Mind-body interventions: applications in neurology.
Half of the adults in the United States use complementary and alternative medicine with mind-body therapy being the most commonly used form. Neurology patients often turn to their physicians for insight into the effectiveness of the therapies and resources to integrate them into their care. The objective of this article is to give a clinical overview of mind-body interventions and their applications in neurology. Medline and PsychInfo were searched on mind-body therapies and neurologic disease search terms for clinical trials and reviews and published evidence was graded. Meditation, relaxation, and breathing techniques, yoga, tai chi, and qigong, hypnosis, and biofeedback are described. Mind-body therapy application to general pain, back and neck pain, carpal tunnel syndrome, headaches, fibromyalgia, multiple sclerosis, epilepsy, muscular dysfunction, stroke, aging, Parkinson disease, stroke, and attention deficit-hyperactivity disorder are reviewed. There are several conditions where the evidence for mind-body therapies is quite strong such as migraine headache. Mind-body therapies for other neurology applications have limited evidence due mostly to small clinical trials and inadequate control groups.


Exploring the full spectrum of macrophage activation.
Macrophages display remarkable plasticity and can change their physiology in response to environmental cues. These changes can give rise to different populations of cells with distinct functions. In this Review we suggest a new grouping of macrophage populations based on three different homeostatic activities - host defence, wound healing and immune regulation. We propose that similarly to primary colours, these three basic macrophage populations can blend into various other 'shades' of activation. We characterize each population and provide examples of macrophages from specific disease states that have the characteristics of one or more of these populations.


Art therapy: Using the creative process for healing and hope among African American older adults.
This article provides an introduction to the field of art therapy and the potential it can offer to address the emotional needs of the frail elderly. Two case studies are discussed, and examples of artwork are provided. The case studies and artwork were created under the guidance of an art therapist at a Program of All-Inclusive Care for the Elderly (PACE) site in an urban African American community. This article explores how art making addresses the specific developmental tasks of the elderly in a culturally competent manner. Included are practical considerations in the choice of art media and directives for working with elderly clients, as well as resources for further information on the use of art in therapy.


Opening up animal research and science-society relations? A thematic analysis of transparency discourses in the United Kingdom.
The use of animals in scientific research represents an interesting case to consider in the context of the contemporary preoccupation with transparency and openness in science and governance. In the United Kingdom, organisations critical of animal research have long called for more openness. More recently, organisations involved in animal research also seem to be embracing transparency discourses. This article provides a detailed analysis of publically available documents from animal protection groups, the animal research community and government/research funders. Our aim is to explore the similarities and differences in the way transparency is constructed and to identify what more openness is expected to achieve. In contrast to the existing literature, we conclude that the slipperiness of transparency discourses may ultimately have transformative implications for the relationship between science and society and that contemporary openness initiatives might be sowing the seeds for change to the status quo.


A workflow to process 3D+time microscopy images of developing organisms and reconstruct their cell lineage.
The quantitative and systematic analysis of embryonic cell dynamics from in vivo 3D+time image data sets is a major challenge at the forefront of developmental biology. Despite recent breakthroughs in the microscopy imaging of living systems, producing an accurate cell lineage tree for any developing organism remains a difficult task. We present here the BioEmergences workflow integrating all reconstruction steps from image acquisition and processing to the interactive visualization of reconstructed data. Original mathematical methods and algorithms underlie image filtering, nucleus centre detection, nucleus and membrane segmentation, and cell tracking. They are demonstrated on zebrafish, ascidian and sea urchin embryos with stained nuclei and membranes. Subsequent validation and annotations are carried out using Mov-IT, a custom-made graphical interface. Compared with eight other software tools, our workflow achieved the best lineage score. Delivered in standalone or web service mode, BioEmergences and Mov-IT offer a unique set of tools for in silico experimental embryology.


Prevalence of depressive disorders in men and women enrolled in cardiac rehabilitation.
Epidemiological studies have demonstrated that depression is an independent risk factor for the development and recurrence of coronary heart disease (CHD). The prevalence of depressive disorders, however, is not well documented in CHD patients enrolled in cardiac rehabilitation (CR). The purpose of this study was to estimate the prevalence of current and lifetime depressive disorders in the CR setting. One hundred ten men and women diagnosed with CHD and enrolled in a phase II CR program were screened via a psychiatric, structured interview to assess current and lifetime history of major depressive disorder, minor depression, and dysthymic disorder. A total of 17 (15.5%) individuals screened positive for a current depressive disorder at entry into the CR program, with 10 (9.1%) individuals screening positive for major depressive disorder, 7 (6.4%) for minor depression, and 6 (5.5%) for dysthymic disorder. With respect to lifetime prevalence of mood disorders, 29 (26.4%) individuals met the diagnostic criteria for at least one depressive disorder during their lifetime. The lifetime prevalence of major depressive disorder, minor depression, and dysthymic disorder was 11.8%, 14.5%, and 10.9%, respectively. Female CR participants evidence significantly higher current and lifetime prevalence rates for depressive disorders compared to their male counterparts. The results of this study suggest that a substantial number of CHD patients enrolled in CR report a clinically significant history of depression. Efforts to assess and treat depression are needed in the CR setting and may be associated with better adherence to lifestyle modification programs.


Polarized sorting of beta-amyloid precursor protein and its proteolytic products in MDCK cells is regulated by two independent signals.
Progressive cerebral deposition of the amyloid (A beta) beta-protein is an early and invariant feature of Alzheimer's disease. A beta is derived by proteolysis from the membrane-spanning beta-amyloid precursor protein (beta APP). beta APP is processed into various secreted products, including soluble beta APP (APPs), the 4-kD A beta peptide, and a related 3-kD peptide (p3). We analyzed the mechanisms regulating the polarized basolateral sorting of beta APP and its proteolytic derivatives in MDCK cells. Deletion of the last 32 amino acids (residues 664-695) of the beta APP cytoplasmic tail had no influence on either the constitutive approximately 90% level of basolateral sorting of surface beta APP, or the strong basolateral secretion of APPs, A beta, and p3. However, deleting the last 42 amino acids (residues 654-695) or changing tyrosine 653 to alanine altered the distribution of cell surface beta APP so that approximately 40-50% of the molecules were inserted apically. In parallel, A beta was now secreted from both surfaces. Surprisingly, this change in surface beta APP had no influence on the basolateral secretion of APPs and p3. This result suggests that most beta APP molecules which give rise to APPs in MDCK cells are cleaved intracellularly before reaching the surface. Consistent with this conclusion, we readily detected intracellular APPs in carbonate extracts of isolated membrane vesicles. Moreover, ammonium chloride treatment resulted in the equal secretion of APPs into both compartments, as occurs with other non-membranous, basolaterally secreted proteins, but it did not influence the polarity of cell surface beta APP. These results demonstrate that in epithelial cells two independent mechanisms mediate the polarized trafficking of beta APP holoprotein and its major secreted derivative (APPs) and that A beta peptides are derived in part from beta APP holoprotein targeted to the cell surface by a signal that includes tyrosine 653.


Efficient three-dimensional metric object modeling from uncalibrated image sequences.
This paper presents a scheme that addresses the practical issues associated with producing a geometric model of a scene using a passive sensing technique. The proposed image-based scheme comprises a recursive structure recovery method and a recursive surface reconstruction technique. The former method employs a robust corner-tracking algorithm that copes with the appearance and disappearance of features and a corner-based structure and motion estimation algorithm that handles the inclusion and expiration of features. The novel formulation and dual extended Kalman filter computational framework of the estimation algorithm provide an efficient approach to metric structure recovery that does not require any prior knowledge about the camera or scene. The newly developed surface reconstruction technique employs a visibility constraint to iteratively refine and ultimately yield a triangulated surface that envelops the recovered scene structure and can produce views consistent with those of the original image sequence. Results on simulated data and synthetic and real imagery illustrate that the proposed scheme is robust, accurate, and has good numerical stability, even when features are repeatedly absent or their image locations are affected by extreme levels of noise.


Morals, morale and motivations in data fabrication: Medical research fieldworkers views and practices in two Sub-Saharan African contexts.
Data fabrication, incorrect collection strategies and poor data management, are considered detrimental to high-quality scientific research. While poor data management have been occasionally excused, fabrication constitutes a cardinal sin - scientific misconduct. Scholarly examinations of fabrication usually seek to expose and capture its prevalence and, less frequently, its consequences and causes. Most accounts centre on high-income countries, individual senior researchers and scientists who are portrayed as irrational, immoral or deceptive. We argue that such accounts contain limitations in overlooking data collected in 'the field', in low-income countries, by junior researchers and non-scientists. Furthermore, the processes and motivations for fabrication and subversive practices are under-examined. Drawing on two separate ethnographies, conducted in 2004-2009 in medical research projects in sub-Saharan Africa, this paper investigates fabrication among fieldworkers using data from observations and informal conversations, 68 interviews and 7 Focus Group Discussions involving diverse stakeholders. Based on an interpretative approach, we examined fieldworkers' accounts that fabrications were motivated by irreconcilable moral concerns, faltering morale resulting from poor management, and inadequate institutional support. To fieldworkers, data fabrication constituted a 'tool' for managing their quotidian challenges. Fabrications ranged from active to passive acts, to subvert, resist and readdress tensions deriving from employment inequalities and challenging socio-economic conditions. We show that geographical and hierarchical distance between high-ranking research actors and fieldworkers in contemporary configurations of international medical research can compartmentalise, and ultimately undermine, the relationships necessary to produce high-quality data. In focusing on fieldworkers, we argue for the inclusion of wide-ranging perspectives in examinations of data fabrication.


