The Repeat Sequences and Elevated Substitution Rates of the Chloroplast accD Gene in Cupressophytes.
The plastid accD gene encodes a subunit of the acetyl-CoA carboxylase (ACCase) enzyme. The length of accD gene has been supposed to expand in Cryptomeria japonica, Taiwania cryptomerioides, Cephalotaxus, Taxus chinensis, and Podocarpus lambertii, and the main reason for this phenomenon was the existence of tandemly repeated sequences. However, it is still unknown whether the accD gene length in other cupressophytes has expanded. Here, in order to investigate how widespread this phenomenon was, 18 accD sequences and its surrounding regions of cupressophyte were sequenced and analyzed. Together with 39 GenBank sequence data, our taxon sampling covered all the extant gymnosperm orders. The repetitive elements and substitution rates of accD among 57 gymnosperm species were analyzed, the results show: (1) Reading frame length of accD gene in 18 cupressophytes species has also expanded. (2) Many repetitive elements were identified in accD gene of cupressophyte lineages. (3) The synonymous and non-synonymous substitution rates of accD were accelerated in cupressophytes. (4) accD was located in rearrangement endpoints. These results suggested that repetitive elements may mediate the chloroplast genome rearrangement and accelerated the substitution rates.


Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.
Cognate interactions between antigen-presenting B and T cells play crucial roles in immunologic responses. T cells that have been activated via the crosslinking of CD3 are able to induce B cell proliferation and immunoglobulin secretion in a major histocompatibility complex-unrestricted and contact-dependent manner. We find that such activated human CD4+ T cells, but not control Ig-treated T cells, may induce normal or leukemic B cells to express B7/BB1 and significantly higher levels of CD54 intercellular adhesion molecule 1 via a process that also requires direct cell-cell contact. To discern what cell surface molecule(s) may be responsible for signalling B cells to express B7/BB1, we added various monoclonal antibodies (mAbs) specific for T or B cell accessory molecules or control mAbs to cocultures of alpha-CD3-activated T cells and resting B cells. We find that only alpha-CD40 mAbs can significantly inhibit the increased expression of B7/BB1, suggesting that the ligand for CD40 expressed on activated T cells may be an important inducer of B7/BB1 expression. Subsequent experiments in fact demonstrate that alpha-CD40 mAbs, but not control mAbs, induce changes in B cell phenotype similar to those induced by activated T cells when the mAbs are presented on Fc gamma RII (CDw32)-expressing L cells. These phenotypic changes have significant effects on B cell function. Whereas chronic lymphocytic leukemia (CLL) B cells normally are very poor stimulators in allogeneic mixed lymphocyte reactions (MLRs), CLL-B cells preactivated via CD40 crosslinking are significantly better presenters of alloantigen, affecting up to 30-fold-greater stimulation of T cell proliferation than that induced by control treated or nontreated CLL-B cells. Similarly, the MLR of T cells stimulated by allogeneic nonleukemic B cells can be enhanced significantly if the stimulator B cells are preactivated via CD40 crosslinking. The enhanced MLR generated by such preactivated B cells may be inhibited by blocking B7/BB1-CD28 interaction with CTLA4Ig. These studies demonstrate a novel, CD40-dependent pathway for inducing B cell expression of B7/BB1 and enhancing B cell antigen-presenting cell activity that can be initiated via cell-cell contact with alpha-CD3-stimulated CD4+ T cells.


Murine dendritic epidermal T cells (DETC) express the homophilic adhesion molecule E-cadherin.
Cadherins mediate homotypic intercellular adhesion in epidermis and other epithelia. E-cadherin is also involved in interactions between murine epidermal Langerhans cells (LC) and keratinocytes (KC). Dendritic epidermal T cells (DETC) comprise another subpopulation of epidermal leukocytes. Using flow cytometry, we determined that DETC expressed levels of E-cadherin similar to those expressed by LC and KC. DETC also adhered congruent to three-fold better to KC and E-cadherin-transfected fibroblasts than to normal fibroblasts. Treatment of DETC with trypsin in the absence of calcium caused a loss of E-cadherin and resulted in an congruent to 80% decrease in DETC-KC adhesion whereas treatment of DETC with trypsin in the presence of calcium did not significantly affect E-cadherin expression or DETC-KC binding. Thus, E-cadherin may be involved in adhesion of DETC to KC. DETC are derived from TCR V gamma 3+ thymocytes that transiently populate embryonic murine thymus. We determined that TCR V gamma 3+ thymocytes as well as other early (fetal day 16) TCR gamma/delta+ thymocytes expressed E-cadherin; TCR gamma/delta+ (TCR V gamma 3-) thymocytes that developed later did not. These results indicate that cells of the T cell lineage can express E-cadherin, and suggest that E-cadherin may play a role in adhesion of DETC (and/or DETC precursors) to KC.


Perceived exertion with glucose ingestion in adolescent males with IDDM.
The rating of perceived exertion (RPE) is an indicator of exercise effort in adolescents that may be influenced by certain pediatric conditions. The purpose of this study was to determine the influence of insulin-dependent diabetes mellitus (IDDM) and glucose intake on RPE. Eight male adolescents with IDDM and eight healthy controls of similar age, weight, and VO2peak cycled for 60 min at 60%VO2peak on two occasions spaced 1-4 wk apart. During a control trial (CT), subjects drank water, and in a glucose trial (GT), glucose at a rate of approximately 1.5 g x kg(-1) x h(-1). Heart rate, ventilation, and RPE (Borg 6-20 scale) were assessed at 5, 25, 35, and 55 min and blood glucose and lactate levels before and at 30 and 60 min. RPE in both trials was 15-25% higher in IDDM versus healthy subjects (F = 8.83; df = 1,14; eta-squared = 0.39; P = 0.01). In CT, it increased from 10.6 +/- 0.4 at 5 min to 15.2 +/- 0.6 at 55 min in IDDM and from 9.3 +/- 0.9 at 5 min to 13.0 +/- 0.8 at 55 min in healthy adolescents. In GT, RPE increased similarly to CT in the IDDM group but was 1-2 points lower in the healthy group. Blood glucose levels were 4.8 +/- 1.8 mmol x L(-1) and 1.8 +/- 0.4 mmol x L(-1) higher by the end of exercise in GT than in CT for the IDDM and healthy groups, respectively. There were no differences in heart rate, ventilation, or lactate levels between the groups or trials. For exercise performed at a similar moderate intensity, RPE in IDDM is higher by 2-3 points than in controls. Compared with water, glucose intake is associated with lower RPE in healthy, but not in IDDM, adolescents.


