blood of patients with pulmonary sarcoidosis when compared with healthy volunteers, using staining with a panel of monoclonal antibodies followed by flow cytometry. The results revealed that the majority of the lung NK cell subpopulation expressed CD56(bright). In contrast, there was a predominant CD56(dim) subset in the blood of both patients and healthy controls. Most lung NK cells expressed C-type lectin-like human leukocyte antigen (HLA)-E-specific inhibitory receptor (i.e. CD94/NKG2A), but only a few lung NK cells expressed killer cell immunoglobulin-like inhibitory receptors specific for HLA-A, -B or -C molecules. In addition, a significantly increased number of CD56+ T-cells were observed in the blood of patients when compared with controls. Upon in vitro stimulation, both lung NK and CD56+ T-cells produced considerable amounts of interferon-gamma and tumour necrosis factor-alpha. Thus, in the lungs of patients with pulmonary sarcoidosis, a distinct phenotype of natural killer cells with the capacity to produce cytokines and actively participate in the T-helper 1-like inflammatory response associated with sarcoidosis was identified.


Effects of two different intensities of aerobic exercise on elderly people with mild cognitive impairment: a randomized pilot study.
To evaluate the effect of different intensities of aerobic exercise on elderly people with mild cognitive impairment. A randomized trial. Residential care homes for elderly people. Forty-eight patients were included in the study. The patients were randomized in three groups. Group A performed aerobic exercise at 40% of heart rate reserve, group B did the same at 60% and group C carried out recreational activities. The duration of the study was three months. Cognitive level and functional ability were assessed by means of the Mini Mental State Examination and the Timed Up and Go test before the intervention, at the end of it and three months later as a follow-up. After completion of the aerobic training programme, the patients' Mini Mental State Examination scores improved marginally (group A from 19.8 ± 5.1 to 20.6 ± 7.3; group B from 20.8 ± 4.6 to 21 ± 5.4). A similar trend was observed for the Timed Up and Go test scores (group A from 18.8 ± 5.3 to 18.5 ± 5 seconds; group B from 15.4 ± 4.2 to 14.3 ± 5.1 seconds). However, no statistically significant differences were found at any time during the evaluation regarding cognitive level and functional autonomy among the three groups. In this pilot study, intensity does not seem to be a determining factor when aerobic exercise is performed by people with mild cognitive impairment.


Prognosis in Moderate and Severe Traumatic Brain Injury: A Systematic Review of Contemporary Models and Validation Studies.
Outcome prognostication in traumatic brain injury (TBI) is important but challenging due to heterogeneity of the disease. The aim of this systematic review is to present the current state-of-the-art on prognostic models for outcome after moderate and severe TBI and evidence on their validity. We searched for studies reporting on the development, validation or extension of prognostic models for functional outcome after TBI with Glasgow Coma Scale (GCS) ≤12 published between 2006-2018. Studies with patients age ≥14 years and evaluating a multi-variable prognostic model based on admission characteristics were included. Model discrimination was expressed with the area under the receiver operating characteristic curve (AUC), and model calibration with calibration slope and intercept. We included 58 studies describing 67 different prognostic models, comprising the development of 42 models, 149 external validations of 31 models, and 12 model extensions. The most common predictors were GCS (motor) score (n = 55), age (n = 54), and pupillary reactivity (n = 48). Model discrimination varied substantially between studies. The International Mission for Prognosis and Analysis of Clinical Trials (IMPACT) and Corticoid Randomisation After Significant Head injury (CRASH) models were developed on the largest cohorts (8509 and 10,008 patients, respectively) and were most often externally validated (n = 91), yielding AUCs ranging between 0.65-0.90 and 0.66-1.00, respectively. Model calibration was reported with a calibration intercept and slope for seven models in 53 validations, and was highly variable. In conclusion, the discriminatory validity of the IMPACT and CRASH prognostic models is supported across a range of settings. The variation in calibration, reflecting heterogeneity in reliability of predictions, motivates continuous validation and updating if clinical implementation is pursued.


Experience Changes How Emotion in Music Is Judged: Evidence from Children Listening with Bilateral Cochlear Implants, Bimodal Devices, and Normal Hearing.
Children using unilateral cochlear implants abnormally rely on tempo rather than mode cues to distinguish whether a musical piece is happy or sad. This led us to question how this judgment is affected by the type of experience in early auditory development. We hypothesized that judgments of the emotional content of music would vary by the type and duration of access to sound in early life due to deafness, altered perception of musical cues through new ways of using auditory prostheses bilaterally, and formal music training during childhood. Seventy-five participants completed the Montreal Emotion Identification Test. Thirty-three had normal hearing (aged 6.6 to 40.0 years) and 42 children had hearing loss and used bilateral auditory prostheses (31 bilaterally implanted and 11 unilaterally implanted with contralateral hearing aid use). Reaction time and accuracy were measured. Accurate judgment of emotion in music was achieved across ages and musical experience. Musical training accentuated the reliance on mode cues which developed with age in the normal hearing group. Degrading pitch cues through cochlear implant-mediated hearing induced greater reliance on tempo cues, but mode cues grew in salience when at least partial acoustic information was available through some residual hearing in the contralateral ear. Finally, when pitch cues were experimentally distorted to represent cochlear implant hearing, individuals with normal hearing (including those with musical training) switched to an abnormal dependence on tempo cues. The data indicate that, in a western culture, access to acoustic hearing in early life promotes a preference for mode rather than tempo cues which is enhanced by musical training. The challenge to these preferred strategies during cochlear implant hearing (simulated and real), regardless of musical training, suggests that access to pitch cues for children with hearing loss must be improved by preservation of residual hearing and improvements in cochlear implant technology.


NOBOX homeobox mutation causes premature ovarian failure.
NOBOX (newborn ovary homeobox gene) is an oocyte-specific homeobox gene that plays a critical role in early folliculogenesis and represents a candidate gene for nonsyndromic ovarian failure. We investigated whether mutations in the NOBOX gene cause premature ovarian failure (POF). We sequenced the NOBOX gene in 96 white women with POF and discovered seven known single-nucleotide polymorphisms and four novel variations, two of which, p.Arg355His and p.Arg360Gln, cause missense mutations in the homeobox domain. Electrophoretic mobility shift assay (EMSA) confirmed that the missense mutation, p.Arg355His, disrupted NOBOX homeodomain binding to NOBOX DNA-binding element (NBE) and had a dominant negative effect on the binding of wild-type NOBOX to DNA. Our findings demonstrate that NOBOX mutations can cause POF.