Outcomes after early splenectomy for hematological disorders.
Acute splenic sequestration crisis is a devastating complication of sickle cell disease that can require prophylactic splenectomy. Historically, splenectomy before 5 years of age was avoided because of fear of overwhelming postsplenectomy sepsis. Recently, splenectomy has been performed as early as 2 years of age, but the safety of this approach is unknown. This study compared outcomes of splenectomy performed in patients under 5 years of age with those 5 years of age and older. A retrospective chart review of patients registered in a children's hospital hematology database was performed to examine intraoperative and postoperative outcomes after splenectomy. Statistical data analysis included Fisher's exact tests for categorical variables and the nonparametric median test for continuous variables. From 1997 to 2012, 30 sickle cell patients underwent splenectomy. At surgery, 18 of the 30 patients were under 5 years of age (Group 1), and 12 patients were 5 years of age or older (Group 2). Almost all procedures were laparoscopic. Both group had similar operative times, rates of conversion, and frequencies of complications. Both groups had similar lengths of follow-up (median, 62 months for Group 1 versus 63 months for Group 2). No portal vein thromboses or postsplenectomy sepsis events occurred in either group. In this study, there was no evidence that the incidence of complications was higher after splenectomy at a younger age. A large, multicenter study is needed to further evaluate the safety of this practice.


Characterizing RNA structures in vitro and in vivo with selective 2'-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq).
RNA molecules adopt a wide variety of structures that perform many cellular functions, including, among others, catalysis, small molecule sensing, and cellular defense. Our ability to characterize, predict, and design RNA structures are key factors for understanding and controlling the biological roles of RNAs. Fortunately, there has been rapid progress in this area, especially with respect to experimental methods that can characterize RNA structures in a high throughput fashion using chemical probing and next-generation sequencing. Here, we describe one such method, selective 2'-hydroxyl acylation analyzed by primer extension sequencing (SHAPE-Seq), which measures nucleotide resolution flexibility information for RNAs in vitro and in vivo. We outline the process of designing and performing a SHAPE-Seq experiment and describe methods for using experimental SHAPE-Seq data to restrain computational folding algorithms to generate more accurate predictions of RNA secondary structure. We also provide a number of examples of SHAPE-Seq reactivity spectra obtained in vitro and in vivo and discuss important considerations for performing SHAPE-Seq experiments, both in terms of collecting and analyzing data. Finally, we discuss improvements and extensions of these experimental and computational techniques that promise to deepen our knowledge of RNA folding and function.


The effects of slow-stroke back massage on minutes of nighttime sleep in persons with dementia and sleep disturbances in the nursing home: a pilot study.
This pilot study tested the effects of a 3-minute slow-stroke back massage (SSBM) on total minutes of nighttime sleep on persons with dementia with sleep disturbances aged 65 years or older in the nursing home. Pilot randomized controlled trial. Participants were randomized to an intervention group (n = 20) who received the 3-minute SSBM or a usual care control condition group (n = 20) who received usual bedtime care. Forty-eight hours of actigraphy data was recorded and analyzed on sleep variables at baseline and postintervention. Descriptive statistics showed a 36-minute increase on minutes of nighttime sleep in the SSBM intervention group (46.1 minutes) compared with the control group (10.32 minutes). Analysis of covariance did not reveal significant differences between the intervention and control groups on minutes of nighttime sleep, F(1, 37) = 1.90, p = .18, partial η(2) = .05, or on other sleep variables. Dose-finding studies are needed to determine the duration of SSBM for sleep promotion. Findings from this pilot study suggest that SSBM may be an effective nursing intervention for sleep in persons with dementia in the nursing home, but further testing is needed to provide definitive results.


An in vivo radiographic evaluation of the accuracy of Apex and iPex electronic Apex locators.
The aim of this study was to evaluate in vivo the clinical applicability of two electronic apex locators (EALs) - Apex (Septodont) and iPex (NSK) - in different groups of human teeth by using radiography. The working lengths (WLs) of 100 root canals were determined electronically. The EAL to be used first was chosen randomly and a K-file was inserted into the root canal until the EAL display indicated the location of the apical constriction (0 mm). The K-file was fixed to the tooth and a periapical radiograph was taken using a radiographic film holder. The K-file was removed and the WL was measured. The same procedure was repeated using the other EAL. Radiographs were examined with the aid of a light-box with lens of ×4 magnification by two blinded experienced endodontists. The distance between the file tip and the root apex was recorded as follows: (A) +1 to 0 mm, (B) -0.1 to 0.5 mm, (C) -0.6 to 1 mm, (D) -1.1 to 1.5 mm, and (E) -1.6 mm or greater. For statistical purposes, these scores were divided into 2 subgroups according to the radiographic apex: acceptable (B, C, and D) and non-acceptable (A and E). Statistically significant differences were not found between the results of Apex and iPex in terms of acceptable and non-acceptable measurements (p>0.05) or in terms of the distance recorded from file tip and the radiographic apex (p>0.05). Apex and iPex EALs provided reliable measurements for WL determination for endodontic therapy.


Variation in Spine Surgeon Selection Criteria Between Neurosurgery and Orthopedic Surgery Patients.
A cross-sectional survey study. The objective of this study is to determine if there are any differences in spine surgeon selection criteria between neurosurgery patients and orthopedic patients. The evolution of the health care delivery system has allowed for increased patient autonomy in provider selection. However, the process and criteria by which patients choose particular spine surgeons is not well understood. Furthermore, differences in physician selection criteria used by patients who present either to a neurosurgery or orthopedic spine surgeon has not been previously established. An anonymous questionnaire consisting of 26 questions was administered to 644 patients seeking treatment from either a single neurosurgery-trained or orthopedics-trained spine surgeon at an urban institution. Four questions pertained to demographic variables. Sixteen questions asked patients to rate specific spine surgeon selection criteria in terms of importance (scale, 1-10). Six questions were multiple choice, asking patients to select their preferences towards aspects of a spine surgeon. Patient responses were compared using χ analysis or Fisher exact test for categorical variables. The 3 most important factors for selecting a spine surgeon were the same for neurosurgery and orthopedic surgery patients: board certification (neurosurgery, orthopedic surgery) (9.07±2.35, 9.22±1.79), in-network provider status (8.01±3.15, 8.09±3.03), and surgeon bedside manner (7.88±2.52, 8.07±2.29). When listing their preference regarding surgeon specialty training, 82.74% of neurosurgery patients and 48.81% of orthopedic surgery patients preferred a surgeon who was trained in neurosurgery. The growth in patient autonomy within the current health care system has emphasized the importance of identifying patient preferences in the physician selection process.Board certification, in-network insurance status, and bedside manner may be the most influential factors for patients in spine surgeon selection irrespective of surgical subspecialty. Patients may also be more likely to seek spine surgeons with neurosurgery training over orthopedic surgery training. The present study provides spine surgeons a framework to improve both patient recruitment and patient satisfaction.


The re-establishment of desiccation tolerance in germinated Arabidopsis thaliana seeds and its associated transcriptome.
The combination of robust physiological models with "omics" studies holds promise for the discovery of genes and pathways linked to how organisms deal with drying. Here we used a transcriptomics approach in combination with an in vivo physiological model of re-establishment of desiccation tolerance (DT) in Arabidopsis thaliana seeds. We show that the incubation of desiccation sensitive (DS) germinated Arabidopsis seeds in a polyethylene glycol (PEG) solution re-induces the mechanisms necessary for expression of DT. Based on a SNP-tile array gene expression profile, our data indicates that the re-establishment of DT, in this system, is related to a programmed reversion from a metabolic active to a quiescent state similar to prior to germination. Our findings show that transcripts of germinated seeds after the PEG-treatment are dominated by those encoding LEA, seed storage and dormancy related proteins. On the other hand, a massive repression of genes belonging to many other classes such as photosynthesis, cell wall modification and energy metabolism occurs in parallel. Furthermore, comparison with a similar system for Medicago truncatula reveals a significant overlap between the two transcriptomes. Such overlap may highlight core mechanisms and key regulators of the trait DT. Taking into account the availability of the many genetic and molecular resources for Arabidopsis, the described system may prove useful for unraveling DT in higher plants.


Excessive fluid intake as a novel cause of proteinuria.
As part of a community screening study to assess the long-term health outcomes among residents of Walkerton, Ontario, after contamination of its municipal water supply by Escherichia coli O157:H7 and Campylobacter in 2000, we identified 100 adults who had proteinuria and polyuria but no medical history or medication use to explain their condition. Fifty-six of the 100 participants underwent both initial and confirmatory urine concentration tests, which showed that their urine osmolality could reach normal levels. We then instructed them to reduce their fluid intake to less than 2 L/d for 1 week. The proteinuria and polyuria were largely reversed by this manoeuvre. We do not know at this time whether the proteinuria associated with excessive fluid intake in these otherwise healthy people will affect their kidney function in the long term.