[Cistatin C as a novel marker of renal function impairement and cardiovascular risk].
Impairment of renal function beginning from subclinical stages is independent risk factor of development of cardiovascular diseases and cardiovascular death. Cystatin C is considered in recent years as an alternative marker of functional state of the kidney and risk of development of cardiovascular diseases. Cystatin C is a protease inhibiting protein with low molecular mass which is characterized by free glomerular filtration and is not subjected to tubular secretion. Formulas are elaborated for calculation glomerular filtration rate basing on cystatin C level. In this review we consider potential advantages of cystatin C for assessment of early impairment of renal function. We also present data on interrelation between cystatin C, metabolic parameters, and markers of target organs damage, on prognostic value of cystatin C in various populations of patients.


Time course of postanoxic akinetic-rigid and dystonic syndromes.
Twelve previously normal patients with anoxic brain damage due to various causes are described. The mean age at anoxia was 27.4 years. Six patients, in their fourth decade or older, developed an early akinetic-rigid syndrome; the mean interval between anoxia and akinetic-rigid syndrome was 3.1 months (range, less than 1 week to 12 months). Four of these six patients also developed dystonia, usually after some months. Six other patients, all children or young adults, developed a pure dystonic syndrome; the mean interval between anoxia and dystonia was 9.7 months (range, 1 week to 36 months). Dystonia was generalized and progressed over a mean period of 21.9 months (range, 3 to 96 months). Severe bulbar involvement was common. Age determined whether an akinetic-rigid or a dystonic syndrome developed in our patients and those reported in the literature. Many, but not all, patients had lesions on brain imaging (or at autopsy). In those with visible lesions in the basal ganglia, those with dystonia tended to have damage in putamen, while those with an akinetic-rigid syndrome tended to have damage in the globus pallidus. There were exceptions.


The developmental fate of the cephalic mesoderm in quail-chick chimeras.
The developmental fate of the cephalic paraxial and prechordal mesoderm at the late neurula stage (3-somite) in the avian embryo has been investigated by using the isotopic, isochronic substitution technique between quail and chick embryos. The territories involved in the operation were especially tiny and the size of the transplants was of about 150 by 50 to 60 microns. At that stage, the neural crest cells have not yet started migrating and the fate of mesodermal cells exclusively was under scrutiny. The prechordal mesoderm was found to give rise to the following ocular muscles: musculus rectus ventralis and medialis and musculus oblicus ventralis. The paraxial mesoderm was separated in two longitudinal bands: one median, lying upon the cephalic vesicles (median paraxial mesoderm--MPM); one lateral, lying upon the foregut (lateral paraxial mesoderm--LPM). The former yields the three other ocular muscles, contributes to mesencephalic meninges and has essentially skeletogenic potencies. It contributes to the corpus sphenoid bone, the orbitosphenoid bone and the otic capsules; the rest of the facial skeleton is of neural crest origin. At 3-somite stage, MPM is represented by a few cells only. The LPM is more abundant at that stage and has essentially myogenic potencies with also some contribution to connective tissue. However, most of the connective cells associated with the facial and hypobranchial muscles are of neural crest origin. The more important result of this work was to show that the cephalic mesoderm does not form dermis. This function is taken over by neural crest cells, which form both the skeleton and dermis of the face. If one draws a parallel between the so-called "somitomeres" of the head and the trunk somites, it appears that skeletogenic potencies are reduced in the former, which in contrast have kept their myogenic capacities, whilst the formation of skeleton and dermis has been essentially taken over by the neural crest in the course of evolution of the vertebrate head.


RNAi-based therapeutics-current status, challenges and prospects.
RNA interference (RNAi) is a collection of small RNA directed mechanisms that result in sequence specific inhibition of gene expression. The notion that RNAi could lead to a new class of therapeutics caught the attention of many investigators soon after its discovery. The field of applied RNAi therapeutics has moved very quickly from lab to bedside. The RNAi approach has been widely used for drug development and several phase I and II clinical trials are under way. However, there are still some concerns and challenges to overcome for therapeutic applications. These include the potential for off-target effects, triggering innate immune responses and most importantly obtaining specific delivery into the cytoplasm of target cells. This review focuses on the current status of RNAi-based therapeutics, the challenges it faces and how to overcome them.


Deletion of ATF4 in AgRP Neurons Promotes Fat Loss Mainly via Increasing Energy Expenditure.
Although many functions of activating transcription factor 4 (ATF4) are identified, a role of ATF4 in the hypothalamus in regulating energy homeostasis is unknown. Here, we generated adult-onset agouti-related peptide neuron-specific ATF4 knockout (AgRP-ATF4 KO) mice and found that these mice were lean, with improved insulin and leptin sensitivity and decreased hepatic lipid accumulation. Furthermore, AgRP-ATF4 KO mice showed reduced food intake and increased energy expenditure, mainly because of enhanced thermogenesis in brown adipose tissue. Moreover, AgRP-ATF4 KO mice were resistant to high-fat diet-induced obesity, insulin resistance, and liver steatosis and maintained at a higher body temperature under cold stress. Interestingly, the expression of FOXO1 was directly regulated by ATF4 via binding to the cAMP-responsive element site on its promoter in hypothalamic GT1-7 cells. Finally, Foxo1 expression was reduced in the arcuate nucleus (ARC) of the hypothalamus of AgRP-ATF4 KO mice, and adenovirus-mediated overexpression of FOXO1 in ARC increased the fat mass in AgRP-ATF4 KO mice. Collectively, our data demonstrate a novel function of ATF4 in AgRP neurons of the hypothalamus in energy balance and lipid metabolism and suggest hypothalamic ATF4 as a potential drug target for treating obesity and its related metabolic disorders.