Neurocognitive predictors of work outcome in recent-onset schizophrenia.
While the role of neurocognitive impairment in predicting functional outcome in chronic schizophrenia is now widely accepted, the results that have examined this relationship in the early phase of psychosis are surprisingly rather mixed. The predictive role of cognitive impairment early in the illness is of particular interest because interventions during this initial period may help to prevent the development of chronic disability. In a University of California, Los Angeles (UCLA) longitudinal study, we assessed schizophrenia patients with a recent first episode of psychosis using a neurocognitive battery at an initial clinically stabilized outpatient point and then followed them during continuous treatment over the next 9 months. Three orthogonal cognitive factors were derived through principal components analysis: working memory, attention and early perceptual processing, and verbal memory and processing speed. All patients were provided a combination of maintenance antipsychotic medication, case management, group skills training, and family education in a UCLA research clinic. A modified version of the Social Adjustment Scale was used to assess work outcome. Multiple regression analyses indicate that the combination of the 3 neurocognitive factors predicts 52% of the variance in return to work or school by 9 months after outpatient clinical stabilization. These data strongly support the critical role of neurocognitive factors in recovery of work functioning after an onset of schizophrenia. Cognitive remediation and other interventions targeting these early cognitive deficits are of major importance to attempts to prevent chronic disability.


A Pilot Study of Lenalidomide Maintenance Therapy after Autologous Transplantation in Relapsed or Refractory Classical Hodgkin Lymphoma.
For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.


Intralymphatic cutaneous anaplastic large cell lymphoma/lymphomatoid papulosis: expanding the spectrum of CD30-positive lymphoproliferative disorders.
Intravascular large B-cell lymphomas and EBV NK/T-cell lymphomas commonly follow an aggressive clinical course. We recently reported an entirely intravascular anaplastic large cell lymphoma (ALCL) in the skin with a surprisingly indolent clinical course; interestingly, this lymphoma involved the lymphatic rather than the blood vasculature. We hypothesized that intravascular skin-limited ALCL is distinct from aggressive systemic intravascular lymphomas in its intralymphatic localization and clinical course. We now describe 18 cases of cutaneous intravascular large cell lymphoproliferations from 4 institutions. All 12 intravascular large T-cell lesions were intralymphatic; the majority (9) were CD30 T-cell lymphoproliferative disorders (TLPDs), 5 further classified as intravascular ALK ALCL. One ALK ALCL and 2 benign microscopic intravascular T-cell proliferations were also intralymphatic. A single case of otherwise typical cutaneous follicle center lymphoma contained intralymphatic centroblasts. The clinical and pathologic characteristics of the CD30 TLPDs were similar to those of their extravascular counterparts, including extralymphatic dermal involvement in a subset, DUSP22-IRF4 translocations in half of tested ALK ALCLs, and associated mycosis fungoides in 1; most were skin-limited at baseline and remained so at relapse. All 5 cases of intravascular large B-cell lymphoma involved the blood vasculature and behaved in a clinically aggressive manner; the ALK ALCL, although intralymphatic, was systemic and clinically aggressive. We propose that cutaneous ALK ALCL and related CD30 ALK TLPDs involving the lymphatics are part of an expanding spectrum of CD30 TLPDs. The identification of intralymphatic as distinct from blood vascular localization may provide critical prognostic and therapeutic information.


Meta-analysis of genome-wide association studies of anxiety disorders.
Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18 000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 × 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 × 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.


A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.
Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.


Heterochromatic position effect at the rosy locus of Drosophila melanogaster: cytological, genetic and biochemical characterization.
This report describes cytological, genetic and biochemical studies designed to characterize two gamma-radiation induced, apparent "underproducer" variants of the rosy locus (ry:3-52.0), ryps1149 and ryps11136. The following observations provide a compelling basis for their diagnosis as heterochromatic position effect variants. They are associated with rearrangements that place heterochromatin adjacent to the rosy region of chromosome 3 (87D). The effect of these mutations on rosy locus expression is subject to modification by abnormal Y chromosome content. The rearrangement alters only the expression of the rosy allele on the same chromosome (cis-acting). The Y chromosome modification is only on the position-affected allele's expression. The recessive lethality associated with the rearrangements relate to specific rosy region vital loci, and for ryps11136, the lethality is not Y chromosome modified. The peptide product of the position-affected allele is qualitatively normal by several criteria. Heterozygous deletion of 87E2-F2 is a suppressor of the rosy position effect. The rosy position effect on XDH production may be assayed in whole larvae and larval fat body tissue as well as in adults.


Antibodies reacting with JCPyV_VP2 _167-15mer as a novel serological marker for JC polyomavirus infection.
JC polyomavirus (JCPyV) is a widespread human polyomavirus that usually resides latently in its host, but can be reactivated under immune-compromised conditions potentially causing Progressive Multifocal Leukoencephalopathy (PML). Detection of antibodies against the major capsid protein VP1 currently is the main marker for assessment of infection with JCPyV. Based on a peptide microarray, peptide JCPyV_VP2_167-15mer was selected and a peptide ELISA was developed for detection of antibodies directed against this peptide. Epitope mapping and computational modelling was performed to further characterize this peptide. In a cohort of 204 healthy subjects it was investigated whether antibodies against JCPyV_VP2_167-15mer were correlated with VP1 serology or urinary viral load. Epitope mapping of peptide JCPyV_VP2_167-15mer showed that the minimal epitope consisted of L173PALTSQEI181 with amino acids P174, L176 and E180 being essential for antibody recognition. Computational analysis was used to predict that this epitope is located at an exposed domain of the VP2 capsid protein, readily accessible for immune recognition upon infection. No correlation could be observed with JCPyV VP1 antibody levels, or urinary viral load. This work indicates that specific antibodies against JCPyV_VP2_167-15mer might be considered as a novel serological marker for infection with JCPyV.


Respiratory syncytial virus hospitalization risk in the second year of life by specific congenital heart disease diagnoses.
Children with hemodynamically significant congenital heart disease (CHD) are at elevated risk of morbidity and mortality due to respiratory syncytial virus (RSV) disease compared to their healthy peers. Previous studies have demonstrated lower RSV hospitalization risk among all children with CHD at 12-23 months of age versus 0-11 months of age. However, RSV hospitalization risk at 12-23 months of age by specific CHD diagnosis has not been characterized. Both case-control and cohort studies were conducted using data from the US National Inpatient Sample from 1997 to 2013 to characterize relative risk of RSV hospitalization among children 12-23 months of age with CHD. Related CHD diagnoses were combined for analysis. Hospitalizations for RSV and unspecified bronchiolitis were described by length of stay, mechanical ventilation use, mortality, and total charges. Over the 17-year period, 1,168,886 live birth hospitalizations with CHD were identified. Multiple specific CHD conditions had an elevated odds ratio or relative risk of RSV hospitalization. Mean total RSV hospitalization charges were significantly higher among children with CHD relative to those without CHD ($19,650 vs $7,939 in 2015 dollars) for this period. Compared to children without CHD, children with Ebstein's anomaly, transposition of the great arteries, aortic stenosis, heterotaxia, and aortic arch anomalies had 367-, 344-, 203-, 117- and 47-fold increased risk of inpatient RSV mortality, respectively. Unspecified bronchiolitis hospitalization odds and relative risk across CHD diagnoses were similar to those observed with RSV hospitalization; however, unspecified bronchiolitis hospitalizations were associated with shorter mean days of stay and less frequently associated with mechanical ventilation or mortality. Among children with more severe CHD diagnoses, RSV disease remains an important health risk through the second year of life. These data can help inform decisions regarding interventions to protect children with CHD from severe RSV disease during their second year of life.


Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine.
Orphenadrine is a drug acting on multiple targets, including muscarinic, histaminic, and NMDA receptors. It is used in the treatment of Parkinson's disease and in musculoskeletal disorders. It is also used as an analgesic, although its mechanism of action is still unknown. Both physiological and pharmacological results have demonstrated a critical role for voltage-gated sodium channels in many types of chronic pain syndromes. We tested the hypothesis that orphenadrine may block voltage-gated sodium channels. By using patch-clamp experiments, we evaluated the effects of the drug on whole-cell sodium currents in HEK293 cells expressing the skeletal muscle (Nav1.4), cardiac (Nav1.5) and neuronal (Nav1.1 and Nav1.7) subtypes of human sodium channels, as well as on whole-cell tetrodotoxin (TTX)-resistant sodium currents likely conducted by Nav1.8 and Nav1.9 channel subtypes in primary culture of rat DRG sensory neurons. The results indicate that orphenadrine inhibits sodium channels in a concentration-, voltage- and frequency-dependent manner. By using site-directed mutagenesis, we further show that orphenadrine binds to the same receptor as the local anesthetics. Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide. Low, clinically relevant orphenadrine concentration produces a significant block of Nav1.7, Nav1.8, and Nav1.9 channels, which are critical for experiencing pain sensations, indicating a role for sodium channel blockade in the clinical efficacy of orphenadrine as analgesic compound. On the other hand, block of Nav1.1 and Nav1.5 may contribute to the proconvulsive and proarrhythmic adverse reactions, especially observed during overdose.


Renal reabsorption of magnesium and calcium by cattle with renal tubular dysplasia.
The concentrations of magnesium and calcium in the serum and urine and their rates of clearance were determined in cattle with renal tubular dysplasia, an autosomal recessive hereditary disease associated with a deletion of the paracellin-1 gene in Japanese Black cattle. There were no significant differences in the serum or urine magnesium concentrations between normal cattle and cattle which were heterozygous or homozygous for the condition. Serum calcium concentrations tended to be lower in the homozygous cattle, and the serum creatinine and urea nitrogen concentrations were significantly higher in the homozygous cattle. The ratio of magnesium:creatinine and the fractional excretion of magnesium were higher in cattle with the disease than in normal cattle. There were no significant differences in urine calcium concentration, the calcium:creatinine ratio, and fractional excretion of calcium between normal cattle and cattle which were homozygous or heterozygous for the condition. The creatinine clearance was significantly lower in the homozygous cattle than in normal cattle. The clearance, excretion rate, reabsorption rate and reabsorption rate:clearance ratio of magnesium in cattle with renal tubular dysplasia were significantly lower than in normal cattle. The clearance rate and reabsorption rate of calcium were also significantly lower in the affected cattle, but the excretion rate and reabsorption rate:clearance of calcium were not different between the normal cattle and the cattle homozygous for the condition. In cattle with the condition the rate of reabsorption of magnesium by the kidneys was low, but the rate of reabsorption of calcium was normal.


Evaluation and error apportionment of an ensemble of atmospheric chemistry transport modeling systems: multivariable temporal and spatial breakdown.
Through the comparison of several regional-scale chemistry transport modeling systems that simulate meteorology and air quality over the European and North American continents, this study aims at (i) apportioning error to the responsible processes using timescale analysis, (ii) helping to detect causes of model error, and (iii) identifying the processes and temporal scales most urgently requiring dedicated investigations. The analysis is conducted within the framework of the third phase of the Air Quality Model Evaluation International Initiative (AQMEII) and tackles model performance gauging through measurement-to-model comparison, error decomposition, and time series analysis of the models biases for several fields (ozone, CO, SO2, NO, NO2, PM10, PM2.5, wind speed, and temperature). The operational metrics (magnitude of the error, sign of the bias, associativity) provide an overallsense of model strengths and deficiencies, while apportioning the error to its constituent parts (bias, variance, and covariance) can help assess the nature and quality of the error. Each of the error components is analyzed independently and apportioned to specific processes based on the corresponding timescale (long scale, synoptic, diurnal, and intraday) using the error apportionment technique devised in the former phases of AQMEII. The application of the error apportionment method to the AQMEII Phase 3 simulations provides several key insights. In addition to reaffirming the strong impact of model inputs (emission and boundary conditions) and poor representation of the stable boundary layer on model bias, results also highlighted the high interdependencies among meteorological and chemical variables, as well as among their errors. This indicates that the evaluation of air quality model performance for individual pollutants needs to be supported by complementary analysis of meteorological fields and chemical precursors to provide results that are more insightful from a model development perspective. This will require evaluaion methods that are able to frame the impact on error of processes, conditions, and fluxes at the surface. For example, error due to emission and boundary conditions is dominant for primary species (CO, particulate matter (PM)), while errors due to meteorology and chemistry are most relevant to secondary species, such as ozone. Some further aspects emerged whose interpretation requires additional consideration, such as the uniformity of the synoptic error being region- and model-independent, observed for several pollutants; the source of unexplained variance for the diurnal component; and the type of error caused by deposition and at which scale.


Serum miRNA-based Prediction of Axillary Lymph Node Metastasis in Breast Cancer.
Sentinel lymph node biopsy (SLNB) is the gold-standard procedure for evaluating axillary lymph node (ALN) status in patients with breast cancer. However, the morbidity of SLNB is not negligible, and the procedure is invasive for patients without ALN metastasis. Here, we developed a diagnostic model for evaluating ALN status using a combination of serum miRNAs and clinicopathologic factors as a novel less-invasive biomarker.Experimental Design: Preoperative serum samples were collected from patients who underwent surgery for primary breast cancer or breast benign diseases between 2008 and 2014. A total of 958 serum samples (921 cases of primary breast cancer, including 630 cases in the no ALN metastasis group and 291 cases in the ALN metastasis group, and 37 patients with benign breast diseases) were analyzed by miRNA microarray. Samples were randomly divided into training and test sets. Logistic LASSO regression analysis was used to construct diagnostic models in the training set, which were validated in the test set. An optimal diagnostic model was identified using a combination of two miRNAs (miR-629-3p and miR-4710) and three clinicopathologic factors (T stage, lymphovascular invasion, and ultrasound findings), which showed a sensitivity of 0.88 (0.84-0.92), a specificity of 0.69 (0.61-0.76), an accuracy of 0.818, and an area under the receiver operating characteristic curve of 0.86 in the test set. Serum miRNA profiles may be useful for the diagnosis of ALN metastasis before surgery in a less-invasive manner than SLNB.


A Qualitative Evaluation of Student Learning and Skills Use in a School-Based Mindfulness and Yoga Program.
Previous studies on school-based mindfulness and yoga programs have focused primarily on quantitative measurement of program outcomes. This study used qualitative data to investigate program content and skills that students remembered and applied in their daily lives. Data were gathered following a 16-week mindfulness and yoga intervention delivered at three urban schools by a community non-profit organization. We conducted focus groups and interviews with nine classroom teachers who did not participate in the program and held six focus groups with 22 fifth and sixth grade program participants. This study addresses two primary research questions: (1) What skills did students learn, retain, and utilize outside the program? and (2) What changes did classroom teachers expect and observe among program recipients? Four major themes related to skill learning and application emerged as follows: (1) youths retained and utilized program skills involving breath work and poses; (2) knowledge about health benefits of these techniques promoted self-utilization and sharing of skills; (3) youths developed keener emotional appraisal that, coupled with new and improved emotional regulation skills, helped de-escalate negative emotions, promote calm, and reduce stress; and (4) youths and teachers reported realistic and optimistic expectations for future impact of acquired program skills. We discuss implications of these findings for guiding future research and practice.


Integrative genomic analysis of aneuploidy in uveal melanoma.
Aneuploidy is a hallmark of cancer and is closely linked to metastasis and poor clinical outcome. Yet, the mechanisms leading to aneuploidy and its role in tumor progression remain poorly understood. The extensive and complex karyotypic abnormalities seen in many solid tumors could hinder the identification of pathogenetically relevant chromosomal alterations. Uveal melanoma is an attractive solid tumor for studying aneuploidy because it is a relatively homogeneous cancer that is highly metastatic and has low nonspecific chromosomal instability. Comparative genomic hybridization and gene expression profiling were used to analyze patterns of aneuploidy in 49 primary uveal melanomas. This analysis was supplemented by a review of cytogenetic findings in 336 published cases. Three prognostically significant tumor subgroups were identified based on the status of chromosomes 3 and 6p. Discrete patterns of chromosomal alterations accumulated in these three subgroups in a nonrandom temporal sequence. Poor clinical outcome was associated with early chromosomal alterations rather than overall aneuploidy. A gene expression signature associated with aneuploidy was enriched for genes involved in cell cycle regulation, centrosome function, and DNA damage repair. One of these genes was PTEN, a tumor suppressor and genomic integrity guardian, which was down-regulated in association with increasing aneuploidy (P = 0.003). The relationship between aneuploidy and poor prognosis may be determined by specific, pathogenetically relevant chromosomal alterations, rather than overall aneuploidy. Such alterations can be identified using integrative genomic methods and may provide insights for novel therapeutic approaches.


Comparing theory-based condom interventions: health belief model versus theory of planned behavior.
This study sought to experimentally manipulate the core constructs of the Health Belief Model (HBM) and the Theory of Planned Behavior (TPB) in order to compare the success of interventions to increase preparatory condom use behavior (i.e., purchasing condoms, talking to a boyfriend or girlfriend about using condoms, and carrying condoms) based on these theories. A total of 258 participants were randomly assigned to one of three computer-based interventions (HBM, TPB, or information-only control). A total of 204 (79.1%) completed follow-up assessments 1 month later. Regression analyses were conducted to determine which set of theoretical constructs accounted for the most variance in behavior at baseline. A series of structural equation models were estimated to determine which constructs were the "active ingredients" of change. The TPB accounted for 32.8% of the variance in risky sexual behavior at baseline, while the HBM only explained 1.6% of the variance. Mediational analyses revealed differential intervention effects on perceived susceptibility, perceived benefits, and attitudes toward condom use. However, it was attitudes toward condom use and condom use self-efficacy that were associated with intentions, which then predicted preparatory condom use behavior at follow-up. Except for attitudes, the mediators that were successfully manipulated by the interventions (i.e., perceived susceptibility, perceived severity, and attitudes) were not the same constructs that predicted intentions (i.e., attitudes and condom use self-efficacy), and subsequently predicted behavior. This suggests that the constructs that explain behavior are not the same as those that produce behavior change.


Inflammatory breast cancer: no longer an absolute contraindication for breast conservation surgery following good response to neoadjuvant therapy.
Inflammatory breast cancer (IBC) is a rare form of breast cancer characterised by an erythematous swollen breast with extensive oedema and has in the past been associated with a very poor prognosis. After diagnosis by core biopsy of the cancer and any involved nodes patients in the Edinburgh Breast Unit (EBU) are primarily managed with neoadjuvant systemic therapy-chemotherapy or endocrine therapy. If the cancer is localised to one or a few well defined lesions then each of these lesions together with the lowest involved node are clipped. Response during neoadjuvant treatment is monitored clinically and by ultrasound plus mammography +/- magnetic resonance imaging (MRI). Following completion of neoadjuvant therapy, imaging is reviewed at a multidisciplinary meeting and patients with a localised single or multiple areas of cancer where all signs of erythema and oedema have settled are considered as to their suitability for breast conserving surgery and whole breast radiotherapy [breast conserving treatment (BCT)]. Here we discuss the results and outcomes of a selected group of patients with IBC who after obtaining a very good response to neoadjuvant chemotherapy or endocrine therapy were treated by BCT and we compare these with other recent publications on this topic. Our data show that patients treated by BCT did not have worse outcomes than patients treated with mastectomy. Importantly other series published recently support our conclusions. Another important observation is that response in estrogen receptor (ER) rich IBC is seen with neoadjuvant endocrine treatment and so not everyone with IBC needs to have neoadjuvant chemotherapy. In conclusion, patients with one or more well defined and localised breast masses and IBC may be suitable for BCT after a major response to neoadjuvant therapy and for these patients BCT should now be considered a viable option.