A Systematic Review of the Effectiveness of Core Stability Exercises in Patients with Non-Specific Low Back Pain.
Low back pain affects millions of people worldwide and can be a difficult condition to manage clinically. Many cases do not have a discernable etiology, further increasing the complexity of finding an effective intervention. Core stabilization exercises (CSE) strengthen the musculature that provides stability to the spine and show promising outcomes. To examine the efficacy of CSE exercises in the treatment of NSLBP in adult patients. Studies were included if they had patients diagnosed with NSLBP, used CSE as a treatment for NSLBP, and were a clinical trial. Exclusion criteria were studies that did not utilize an objective pain scale, patients who had a specific diagnosed pathology contributing to the NSLBP or received treatment for their NSLBP within the prior six months. The literature was systematically searched in the PubMed, Sports Medicine & Education Index, and CINHAL databases, using the search terms core stabilization, low back pain, and exercise. The initial search yielded 229 articles and was refined using search terms 'NOT analysis' in order to target randomized control trials and exclude meta-analyses to narrow the search. Full-text of the articles were assessed for eligibility by utilizing inclusion and exclusion criteria that were included in this review. Articles were assessed for quality using the PEDro scale and relevant data were extracted. Five moderate-quality studies (PEDRO range: 5-8) support CSE is an effective method to decrease pain, improve functionality, and increase core strength in patients with NSLBP. Although there are other commonly used methods to treating NSLBP, CSE have shown to be a beneficial method to treating NSLBP. Grade B evidence suggests core stabilization exercises can be considered a favorable method for treating pain in patients with NSLBP. 1b.


Combined Treatment Fkt-Botulinum Toxin Type A (Btx-A) in Patients with Strumpell-Lorrain Disease.
The Hereditary Spastic Paraparesis (HSP) or Strumpell-Lorrain disease is a heterogeneous neurodegenerative disease of the spinal cord. It is genetically transmitted and characterized by a progressive muscle weakness, spasticity of the lower limbs and awkward gain. There is no specific pharmacological treatment. The pharmacological therapy decreases the muscle tone and prevents stiffening). Physiotherapy restrains the progression of muscle atrophy, delays contraction of the tendons and gives greater mobility to people affected by the disease. The aim of this study is to demonstrate the efficacy of the combined treatment Fkt and Btx-A in patients with HSP. Retrospective study was conducted recruiting ten patients with spasticity according to Asworth modified scale of at least 2 and with gait deficit. They received treatment for 5 years with incobotulinumtoxinA and physiokinesiotherapy for addressing spasticity in the lower limbs. We evaluated muscle tone with miometric measurement both at the first visit (T0), and at subsequent ones (T1 after 30 days, T2 after 3 months from the first infiltration, T3 after 4 months up to the date of the following infiltration, T4 after 5 months). Baropodometric examination has proven essential for the study of the distribution of loads in statics and dynamics. The data analysis regarding tone assessment through measurements with Myoton highlighted hypertonus reduction in all the three muscle groups examined at T1 and the maintenance of constant values up to 5 months after the first infiltration. It also showed an increase in the percentage of back foot loading in both feet up to T4 (new inoculation, p<0, 05%). Baropodometric examination in dynamics (in particular the speed of the step) showed a gradual increase in this parameter which reaches a peak at 5 months (p<0, 05%) and then declines again in conjunction with the next infiltration treatment. This study showed the benefit of combined treatment with Btx and Fkt. The use of a local muscle relaxant drug with a physical targeted exercise guarantees better mobility of the treated segments, reducing tendon retractions as much as possible, and guarantees an adequate postural alignment. Baropodometric examination highlights a more advantageous distribution load, quite essential for avoiding tendinitis due to overload. Our data observation in the 5 years study shows how the curve relative to the speed of step and the graphics related to the variations of muscle tone remain almost constant with detectable improvement.


Reduced overpotentials for electrocatalytic water splitting over Fe- and Ni-modified BaTiO3.
Water electrolysis is a key technology for the replacement of fossil fuels by environmentally friendly alternatives, but state-of-the-art water oxidation catalysts rely on rare elements such as Pt groups and other noble metals. In this article, we employ first-principles calculations to explore the potential of modified barium titanate (BaTiO3), an inexpensive perovskite oxide that can be synthesized from earth-abundant precursors, for the design of efficient water oxidation electrocatalysts. Our calculations identify Fe and Ni doping as a means to improve the electrical conductivity and to reduce the overpotential required for water oxidation over BaTiO3. Based on computed Pourbaix diagrams and pH/potential-dependent surface phase diagrams, we further show that BaTiO3 is stable under reaction conditions and is not sensitive with respect to poisoning by reaction intermediates and hydrogen adsorption. This proof of concept demonstrates that even minor compositional modifications of existing materials may greatly improve their catalytic activity, a fact that is often neglected when larger composition spaces are screened.


Narcolepsy in a pediatric population.
Narcolepsy, a sleep-wake disorder of unknown cause, has been reported as occurring in the pediatric population, but only two reports of cases in the literature have included polysomnographic data on children with narcolepsy. We compared the clinical and polysomnographic data on a series of eight patients 15 years of age or younger and an adult comparison group with narcolepsy. All patients presented with excessive daytime sleepiness, and no significant difference was found between groups for the incidence of cataplexy, hypnagogic hallucinations, and sleep paralysis. On polysomnographic evaluation the pediatric group had increased total sleep time, percent-stage 3/4 sleep, percent rapid eye movement sleep, and decreased stage 1 sleep, which all are expected age-related differences. The pediatric group also showed a greater degree of daytime sleepiness and an increased frequency of sleep-onset rapid eye movement periods. While pediatric patients with narcolepsy resemble adults in their mode of presentation and the incidence of accessory symptoms, the increase in severity of sleepiness highlights the importance of diagnosing narcolepsy in children as early as possible so that treatment can be initiated.


Prevalence of Asthma Characteristics in COPD Patients in a Dutch Well-Established Asthma/COPD Service for Primary Care.
Primary care COPD guidelines indicate that COPD patients with asthma characteristics should be treated as having asthma. This study aims to describe the prevalence of asthma characteristics in patients with a pulmonologist-confirmed working diagnosis of COPD or ACO. This retrospective cross-sectional study used real-life data (collected between 2007 and 2017) from a Dutch asthma/COPD-service, a structured web-based system in which pulmonologists support general practitioners in their diagnosis of patients with suspicion of obstructive lung disease. The prevalence of asthma characteristics (history of asthma, atopy, symptoms, and reversibility) and blood eosinophil (Eos) counts were assessed in patients with a working diagnosis of COPD or ACO. Of the 14,141 patients, ≥40 years in the dataset, 4475 (31.6%) were diagnosed with asthma, 3532 (25.0%) with COPD, and 1276 (9.0%) with ACO. Asthma characteristics were present in 65.6% (n=1956) of the COPD and 90.9% (n=1059) of the ACO patients. Eos counts of ≥ 300 cells per μL were found in 35.7% (n=924) of the COPD patients and 35.3% (n=341) of the ACO patients. In this group of COPD and ACO patients remotely diagnosed by pulmonologists, a substantial proportion would be considered to have asthma characteristics according to the guidelines. This may explain the high number of inhaled corticosteroid (ICS) prescriptions found in primary care COPD patients. Prospective studies are necessary to identify patients who may or may not benefit from ICS containing treatment. Hence, personalized care in primary care can be optimized.


Direct medical costs attributable to peripheral fractures in Canadian post-menopausal women.
This study determined the cost of treating fractures at osteoporotic sites (except spine fractures) for the year following fracture. While the average cost of treating a hip fracture was the highest of all fractures ($46,664 CAD per fracture), treating other fractures also accounted for significant expenditures ($5,253 to $10,410 CAD per fracture). This study aims to determine the mean direct medical cost of treating fractures at peripheral osteoporotic sites in the year post-fracture (through 2 years post-hip fracture). Health administrative databases from the province of Quebec, Canada were used to estimate the cost of treating peripheral fractures at osteoporotic sites for the year following fracture (through 2 years for hip fractures). Included in costs analyses were physician claims, emergency and outpatient clinic costs, hospitalization costs, and subsequent costs for treatment of complications. A total of 15,827 patients (mean age 72 years) who suffered one fracture at an osteoporotic site had data for analyses. Hip/femur fractures had the highest rate of hospital stays related to fracture (91%) and the highest rate of hospital stays associated with a post-fracture complication (8%). In the year following fracture, the mean (SD) costs (2009 Canadian dollars) of treating acute fractures and post-fracture complications were: hip/femur fracture $46,664 ($43,198), wrist fracture $5,253 ($18,982), and fractures at other peripheral sites $10,410 ($27,641). The average (SD) cost of treating post-fracture complications at the hip/femur in the second year post-fracture was $1,698 ($12,462). Hospitalizations associated with the fracture accounted for 88% of the total cost of fracture treatment. The treatment of hip fractures accounts for a significant proportion of the costs associated with the treatment of peripheral osteoporotic fractures. Interventions to reduce the incidence of fractures, particularly hip fractures, would result in significant cost savings to the health care system and would preserve quality of life in many patients.


The L2/HNK-1 carbohydrate is preferentially expressed by previously motor axon-associated Schwann cells in reinnervated peripheral nerves.
The carbohydrate epitope L2/HNK-1 (hereafter designated L2) is expressed in the adult mouse by myelinating Schwann cells of ventral roots and muscle nerves, but rarely by those of dorsal roots or cutaneous nerves. Since substrate-coated L2 glycolipids promote outgrowth of cultured motor but not sensory neurons, L2 may thus influence the preferential reinnervation of muscle nerves by regenerating motor axons in vivo. In the present study, we have analyzed the influence of regenerating axons on L2 expression by reinnervated Schwann cells by directing motor or sensory axons into the muscle and cutaneous branches of femoral nerves of 8-week-old mice. We observed that regenerating axons from cutaneous branches did not lead to immunocytochemically detectable L2 expression in muscle or cutaneous nerve branches. Axons regenerating from muscle branches led to a weak L2 expression by few Schwann cells of the cutaneous branch, but provoked a strong L2 expression by many Schwann cells of the muscle branch. Myelinating Schwann cells previously associated with motor axons thus differed from previously sensory axon-associated myelinating Schwann cells in their ability to express L2 when contacted by motor axons. This upregulation of L2 expression during critical stages of reinnervation may provide motor axons regenerating into the appropriate, muscle pathways with an advantage over those regenerating into the inappropriate, sensory pathways.