A Case Study of the Technology Use and Information Flow at a Hospital-Driven Telemedicine Service.
Health care services face the challenge of providing individualised treatment to a growing ageing population prone to chronic conditions and multi-morbidities. The research project Patients and Professionals in Productive Teams aims to study health care services that are run with a patient-centred teamwork approach. In this context, a case study was made of a hospital-driven telemedicine service for chronic obstructive pulmonary disease patients after hospital discharge, with a focus on information flow and technology use. The methods used were observation and interviews with key informants. The results showed that the technology was perceived as well-functioning for telemedicine support, but the technology used was a standalone system and not integrated with the electronic health record of the hospital. In addition, there was lack of support to provide the patients at home with written instructions on advices of medical treatment and care. The electronic information used for this telemedicine services, allowed shared access of information for teamwork between professional only within the hospital.


Y chromosomal DNA variation and the peopling of Japan.
Four loci mapping to the nonrecombining portion of the Y chromosome were genotyped in Japanese populations from Okinawa, the southernmost island of Japan; Shizuoka and Aomori on the main island of Honshu; and a small sample of Taiwanese. The Y Alu polymorphic (YAP) element is present in 42% of the Japanese and absent in the Taiwanese, confirming the irregular distribution of this polymorphism in Asia. Data from the four loci were used to determine genetic distances among populations, construct Y chromosome haplotypes, and estimate the degree of genetic diversity in each population and on different Y chromosome haplotypes. Evolutionary analysis of Y haplotypes suggests that polymorphisms at the YAP (DYS287) and DXYS5Y loci originated a single time, whereas restriction patterns at the DYS1 locus and microsatellite alleles at the DYS19 locus arose more than once. Genetic distance analysis indicated that the Okinawans are differentiated from Japanese living on Honshu. The data support the hypotheses that modern Japanese populations have resulted from distinctive genetic contributions involving the ancient Jomon people and Yayoi immigrants from Korea or mainland China, with Okinawans experiencing the least amount of admixture with the Yayoi. It is suggested that YAP+ chromosomes migrated to Japan with the Jomon people > 10,000 years ago and that a large infusion of YAP- chromosomes entered Japan with the Yayoi migration starting 2,300 years ago. Different degrees of genetic diversity carried by these two ancient chromosomal lineages may be explained by the different life-styles (hunter-gatherer versus agriculturalist). of the migrant groups, the size of the founding populations, and the antiquities of the founding events.


Timing of Antiretroviral Treatment, Immunovirologic Status, and TB Risk: Implications for Testing and Treatment.
Tuberculosis (TB) risk and mortality increase in the 6 months after highly active antiretroviral therapy (HAART) initiation. This short-term risk may be a consequence of HAART initiation and immune reconstitution. Alternatively, it may be due to confounding by low CD4 counts and high HIV viral loads (VLs). We assessed the TB risk before and after HAART initiation while appropriately controlling for time-updated laboratory values and HAART exposure. We conducted an observational cohort study among persons enrolled in the North American AIDS Cohort Collaboration on Research and Design from 1998 through 2011. A marginal structural model was constructed to estimate the association of HAART initiation and TB risk. Inverse probability weights for the probability of HAART initiation were incorporated. Among 26,342 patients, 94 cases of TB were diagnosed during 147,557 person-years (p-y) of follow-up. The unadjusted TB rates were 93/100,000 p-y [95% confidence interval (CI): 63 to 132] before HAART initiation, 203/100,000 p-y (95% CI: 126 to 311) ≤6 months after HAART initiation, and 40/100,000 p-y (95% CI: 29 to 55) >6 months on HAART. After controlling for time-updated laboratory values, the adjusted odds of TB ≤6 months after HAART initiation and >6 months was 0.65 (95% CI: 0.28 to 1.51) and 0.29 (95% CI: 0.16 to 0.53), respectively. TB risk in the first 6 months after HAART initiation is not higher than that before HAART initiation after adjusting for CD4 count and VLs. These findings suggest that short-term TB risk may be related to low CD4 counts and high VLs near HAART initiation and support early HAART initiation to decrease TB risk.


Personal and collective evaluations of the 2010 health care reform.
The 2010 health care reform law has been as controversial as any piece of American legislation in recent memory. Although numerous polls have been conducted on the public's views of the reform, we do not know much about how citizens evaluated the policy alternatives. Are citizens more focused on how policy affects them personally or how it affects the nation as a whole? Further, are these evaluations made more on the basis of past experience or assessments of how the policy will affect the future? Using an original survey of public opinion administered during the 2009 congressional debate, we examine how these evaluative dimensions (and several other factors) shaped public support for overall reform, for associated policy goals, and for available policy tools. We find evidence that retrospective and prospective collective evaluations mattered most, as did personal prospective assessments, but evidence on personal retrospective factors is somewhat mixed.


A Cluster Randomized Trial of Tailored Breastfeeding Support for Women with Gestational Diabetes.
Women with gestational diabetes mellitus (GDM) and their infants are at increased risk of developing metabolic disease; however, longer breastfeeding is associated with a reduction in these risks. We tested an intervention to increase breastfeeding duration among women with GDM. We conducted a cluster randomized trial to determine the efficacy of a breastfeeding education and support program for women with GDM. Women were enrolled between 22 and 36 weeks of pregnancy and cluster randomized to an experimental lifestyle intervention or wait-list control group. Breastfeeding duration and intensity were prespecified secondary outcomes of the trial. Duration of exclusive and any breastfeeding was assessed at 6 weeks and at 4, 7, and 10 months postpartum. We quantified differences in breastfeeding rates using Kaplan-Meier estimates, log-rank tests, and Cox regression models. We enrolled 100 women, of whom 52% were African American, 31% non-Hispanic white, 11% Hispanic, 9% American Indian or Alaskan Native, 2% Asian, 2% other, and 4% more than one race. In models accounting for within-cluster correlation and adjusted for study site, breastfeeding intention, and African American race, women allocated to the intervention group were less likely to stop breastfeeding (adjusted hazard ratio [HR] 0.40, 95% confidence interval [CI] 0.21-0.74) or to introduce formula (adjusted HR 0.50, 95% CI 0.34-0.72). Our results suggest that targeted breastfeeding education for women with GDM is feasible and efficacious. http://clinicaltrials.gov/ct2/show/NCT01809431.


Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children.
Gastric acidity (GA) inhibitors, including histamine-2 receptor antagonists (H2 blockers) and proton pump inhibitors (PPIs), are the mainstay of gastroesophageal reflux disease (GERD) treatment. A prolonged GA inhibitor-induced hypochlorhydria has been suggested as a risk factor for severe gastrointestinal infections. In addition, a number of papers and a meta-analysis have shown an increased risk of pneumonia in H2-blocker-treated intensive care patients. More recently, an increased risk of community-acquired pneumonia associated with GA inhibitor treatment has been reported in a large cohort of adult patients. These findings are particularly relevant to pediatricians today because so many children receive some sort of GA-blocking agent to treat GERD. To test the hypothesis that GA suppression could be associated with an increased risk of acute gastroenteritis and pneumonia in children treated with GA inhibitors, we conducted a multicenter, prospective study. The study was performed by expert pediatric gastroenterologists from 4 pediatric gastroenterology centers. Children (aged 4-36 months) consecutively referred for common GERD-related symptoms (for example, regurgitation and vomiting, feeding problems, effortless vomiting, choking), from December 2003 to March 2004, were considered eligible for the study. Exclusion criteria were a history of GA inhibitors therapy in the previous 4 months, Helicobacter pylori infection, diabetes, chronic lung or heart diseases, cystic fibrosis, immunodeficiency, food allergy, congenital motility gastrointestinal disorders, neuromuscular diseases, or malnutrition. Control subjects were recruited from healthy children visiting the centers for routine examinations. The diagnosis of GERD was confirmed in all patients by standard criteria. GA inhibitors (10 mg/kg ranitidine per day in 50 children or 1 mg/kg omeprazole per day in 50 children) were prescribed by the physicians for 2 months. All enrolled children were evaluated during a 4-month follow-up. The end point was the number of patients presenting with acute gastroenteritis or community-acquired pneumonia during a 4-month follow-up study period. We obtained data in 186 subjects: 95 healthy controls and 91 GA-inhibitor users (47 on ranitidine and 44 on omeprazole). The 2 groups were comparable for age, gender, weight, length, and incidence of acute gastroenteritis and pneumonia in the 4 months before enrollment. Rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was significantly increased in patients treated with GA inhibitors compared with healthy controls during the 4-month follow-up period. In the GA inhibitor-treated group, the rate of subjects presenting with acute gastroenteritis and community-acquired pneumonia was increased when comparing the 4 months before and after enrollment. No differences were observed between H2 blocker and PPI users in acute gastroenteritis and pneumonia incidence in the previous 4 months and during the follow-up period. On the contrary, in healthy controls, the incidence of acute gastroenteritis and pneumonia remained stable. This is the first prospective study performed in pediatric patients showing that the use of GA inhibitors was associated with an increased risk of acute gastroenteritis and community-acquired pneumonia in GERD-affected children. It could be interesting to underline that we observed an increased incidence of intestinal and respiratory infection in otherwise healthy children taking GA inhibitors for GERD treatment. On the contrary, the majority of the previous data showed that the patients most at risk for pneumonia were those with significant comorbid illnesses such as diabetes or immunodeficiency, and this points to the importance of GA suppression as a major risk factor for infections. In addition, this effect seems to be sustained even after the end of therapy. The results of our study are attributable to many factors, including direct inhibitory effect of GA inhibitors on leukocyte functions and qualitative and quantitative gastrointestinal microflora modification. Additional studies are necessary to investigate the mechanisms of the increased risk of infections in children treated with GA inhibitors, and prophylactic measures could be considered in preventing them.