Utility of Combined EZH2, p-ERK1/2, p-STAT, and MYC Expression in the Differential Diagnosis of EZH2-positive Hodgkin Lymphomas and Related Large B-Cell Lymphomas.
EZH2 is a methyltransferase that plays an important tumorigenic role in various neoplasms. We previously found that EZH2 is expressed in a range of aggressive B-cell lymphomas (ABCLs), T-cell lymphomas, and histiocytic neoplasms, with differential expression of intracellular signaling molecules p-ERK, MYC, and p-STAT3, potential regulators of EZH2 expression. We studied EZH2 expression in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), classic Hodgkin lymphoma (cHL), T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), and B-cell Lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphomas and classic Hodgkin lymphoma (BCLu-DLBCL/cHL), as well as the coexpression of p-ERK, MYC, and p-STAT3 in these neoplasms. The neoplastic LP cells of NLPHL and Hodgkin/Reed-Sternberg cells of cHL were strongly positive for EZH2, as were the neoplastic cells in THRLBCL and BCLu-DLBCL/cHL. EZH2 expression correlated with proliferation rate, as assessed by Ki-67 staining. LP cells in NLPHL and Hodgkin/Reed-Sternberg cells in cHL were strongly positive for p-ERK, p-STAT3, and MYC, as were the neoplastic cells in THRLBCL and BCLu-DLBCL/cHL, in contrast to the differential expression of these molecules seen in ABCLs. These findings suggest that combined expression of p-ERK, MYC, and p-STAT3 is a useful immunohistochemical pattern for the diagnosis of EZH2-positive Hodgkin lymphomas and related lymphomas, in contrast to ABCLs. Furthermore, the overexpression of EZH2, in association with coexpression of tumorigenic signaling molecules, suggests an oncogenic role for this molecule in the development of Hodgkin lymphomas and related lymphomas. THRLBCL and BCLu-DLBCL/cHL appear to have a mechanism for the regulation of EZH2 expression that is similar to NLPHL and cHL and different from that of ABCLs. In addition, EZH2 and associated signaling cascades may serve as therapeutic targets for the treatment of Hodgkin lymphomas and related lymphomas.


Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells.
Low vitality (a component of fatigue) in middle-aged and older adults is an important complaint often identified as a symptom of a disease state or side effect of a treatment. No studies to date have investigated the potential link between dysfunctional mitochondrial ATP production and low vitality. Therefore, we measured a number of cellular parameters related to mitochondrial activity in peripheral blood mononuclear cells (PBMCs) isolated from middle-aged men, and tested for association with vitality. These parameters estimate mitochondrial respiration, reactive oxygen species (ROS) production, and deoxyribonucleotide (dNTP) balance in PBMCs. The population was drawn from the Metropolit cohort of men born in 1953. Vitality level was estimated from the Medical Outcomes Study Short Form 36 (SF-36) vitality scale. We found that vitality score had no association with any of the mitochondrial respiration parameters. However, vitality score was inversely associated with cellular ROS production and cellular deoxythymidine triphosphate (dTTP) levels and positively associated with deoxycytidine triphosphate (dCTP) levels. We conclude that self-reported persistent low vitality is not associated with specific aspects of mitochondrial oxidative phosphorylation capacity in PBMCs, but may have other underlying cellular dysfunctions that contribute to dNTP imbalance and altered ROS production.


Bronchoalveolar lavage.
Bronchoalveolar lavage has a well established role in the diagnosis of pulmonary infections, particularly those due to opportunistic organisms in an immunocompromised host. Recent studies of infants and adults with inflammatory lung disease have helped our understanding of the mechanisms underlying these disorders and their responses to treatment. With increasing recognition that pulmonary events in utero and in early infancy are important in the pathogenesis of lung diseases such as asthma, studies of the lung's responses to various environmental insults in this population might guide us to developing effective preventative and therapeutic strategies. Bronchoalveolar lavage is one method for assessing a number of pulmonary components and may be useful in this regard, particularly if combined with new methods for examining inflammatory responses, such as those utilising the polymerase chain reaction to assess cellular expression for inflammatory cytokines and growth factors.


The role of proficiency testing in ensuring quality: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference working group 3.
Implementation of proficiency testing for gynecologic cytology was delayed 20 years because of challenges addressing the subjective nature of cytologic interpretation and replicating normal working conditions. Concern remains regarding test scoring, slide validation, test environment, and other issues. How these test results are, or should be, used in quality management has never been explored. To provide information on good laboratory practices for gynecologic cytology proficiency testing based on findings from the College of American Pathologists' survey-based project funded by the Centers for Disease Control and Prevention. An expert working group evaluated results from a Web-based, national laboratory survey plus responses from follow-up questions and findings from the literature. The group created statements on good laboratory practices pertinent to proficiency testing and its role in quality management, which were discussed and voted on at a consensus conference. Two-thirds of laboratories report having an individual with an unsuccessful proficiency testing score. More than 90% did not initiate any remedial action for 1 or 2 unsuccessful tests; 84% of laboratories reported they actively monitored results from proficiency testing, but most laboratories did not initiate any remedial action for cytotechnologists (81.4%; 376 of 462) or pathologists (87.7%; 405 of 462) who passed a proficiency test but who did not score 100%. Proficiency testing pass-fail rates should be monitored globally for the laboratory and for each individual. Proficiency testing slides should be prescreened by cytotechnologists for pathologists who are not primary screeners. Remedial action should not be required for a passed, but imperfect, test. No remedial action is required for an unsuccessful, first proficiency test result before retesting.


Changing postgraduate medical education: a commentary from the United Kingdom.
The current changes in postgraduate training in the United Kingdom are largely driven by government rather than the profession, and are aimed at producing a medical workforce more quickly and more fit-for-purpose in a rapidly changing National Health Service. Most aspects of the changes are, as yet, untested. Postgraduate training now consists of a 2-year varied Foundation program, followed by selection to a longer training program within a chosen specialty (often with further selection points to different subspecialties after 2 years). Assessment systems are a combination of workplace-based assessments and national examinations of knowledge and skill. The changing, highly managed and partially privatised health service in the UK presents challenges in terms of providing appropriate clinical experience for training. Postgraduate medical education is now regulated by the Postgraduate Medical Education and Training Board, which sets standards for all aspects of training, and approves curricula, programs and assessment systems. The lessons to be learned from the UK are: When education changes, the actual rationale should be clear. It is important to understand the difference between political and professional agendas. Protection of adequate clinical experience is paramount. Competence models can "instrumentalise" medical education (ie, deconstruct integrated professional performance, attempt to micromanage, streamline, objectify and rationalise for purposes of cost or time containment or for managerial imperatives). Standards for medical education should be clear, but not at too specific a level. If trainees' career structures change, careers advice must also change.


Comparison of occlusal loading conditions in a lower second premolar using three-dimensional finite element analysis.
This study aimed to compare the patterns of stress distribution in a lower second premolar using three conventional occlusal loadings and two more realistic loading scenarios based on occlusal contact areas. The teeth of a dried modern human skull were micro-CT scanned in maximum intercuspation contact with a Viscom X8060 NDT X-ray system. A kinematic analysis of the surface contacts between antagonistic right upper and lower teeth during the power stroke was carried out in the Occlusal Fingerprint Analyser (OFA) software. Stress distribution in the lower right second premolar was analysed using three-dimensional finite element (FE) methods, considering occlusal information taken from OFA results (cases 4-5). The output was compared to that obtained by loading the tooth with a single point force (cases 1-3). Results for cases 1-3 differ considerable from those of cases 4-5. The latter show that tensile stresses might be concentrated in grooves and fissures of the occlusal surface, in the marginal ridges, in the disto-lingual and in the distal side of the root. Moreover, the premolar experiences high tensile stresses in the buccal aspect of the crown, supporting the idea that abfraction might be a dominant factor in the aetiology of non-carious cervical lesions. The application of FE methods in dental biomechanics can be advanced considering individual wear patterns. More realistic occlusal loadings are of importance for both new developments in prosthetic dentistry and improvements of materials for tooth restoration, as well to address open questions about the worldwide spread problem of dental failure.


Effect of IRT5 probiotics on dry eye in the experimental dry eye mouse model.
To investigate the clinical effects of IRT5 probiotics in the environmental dry eye model. Eight week old male C57BL/6 mice were randomly divided into two groups; control group (n = 16) received oral gavage of 300 μL phosphate-buffered saline (PBS) alone once daily, IRT5 group (n = 9) received oral gavage of 1 x 109 CFU IRT5 probiotics powder in 300 μL PBS once daily, both groups for 11 to 12 days. Simultaneously, all mice underwent dry eye induction. Tear secretion, corneal staining and conjunctival goblet cell density were evaluated. Quantative real-time polymerase chain reaction (RT-PCR) for inflammation-related markers was performed. 16S ribosomal RNA of fecal microbiome was analyzed and compositional difference, alpha and beta diversities were assessed. There was no difference in NEI score but significant increase in tear secretion was observed in IRT5 group (p < 0.001). There was no significant difference in goblet cell density between groups. Quantative RT-PCR of cornea and conjunctiva revealed increased TNF-α expression in IRT5 group (p < 0.001) whereas other markers did not significantly differ from control. IRT5 group had significantly increased species diversity by Shannon index (p = 0.041). Beta diversity of genus by UniFrac principle coordinates analysis showed significant distance between groups (p = 0.001). Compositional differences between groups were observed and some were significantly associated with tear secretion. Multivariate linear regression analysis revealed Christensenellaceae (p = 0.009), Lactobacillus Helveticus group (p = 0.002) and PAC001797_s (p = 0.011) to strongly influence tear secretion. In experimental dry eye model, IRT5 probiotics treatment partially improves experimental dry eye by increasing tear secretion which was associated with and influenced by the change in intestinal microbiome. Also, intestinal microbiome may affect the lacrimal gland through a different mechanism other than regulating inflammation.


Do the contemporary dietary patterns of children align with national food and nutrient recommendations?
Childhood nutrition is important in optimising growth, development and future health. The present study compared dietary intakes of Australian children aged 4-8 years with (i) Australian Guide to Healthy Eating (AGHE) food group recommendations and (ii) age-specific Nutrient Reference Values (NRVs), in addition to (iii) describing food group intakes of children meeting key NRVs. Data were obtained from a representative sample of children (n = 789) from the National Nutrition and Physical Activity Survey between May 2011 and June 2012. Parent-reported 24-h recall dietary data were disaggregated into five core food groups, along with energy-dense, nutrient-poor (EDNP) foods, with intakes being compared with AGHE recommendations. Food group intakes were compared for children meeting the NRVs for 10 nutrients used for the development of AGHE food groups. Chi-squared and t-tests were performed to determine differences in food group intakes with P < 0.05 considered statistically significant. Only one child met the recommended daily servings for all AGHE core food groups and none met both core and energy-dense, nutrient-poor (EDNP) food group recommendations. The lowest level of alignment (percentage meeting recommendations) was for vegetables (4.6%) and the highest was for fruit (47.7%). Mean (SD) daily intake of EDNP foods [4.7 (3.2) serves day-1 ] accounted for 38.4% of total energy intakes. Children meeting key NRVs (n = 395) consumed greater daily servings of fruit [2.2 (1.7)], dairy [2.2 (1.2)] and EDNP foods [5.0 (3.4)] compared to the total sample (n = 789). Significant discrepancies exist between contemporary dietary patterns of Australian children and national recommendations. Future AGHE revisions should incorporate greater diversity of consumption patterns, including sub-categories of EDNP foods.