Characterisation of the laccase-encoding gene abr2 of the dihydroxynaphthalene-like melanin gene cluster of Aspergillus fumigatus.
Aspergillus fumigatus is an important pathogen of the immunocompromised host. Previously, it was shown that the polyketide synthase encoded by the pksP (alb1) gene represents a virulence determinant. pksP is part of a gene cluster involved in dihydroxynaphthalene (DHN)-like melanin biosynthesis. Because a putative laccase-encoding gene (abr2) is also part of the cluster and a laccase was found to represent a virulence factor in Cryptococcus neoformans, here, the Abr2 laccase was characterised. Deletion of the abr2 gene changed the gray-green conidial pigment to a brown color and the ornamentation of conidia was reduced compared with wild-type conidia. In contrast to the white pksP mutant, the susceptibility of the Deltaabr2 mutant against reactive oxygen species (ROS) was not increased, suggesting that the intermediate of DHN-like melanin produced up to the step catalysed by Abr2 already possesses ROS scavenging activity. In an intranasal mouse infection model, the Deltaabr2 mutant strain showed no reduction in virulence compared with the wild type. In the Deltaabr2 mutant, overall laccase activity was reduced only during sporulation, but not during vegetative growth. An abr2p-lacZ gene fusion was expressed during sporulation, but not during vegetative growth confirming the pattern of laccase activity due to Abr2.


Shared and specific independent components analysis for between-group comparison.
Independent component analysis (ICA) has been extensively used in individual and within-group data sets in real-world applications, but how can it be employed in a between-groups or conditions design? Here, we propose a new method to embed group membership information into the FastICA algorithm so as to extract components that are either shared between groups or specific to one or a subset of groups. The proposed algorithm is designed to automatically extract the pattern of differences between different experimental groups or conditions. A new constraint is added to the FastICA algorithm to simultaneously deal with the data of multiple groups in a single ICA run. This cost function restricts the specific components of one group to be orthogonal to the subspace spanned by the data of the other groups. As a result of performing a single ICA on the aggregate data of several experimental groups, the entire variability of data sets is used to extract the shared components. The results of simulations show that the proposed algorithm performs better than the regular method in both the reconstruction of the source signals and classification of shared and specific components. Also, the sensitivity to detect variations in the amplitude of shared components across groups is enhanced. A rigorous proof of convergence is provided for the proposed iterative algorithm. Thus, this algorithm is guaranteed to extract and classify shared and specific independent components across different experimental groups and conditions in a systematic way.


Effects of aging on glomerular function and number in living kidney donors.
To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (≥ 55 years) compared to 33 younger (≤ 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.


Application of a split luciferase complementation assay for the detection of viral protein-protein interactions.
Intraviral protein-protein interactions are critical for virus survival in the host. Discovery of such interactions is important to understand molecular mechanisms of viral replication and pathogenesis. The development of a cell-based assay that can be employed to examine systematically viral protein interactions is described. The method, known as the split luciferase complementation assay (SLCA), is based on the principle that N- and C-terminal domains of luciferase alone do not emit luminescence; however, if fused to interacting proteins the two non-functional halves can be brought into close enough proximity through a specific protein-protein interaction to restore the functions of the enzyme and emit detectable light. The well-studied influenza B polymerase acidic protein (PA) and basic protein 1 (PB1) interaction was used as a model system to develop the assay. Consistent with previous studies, a strong PA-PB1 interaction was demonstrated in the assay. The PA-PB1 interaction was also disrupted by single amino acid mutations in the N-terminal domain of PB1 that is responsible for binding PA. The described SLCA is highly specific and easy to perform, and thus may be useful for studying protein-protein interactions in viral diseases.


[Use of midodrine and frozen semen to treat semen transport disturbances. Report of 2 cases].
Retrograde ejaculation severely compromises male fertility. The use of sympathicomimetics for the treatment of this condition has poor results, except in patients with partial retrograde ejaculation, whose semen has a higher spermatozoa concentration. The semen of two patients with partial retrograde ejaculation was collected and frozen after the injection of a sympathicomimetic (Midodrine). The frozen/thawed samples were mixed with fresh semen recently ejaculated to obtain a minimal number of motile spermatozoa, and used for intrauterine insemination (> de 1 x 10(6) motile spermatozoa/ml). In both cases, pregnancies that developed satisfactorily, were obtained.


Nuclear polarity and nuclear trafficking in Drosophila.
There has been considerable progress in understanding the mechanism of movement of proteins and RNA between the nucleus and cytoplasm in single cells and in vitro. Recently, some components of the nuclear trafficking machinery have also been identified in Drosophila melanogaster allowing the study of phenotypes of mutant trafficking genes during multicellular development. Furthermore,Drosophila has highly polarized cells at a number of different developmental stages and many asymmetrically localized transcripts and proteins that allow the study of nuclear polarity and orientation and its role in mRNA export and cytoplasmic localization.


Specificity of respiratory pathways involved in the reduction of sulfur compounds by Salmonella enterica.
The tetrathionate (Ttr) and thiosulfate (Phs) reductases of Salmonella enterica LT2, together with the polysulfide reductase (Psr) of Wolinella succinogenes, are unusual examples of enzymes containing a molybdopterin active-site cofactor since all formally catalyse sulfur-sulfur bond cleavage. This is in contrast to the oxygen or hydrogen transfer reactions exhibited by other molybdopterin enzymes. Here the catalytic specificity of Ttr and Phs has been compared using both physiological and synthetic electron-donor systems. Ttr is shown to catalyse reduction of trithionate but not sulfur or thiosulfate. In contrast, Phs cannot reduce tetrathionate or trithionate but allows whole cells to utilize elemental sulfur as an electron acceptor. Mechanisms are proposed by which the bacterium is able to utilize an insoluble sulfur substrate by means of reactions at the cytoplasmic rather than the outer membrane.


Molecular hydrogen increases resilience to stress in mice.
The inability to successfully adapt to stress produces pathological changes that can lead to depression. Molecular hydrogen has anti-oxidative and anti-inflammatory activities and neuroprotective effects. However, the potential role of molecular hydrogen in stress-related disorders is still poorly understood. The present study aims to investigate the effects of hydrogen gas on resilience to stress in mice. The results showed that repeated inhalation of hydrogen-oxygen mixed gas [67%:33% (V/V)] significantly decreased both the acute and chronic stress-induced depressive- and anxiety-like behaviors of mice, assessed by tail suspension test (TST), forced swimming test (FST), novelty suppressed feeding (NSF) test, and open field test (OFT). ELISA analyses showed that inhalation of hydrogen-oxygen mixed gas blocked CMS-induced increase in the serum levels of corticosterone, adrenocorticotropic hormone, interleukin-6, and tumor necrosis factor-α in mice exposed to chronic mild stress. Finally, inhalation of hydrogen gas in adolescence significantly increased the resilience to acute stress in early adulthood, which illustrates the long-lasting effects of hydrogen on stress resilience in mice. This was likely mediated by inhibiting the hypothalamic-pituitary-adrenal axis and inflammatory responses to stress. These results warrant further exploration for developing molecular hydrogen as a novel strategy to prevent the occurrence of stress-related disorders.


Early lactation feed intake and milk yield responses of dairy cows offered grass silages harvested at early maturity stages.
The main objective was to evaluate the potential of grass silages of very high quality to support a high milk yield with a low or moderate, or even without concentrate supplementation. Production responses to increased levels of concentrate supplementation with 3 primary growth grass silages differing in digestibility were studied using 66 Norwegian Red dairy cows. Roundbale silage was produced from a timothy-dominated sward at very early (H1), early (H2), and normal (H3) stages of crop maturity. Crops were rapidly wilted (<24h) and a formic acid-based additive was applied. All silages were restrictedly fermented. Silage digestible organic matter in dry matter (DM) values were 747, 708, and 647 g/kg of DM for H1, H2, and H3, respectively. Dietary treatments were fed in a 3×3 factorial arrangement of the 3 silages supplemented with 3 concentrate levels (4, 8, and 12 kg/d) and, additionally, H1 was offered without concentrates and H3 with 16 kg/d, giving a total of 11 diets. Cows, blocked according to parity and calving date, were introduced to the experiment before calving and kept in the experiment until wk 16 of lactation. Silage was offered ad libitum in loose housing and concentrate was available in automatic feed stations. Intake of grass silage when fed as the sole feed was 16.9 kg of DM on average for lactation wk 1 to 16. When H1 was supplemented with 4 or 8 kg of concentrates, silage DM intake did not change, but total DM intake increased to 20.6 and 23.7 kg/d, respectively. Energy-corrected milk (ECM) yield increased from 23.4 kg when H1 was offered without concentrate supplement to 29.1 and 32.8 kg when supplemented with 4 or 8 kg concentrate, respectively. None of the other diets equaled the yield obtained by H1 plus 8 kg of concentrate. Feed intake and yield of cows offered H3 plus 4 kg of concentrates were strongly constrained by high dietary fiber concentration. They consumed 16.5 g of neutral detergent fiber/kg of body weight and spent more time eating silage than cows offered other diets. The highest concentrate level within each silage quality produced similar or lower ECM yield than that with 4 kg less concentrates. The obtained milk yield responses suggest that provision of 8.0, 8.4, and 11.5 kg of concentrates to H1, H2, and H3, respectively, would maximize ECM yield within each silage type. However, H1 may successfully be used with less concentrates, or even without, if future conditions should limit the amount of concentrates available for ruminant production.