Prednisone versus prednisone plus ciclosporin versus prednisone plus methotrexate in new-onset juvenile dermatomyositis: a randomised trial.
Most data for treatment of dermatomyositis and juvenile dermatomyositis are from anecdotal, non-randomised case series. We aimed to compare, in a randomised trial, the efficacy and safety of prednisone alone with that of prednisone plus either methotrexate or ciclosporin in children with new-onset juvenile dermatomyositis. We did a randomised trial at 54 centres in 22 countries. We enrolled patients aged 18 years or younger with new-onset juvenile dermatomyositis who had received no previous treatment and did not have cutaneous or gastrointestinal ulceration. We randomly allocated 139 patients via a computer-based system to prednisone alone or in combination with either ciclosporin or methotrexate. We did not mask patients or investigators to treatment assignments. Our primary outcomes were the proportion of patients achieving a juvenile dermatomyositis PRINTO 20 level of improvement (20% improvement in three of six core set variables at 6 months), time to clinical remission, and time to treatment failure. We compared the three treatment groups with the Kruskal-Wallis test and Friedman's test, and we analysed survival with Kaplan-Meier curves and the log-rank test. Analysis was by intention to treat. Here, we present results after at least 2 years of treatment (induction and maintenance phases). This trial is registered with ClinicalTrials.gov, number NCT00323960. Between May 31, 2006, and Nov 12, 2010, 47 patients were randomly assigned prednisone alone, 46 were allocated prednisone plus ciclosporin, and 46 were randomised prednisone plus methotrexate. Median duration of follow-up was 35.5 months. At month 6, 24 (51%) of 47 patients assigned prednisone, 32 (70%) of 46 allocated prednisone plus ciclosporin, and 33 (72%) of 46 administered prednisone plus methotrexate achieved a juvenile dermatomyositis PRINTO 20 improvement (p=0.0228). Median time to clinical remission was 41.9 months in patients assigned prednisone plus methotrexate but was not observable in the other two treatment groups (2.45 fold [95% CI 1.2-5.0] increase with prednisone plus methotrexate; p=0.012). Median time to treatment failure was 16.7 months in patients allocated prednisone, 53.3 months in those assigned prednisone plus ciclosporin, but was not observable in patients randomised to prednisone plus methotrexate (1.95 fold [95% CI 1.20-3.15] increase with prednisone; p=0.009). Median time to prednisone discontinuation was 35.8 months with prednisone alone compared with 29.4-29.7 months in the combination groups (p=0.002). A significantly greater proportion of patients assigned prednisone plus ciclosporin had adverse events, affecting the skin and subcutaneous tissues, gastrointestinal system, and general disorders. Infections and infestations were significantly increased in patients assigned prednisone plus ciclosporin and prednisone plus methotrexate. No patients died during the study. Combined treatment with prednisone and either ciclosporin or methotrexate was more effective than prednisone alone. The safety profile and steroid-sparing effect favoured the combination of prednisone plus methotrexate. Italian Agency of Drug Evaluation, Istituto Giannina Gaslini (Genoa, Italy), Myositis Association (USA).


Collaboration between community pharmacists and family physicians: lessons learned from the Seniors Medication Assessment Research Trial.
To learn about the experiences of specially trained expanded role pharmacists (ERPs) and family physicians in a program in which they worked together to optimize drug therapy for elderly patients (aged 65 and older) and to identify shortcomings of the program, obstacles to its implementation, and strategies to overcome these obstacles. Qualitative opinion analysis. Six family physicians and six community-based ERPs who had participated in a randomized controlled trial (Seniors Medication Assessment Research Trial [SMART]). In-depth interviews. Themes that emerged from the interviews regarding the strengths and weaknesses of and ways to improve the program. ERPs and physicians differed in their perceptions of appropriate roles for ERPs. ERPs saw the program as an opportunity to take on new professional roles. Physicians appreciated the information they received from ERPs about their patients' adherence and use of nonprescription medications, but they did not want ERPs to directly counsel their patients. Some physicians questioned the value of the program for some patients, since the inclusion criteria for patients were broad and not all patients meeting the criteria needed intense interventions by ERPs. Both ERPs and physicians identified the need to refine the referral process and to work out professional role relationships and ongoing collaboration more fully. If the program were to be implemented as a routine service, physicians were concerned about the demands on their staff and office space and the need for an external compensation mechanism. Issues to be addressed for future programs include clarification of the roles of pharmacist and physician when the professionals work together, targeting of appropriate patients for the program, identification of a more efficient way to deliver recommendations, and development of an appropriate compensation mechanism.


Nursing workload in hematopoietic stem cell transplantation: a cohort study.
Objective Measure nursing workload required by patients submitted to autologous and allogeneic hematopoietic stem cell transplantation (HSCT) and analyze the Nursing Activities Score (NAS) of the nursing team during the hospitalization period for HSCT. Method A prospective cohort study conducted from January 2013 to April 2014 with 62 patients hospitalized in the HSCT unit of a university hospital in Campinas, São Paulo, Brazil. The workload was measured through NAS and data analysis was through chi-square test or Fisher's exact test, Mann-Whitney test and Spearman's correlation coefficient; with 5% significance level. Results Mean nursing workload was 67.3% (SD of 8.2) in autologous HSCT patients and 72.4% (SD of 13.0) in allogeneic HSCT patients (p=0.1380).Monitoring and titration showed, in more than 50% of the time, patients demanded intensified care, requiring two hours or more in a nursing shift for reasons of safety, severity or therapy. Conclusion The nursing workload and the NAS items with the highest scores reflect the magnitude, complexity and specificity of care required by patients submitted to HSCT.


Fermentative hydrogen production from glucose and starch using pure strains and artificial co-cultures ofClostridium spp.
Pure bacterial strains give better yields when producing H2 than mixed, natural communities. However the main drawback with the pure cultures is the need to perform the fermentations under sterile conditions. Therefore, H2 production using artificial co-cultures, composed of well characterized strains, is one of the directions currently undertaken in the field of biohydrogen research. Four pure Clostridium cultures, including C. butyricum CWBI1009, C. pasteurianum DSM525, C. beijerinckii DSM1820 and C. felsineum DSM749, and three different co-cultures composed of (1) C. pasteurianum and C. felsineum, (2) C. butyricum and C. felsineum, (3) C. butyricum and C. pasteurianum, were grown in 20 L batch bioreactors. In the first part of the study a strategy composed of three-culture sequences was developed to determine the optimal pH for H2 production (sequence 1); and the H2-producing potential of each pure strain and co-culture, during glucose (sequence 2) and starch (sequence 3) fermentations at the optimal pH. The best H2 yields were obtained for starch fermentations, and the highest yield of 2.91 mol H2/ mol hexose was reported for C. butyricum. By contrast, the biogas production rates were higher for glucose fermentations and the highest value of 1.5 L biogas/ h was observed for the co-culture (1). In general co-cultures produced H2 at higher rates than the pure Clostridium cultures, without negatively affecting the H2 yields. Interestingly, all the Clostridium strains and co-cultures were shown to utilize lactate (present in a starch-containing medium), and C. beijerinckii was able to re-consume formate producing additional H2. In the second part of the study the co-culture (3) was used to produce H2 during 13 days of glucose fermentation in a sequencing batch reactor (SBR). In addition, the species dynamics, as monitored by qPCR (quantitative real-time PCR), showed a stable coexistence of C. pasteurianum and C. butyricum during this fermentation. The four pure Clostridium strains and the artificial co-cultures tested in this study were shown to efficiently produce H2 using glucose and starch as carbon sources. The artificial co-cultures produced H2 at higher rates than the pure strains, while the H2 yields were only slightly affected.