Self-efficacy and self-care behaviours among adults with type 2 diabetes.
Type 2 Diabetes Mellitus (T2DM) has an impact on an individuals' health and is influenced by glycemic control. To examine the relationship between glycemic control, demographic and clinical factors on self-efficacy and self-care behaviours among adults with T2DM. A correlational, descriptive study was used. One hundred and forty Omani adults with T2DM were recruited from a public hospital. Data on self-efficacy, self-care behaviours and glycemic control were collected between April and July 2016. The study was approved by the College Ethics Committee and Hospital Board. Bivariate and multivariate analyses were conducted. Most adults had a fasting blood glucose >7.2mmol/L (90.7%), with the majority demonstrating 'uncontrolled' or poor HbA1c of >8% (65%). Variance of self-care behaviour (20.6%) and 31.3% of the variance of the self-efficacy was explained by the age, duration of diabetes, medication, HbA1c and prevention of activities of living. Adults with T2DM with poor glycemic control were more probable to have poor self-efficacy and self-care behaviours. Glycemic control has an effect on improving diet, exercise, medication, foot care efficacy and behaviours. The study recommends using these findings to plan self-efficacy and self-care behaviour to improve glycemic control among adults with T2DM.


Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial.
Tardive dyskinesia results from exposure to dopamine receptor antagonists, such as typical and atypical antipsychotics. If clinically appropriate, clinicians often manage this disorder by lowering the dose of, or discontinuing, the causative drug. There is a significant unmet need for a treatment option that does not disrupt treatment regimens for underlying psychiatric illnesses. We aimed to assess the efficacy, safety, and tolerability of fixed doses of deutetrabenazine-a novel vesicular monoamine transporter-2 inhibitor-in patients with tardive dyskinesia. We did this double-blind, randomised, placebo-controlled, phase 3 trial at 75 centres in the USA and Europe. Patients aged 18-80 years with tardive dyskinesia (≥3 months before screening) were randomly assigned centrally (1:1:1:1), via interactive response technology, to receive one of three fixed doses of deutetrabenazine (12 mg/day, 24 mg/day, or 36 mg/day) or matching placebo. Randomisation was stratified by baseline use of dopamine receptor antagonists. Patients were started on oral deutetrabenazine 12 mg/day, and this dose was increased through week 4 until the randomised dose was achieved, then maintained over 8 weeks. During the treatment period, patients, investigators, their site personnel, and sponsor were masked to group assignment. The primary efficacy endpoint was change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to week 12 in patients with at least one post-baseline rating. The primary efficacy analysis was done in the modified intention-to-treat population (baseline AIMS score ≥6 and at least one post-baseline rating). The safety analysis was done in patients who received any study drug. This trial is registered with ClinicalTrials.gov, number NCT02291861. Between Oct 29, 2014, and Aug 19, 2016, we randomly assigned 298 patients to receive at least one dose of placebo (n=74), deutetrabenazine 12 mg/day (n=75), 24 mg/day (n=74), or 36 mg/day (n=75); 222 patients comprised the modified intention-to-treat population and 293 patients comprised the safety population. From baseline to week 12, the least-squares mean AIMS score improved by -3·3 points (SE 0·42) in the deutetrabenazine 36 mg/day group, -3·2 points (0·45) in the 24 mg/day group, and -2·1 points (0·42) in the 12 mg/day group, with a treatment difference of -1·9 points (SE 0·58, 95% CI -3·09 to -0·79; p=0·001), -1·8 points (0·60, -3·00 to -0·63; p=0·003), and -0·7 points (0·57, -1·84 to 0·42; p=0·217), respectively, versus -1·4 points (0·41) in the placebo group. The rate of adverse events was similar between patients in the deutetrabenazine 36 mg/day group (n=38/74 [51%]), 24 mg/day group (n=32/73 [44%]), and 12 mg/day group (n=36/74 [49%]), and those in the placebo group (n=34/72 [47%]). Serious adverse events were reported in four (5%) patients given deutetrabenazine 36 mg/day, six (8%) patients given 24 mg/day, and two (3%) patients given 12 mg/day, compared with four (6%) patients given placebo. Two (1%) patients in the safety population died, one each in the deutetrabenazine 24 mg/day and 36 mg/day groups; neither death was deemed related to study drug by the investigator or sponsor. Deutetrabenazine 24 mg/day and 36 mg/day provided a significant reduction in tardive dyskinesia, with favourable safety and tolerability. These findings suggest that dosing regimens could be individualised and tailored for patients on the basis of dyskinesia control and tolerability. Teva Pharmaceutical Industries.


Glutamine prevents apoptosis in intestinal epithelial cells and induces differential protective pathways in heat and oxidant injury models.
Glutamine (GLN) can decrease mortality and length of hospital stay in the critically ill. GLN protects via enhancing protective heat shock proteins (HSPs) in heat stress (HS). GLN's effect on HSPs in oxidant injury and apoptosis remains to be elucidated. The purpose of this study was to determine if GLN protects via decreasing apoptosis during both heat and oxidative stress. IEC-18 cells were treated (15 minutes) with 0 mM GLN (control cells [CTs]) or 8 mM GLN and exposed to either lethal injury (44°C for 50 minutes or 4 mM H(2)O(2) for 30 minutes) or nonlethal injury (43°C for 45 minutes or 600 µM H(2)O(2) for 30 minutes). Survival was determined via MTS assay. Injured groups were normalized to noninjured controls. HSPs and cleaved caspase-3 (CC3), a key mediator for apoptosis, were evaluated via Western blot following a 3-hour recovery. MTS assays showed GLN increased survival 4- to 5-fold (P < .001 vs HS CT or H(2)O(2)). Western blot showed GLN increased all 3 HSPs in HS (P < .001 vs HS CTs) but only HSP32 during oxidant injury (P < .02 vs H(2)O(2) only). GLN decreased CC3 in both injuries (P < .03 vs non-GLN-treated cells). GLN protects intestinal cells from both heat and oxidant injury. HSP25, 32, and 70 levels increased with GLN during HS, but in oxidant injury, only HSP32 increased, suggesting GLN's mechanism of protection may vary in different models of injury. In both injuries, GLN lowered the expression of CC3, indicating prevention of apoptosis may be a key mechanism by which GLN protects.


Antibiotic resistance pattern among common bacterial uropathogens with a special reference to ciprofloxacin resistant Escherichia coli.
The resistance of bacteria causing urinary tract infection (UTI) to commonly prescribed antibiotics is increasing both in developing as well as in developed countries. Resistance has emerged even to more potent antimicrobial agents. The present study was undertaken to report the current antibiotic resistance pattern among common bacterial uropathogens isolated in a tertiary care hospital in south India, with a special reference to ciprofloxacin. A total of 19,050 consecutive urine samples were cultured and pathogens isolated were identified by standard methods. Antibiotic susceptibility was done by Kirby Bauer disk diffusion method. The clinical and demographic profile of the patients was noted. Of the 19,050 samples, 62 per cent were sterile, 26.01 per cent showed significant growth, 2.3 per cent showed insignificant growth and 9.6 per cent were found contaminated. Significant association (P<0.001) of prior use of antibiotics in males, UTI in adults, gynaecological surgery in females, obstructive uropathy in males and complicated UTI in females with the occurrence of UTI with ciprofloxacin resistant Escherichia coli was noted. Significant association was noted in females with prior antibiotics, with prior urological surgery and in males with prior complicated UTI. There was no significant association with diabetes mellitus with the occurrence of UTI with ciprofloxacin resistant E. coli. Fluoroquinolone resistance was found to increase with age. INTERPRETATIONS & CONCLUSIONS: Ciprofloxacin resistance has emerged due to its frequent use. This resistance was seen more in the in-patients, elderly males and females. Also the resistance to other antibiotics was also high. Increasing antibiotic resistance trends indicate that it is imperative to rationalize the use of antimicrobials in the community and also use these conservatively.


Response of aged parkinsonian monkeys to in vivo gene transfer of GDNF.
This study assessed the potential for functional and anatomical recovery of the diseased aged primate nigrostriatal system, in response to trophic factor gene transfer. Aged rhesus monkeys received a single intracarotid infusion of MPTP, followed one week later by MRI-guided stereotaxic intrastriatal and intranigral injections of lentiviral vectors encoding for glial derived neurotrophic factor (lenti-GDNF) or beta-galactosidase (lenti-LacZ). Functional analysis revealed that the lenti-GDNF, but not lenti-LacZ treated monkeys displayed behavioral improvements that were associated with increased fluorodopa uptake in the striatum ipsilateral to lenti-GDNF treatment. GDNF ELISA of striatal brain samples confirmed increased GDNF expression in lenti-GDNF treated aged animals that correlated with functional improvements and preserved nigrostriatal dopaminergic markers. Our results indicate that the aged primate brain challenged by MPTP administration has the potential to respond to trophic factor delivery and that the degree of neuroprotection depends on GDNF levels.


Growth and molecular interactions of the anti-EGFR antibody cetuximab and the DNA cross-linking agent cisplatin in gefitinib-resistant MDA-MB-468 cells: new prospects in the treatment of triple-negative/basal-like breast cancer.
Three prominent hallmarks of triple-negative/basal-like breast carcinomas, a subtype of breast cancer gene phenotype associated with poor relapse-free and overall survival, are overexpression of the epidermal growth factor receptor (EGFR), hyperactivation of the MEK/ERK transduction pathway and high sensitivity to DNA-damaging agents. The cytotoxic interaction between EGFR inhibitors (monoclonal antibodies such as cetuximab and small molecule tyrosine kinase inhibitors such as gefitinib) and DNA cross-linking agents (e.g. platinum derivatives) might represent a promising combination for the treatment of triple-negative/basal-like breast tumors that are dependent upon EGFR/MEK/ERK signaling. We evaluated the growth and molecular interactions of the anti-EGFR antibody cetuximab (erbitux) and the DNA cross-linking agent cisplatin (cis-diammedichloroplatinum; CDDP) in the gefitinib-resistant MDA-MB-468 breast cancer cell line, an in vitro model system that shows many of the recurrent basal-like molecular abnormalities including ER-PR-HER2-negative status, TP53 deficiency, EGFR overexpression, PTEN loss and constitutive activation of the MEK/ERK pathway. Unlike other basal-like breast cancer models, MDA-MB-468 cells do not carry mutations of the key DNA repair gene BRCA1. Concurrent treatment with sub-optimal doses of cetuximab significantly enhanced CDDP-induced apoptotic cell death. However, an isobologram-based mathematical assessment of the nature of the interaction revealed a loss of synergism when employing a high-dose of cetuximab. Since BRCA1 depletion has been found to decrease DNA damage repair and cell survival in MDA-MB-468 cells when treated with DNA-damaging drugs, we employed ELISA-based quantitative analyses to measure BRCA1 protein levels in CDDP+/- cetuximab-treated cells. Cetuximab as single agent was as efficient as CDDP at increasing BRCA1 protein expression. Interestingly, cetuximab co-exposure significantly antagonized the ability of CDDP to up-regulate BRCA1 expression. Low-scale phosphor-proteomic approaches [i.e. phospho-receptor tyrosine kinase (RTK) and phospho-mitogen-activated protein kinases (MAPKs) Array Proteome Profiler capable of simultaneously identifying the relative levels of phosphorylation of 42 different RTKs and 23 different MAPKs and other serine/threonine kinases, respectively] revealed the ability of Cetuximab, as single agent, to paradoxically induce hyper-phosphorylation of EGFR while concomitantly deactivating p42/44 (ERK1/ERK2) MAPK. Unexpectedly, ELISA-based quantitative analyses of EGFR protein content demonstrated that simultaneous exposure to cetuximab and optimal doses of CDDP completely depleted EGFR protein in MDA-MB-468 cells. Although these findings preclinically support, at least in part, ongoing clinical trials for 'triple-negative/basal-like' metastatic breast cancer patients who are receiving either cetuximab alone versus cetuximab plus carboplatin (http://www.clinicaltrials.gov/ct/show/NCT00232505), the unexpected ability of CDDP to promote a complete depletion of the cetuximab target EGFR further suggests that treatment schedules, cetuximab/CDDP doses and BRCA1 status should be carefully considered when combining anti-EGFR antibodies and platinum derivatives in triple-negative/basal-like breast carcinomas.


Activated retinal glia mediated axon regeneration in experimental glaucoma.
Glaucoma, a leading cause of blindness, is a neurodegenerative disease characterized by progressive loss of retinal ganglion cell axons in the optic nerve and their cell bodies in the retina. Reactive retinal glial changes have been observed in glaucoma but the role of such glial changes in the pathogenesis of the condition remains unclear. In the present study we found that retinal ganglion cells in an experimental animal model of glaucoma have an increased axon regenerative potential. Regeneration of adult rat retinal ganglion cell axons after optic nerve crush was significantly increased in vivo when combined with intraocular pressure-induced experimental glaucoma. This enhanced axon regeneration response was correlated with a significant increase in activation of glial fibrillary acidic protein+retinal glia. Using a dissociated retinal ganglion cell culture model we showed that reducing the number of activated retinal glia with a glial specific toxin, α-Aminoadipic acid, significantly reduced the growth potential of retinal ganglion cells from glaucomatous rat eyes, suggesting that activated retinal glia mediate, at least in part, the growth promoting effect. This was shown to be mediated by both membrane-bound and soluble glial-derived factors. Neurotrophin and ciliary neurotrophic/leukemia inhibitory factor blockers did not affect the regenerative potential, excluding these growth factors as principal mediators of the enhanced growth response occurring in glaucomatous retinal cultures. These observations are the first to reveal that retinal ganglion cells from glaucomatous rat eyes have an enhanced regenerative capacity. Furthermore, our results suggest that activated retinal glia mediate at least part of this response. Further work to understand and enhance the regeneration-promoting effect of activated retinal glia is required to determine if this approach could be useful as part of a therapeutic strategy to encourage optic nerve regeneration in glaucoma.


Strategies for epidemiologic studies of lead in bone in occupationally exposed populations.
Lead exposure is widespread among industrial populations in the United States. X-ray fluorescence (XRF) analysis of the lead content of bone offers a promising approach to acquisition of individualized data on chronic lead absorption in occupationally exposed populations. Dosimetric data obtained by XRF will permit accurate definition of dose-response relationships for such chronic consequences of lead exposure as central and peripheral neurologic impairment, renal disease. hypertension, and possibility reproductive dysfunction. Additionally, data on bone lead content obtained by XRF will permit validation of models describing the body lead burden and will allow direct assessment of the efficacy of therapeutic chelation. XRF data may also permit assessment of the possible role of genetic polymorphism of the enzyme delta-aminolevulinic dehydrase as a determinant of the pharmacokinetics and toxicity of lead. In both cross-sectional and prospective epidemiologic studies of body lead burden in occupationally exposed populations, the K-XRF instrument appears to be the technology of choice.


Twenty years of enamel matrix derivative: the past, the present and the future.
On June 5th, 2015 at Europerio 8, a group of leading experts were gathered to discuss what has now been 20 years of documented evidence supporting the clinical use of enamel matrix derivative (EMD). Original experiments led by Lars Hammarström demonstrated that enamel matrix proteins could serve as key regenerative proteins capable of promoting periodontal regeneration including new cementum, with functionally oriented inserting new periodontal ligament fibres, and new alveolar bone formation. This pioneering work and vision by Lars Hammarström has paved the way to an enormous amount of publications related to its biological basis and clinical use. Twenty years later, it is clear that all these studies have greatly contributed to our understanding of how biologics can act as mediators for periodontal regeneration and have provided additional clinical means to support tissue regeneration of the periodontium. This review article aims to: (1) provide the biological background necessary to understand the rational for the use of EMD for periodontal regeneration, (2) present animal and human histological evidence of periodontal regeneration following EMD application, (3) provide clinically relevant indications for the use of EMD and (4) discuss future avenues of research including key early findings leading to the development of Osteogain, a new carrier system for EMD specifically developed with better protein adsorption to bone grafting materials.


Marketing Strategy, Serving Size, and Nutrition Information of Popular Children's Food Packages in Taiwan.
A content analysis was used to investigate the marketing strategies, serving size, and nutrition quality in Taiwan popular children's snacks and drinks. A total of 361 snacks and 246 drinks were collected. It was found that 38.6% of snacks and 25.3% of drinks were child-targeted (CT) foods, and 78.1% and 85.4% of the snacks and drinks had health and nutrition marketing (HNM). Serving size was significantly positively correlated to calories among different food categories in this study. Only the CT breads, ready-to-eat cereals, and fruit/vegetable juice had smaller serving sizes than did the corresponding non-CT products. These CT products had significantly fewer calories than did the corresponding non-CT products. Approximately 30% of snacks and 18% of drinks had both CT and HNM. Moreover, 82.7% of CT snacks and 100.0% of CT drinks with HNM were high in sugar. About 95% of foods with no added sugar claim were high sugar. CT foods are not necessarily healthier than non-CT foods, even the CT food with HNM. Health professionals should help parents assess the nutrition quality of the popular children's foods. Further research was needed to investigate the effect of these marketing strategies and serving size on children's food consumption.


Relationship between the self-assessment and clinical assessment of health status and work ability.
Clinical assessments of health status and work ability were compared with subjective assessments reported on a questionnaire. The clinical examinations included cardiorespiratory, musculoskeletal, and psychological measurements. The subjective work ability comprised an index based on estimations of work ability in relation to diseases, job demands, and psychological resources. For the clinical examinations 89 male and 85 female workers aged 44-58 years were selected according to health and subjective work ability as reported on the questionnaire. Half of the group was healthy and half suffered from either coronary artery disease (men) or low-back pain (women), and the subjective estimations of work ability varied from good to poor. The results indicated that the questionnaire responses on health and work ability related well with the clinically assessed factors at the group level. Some divergence was detected at the individual level, but it could usually be explained on the basis of the available data.