Targeting market segment needs with public-good crop breeding investments: A case study with potato and sweetpotato focused on poverty alleviation, nutrition and gender.
Crop breeding programs have often focused on the release of new varieties that target yield improvement to achieve food security and reduce poverty. While continued investments in this objective are justified, there is a need for breeding programs to be increasingly more demand-driven and responsive to the changing customer preferences and population dynamics. This paper analyses the responsiveness of global potato and sweetpotato breeding programs pursued by the International Potato Center (CIP) and its partners to three major development indicators: poverty, malnutrition and gender. The study followed a seed product market segmentation blueprint developed by the Excellence in Breeding platform (EiB) to identify, describe, and estimate the sizes of the market segments at subregional levels. We then estimated the potential poverty and nutrition impacts of investments in the respective market segments. Further, we employed the G+ tools involving multidisciplinary workshops to evaluate the gender-responsiveness of the breeding programs. Our analysis reveals that future investments in breeding programs will achieve greater impacts by developing varieties for market segments and pipelines that have more poor rural people, high stunting rates among children, anemia prevalence among women of reproductive age, and where there is high vitamin A deficiency. In addition, breeding strategies that reduce gender inequality and enhance appropriate change of gender roles (hence gender transformative) are also required.


Strong Rashba-Edelstein Effect-Induced Spin-Orbit Torques in Monolayer Transition Metal Dichalcogenide/Ferromagnet Bilayers.
The electronic and optoelectronic properties of two-dimensional materials have been extensively explored in graphene and layered transition metal dichalcogenides (TMDs). Spintronics in these two-dimensional materials could provide novel opportunities for future electronics, for example, efficient generation of spin current, which should enable the efficient manipulation of magnetic elements. So far, the quantitative determination of charge current-induced spin current and spin-orbit torques (SOTs) on the magnetic layer adjacent to two-dimensional materials is still lacking. Here, we report a large SOT generated by current-induced spin accumulation through the Rashba-Edelstein effect in the composites of monolayer TMD (MoS2 or WSe2)/CoFeB bilayer. The effective spin conductivity corresponding to the SOT turns out to be almost temperature-independent. Our results suggest that the charge-spin conversion in the chemical vapor deposition-grown large-scale monolayer TMDs could potentially lead to high energy efficiency for magnetization reversal and convenient device integration for future spintronics based on two-dimensional materials.


Iron load and redox stress in skeletal muscle of aged rats.
Loss of skeletal muscle mass (sarcopenia) is a major contributor to disability in old age. We used two-dimensional gel electrophoresis and mass spectrometry to screen for changes in proteins, and cDNA profiling to assess transcriptional regulations in the gastrocnemius muscle of adult (4 months) and aged (30 months) male Sprague-Dawley rats. Thirty-five proteins were differentially expressed in aged muscle. Proteins and mRNA transcripts involved in redox homeostasis and iron load were increased, representing novel components that were previously not associated with sarcopenia. Tissue iron levels were elevated in senescence, paralleling an increase in transferrin. Proteins involved in redox homeostasis showed a complex pattern of changes with increased SOD1 and decreased SOD2. These results suggest that an elevated iron load is a significant component of sarcopenia with the potential to be exploited clinically, and that mitochondria of aged striated muscle may be more vulnerable to radicals produced in cell respiration.


Perinatal glucocorticoid treatment produces molecular, functional, and morphological changes in the anterior pituitary gland of the adult male rat.
Stress or glucocorticoid (GC) treatment in perinatal life can induce long-term changes in the sensitivity of the hypothalamo-pituitary-adrenocortical axis to the feedback actions of GCs and, hence, in GC secretion. These changes have been ascribed largely to changes in the sensitivity of the limbic system, and possibly the hypothalamus, to GCs. Surprisingly, the possibility that early life stress/GC treatment may also exert irreversible effects at the pituitary level has scarcely been addressed. Accordingly, we have examined the effects of pre- and neonatal dexamethasone treatment on the adult male pituitary gland, focusing on the following: 1) the integrity of the acute annexin 1 (ANXA1)-dependent inhibitory actions of GCs on ACTH secretion, a process requiring ANXA1 release from folliculostellate (FS) cells; and 2) the morphology of FS cells and corticotrophs. Dexamethasone was given to pregnant (d 16-19) or lactating (d 1-7 postpartum) rats via the drinking water (1 microg/ml); controls received normal drinking water. Pituitary tissue from the offspring was examined ex vivo at d 90. Both treatment regimens reduced ANXA1 expression, as assessed by Western blotting and quantitative immunogold labeling. In particular, the amount of ANXA1 located on the outer surface of the FS cells was reduced. By contrast, IL-6 expression was increased, particularly by the prenatal treatment. Pituitary tissue from untreated control rats responded to dexamethasone with an increase in cell surface ANXA1 and a reduction in forskolin-induced ACTH release. In contrast, pituitary tissue from rats treated prenatally or neonatally with dexamethasone was unresponsive to the steroid, although, like control tissue, it responded readily to ANXA1, which readily inhibited forskolin-driven ACTH release. Prenatal dexamethasone treatment reduced the size but not the number of FS cells. It also caused a marked reduction in corticotroph number and impaired granule margination without affecting other aspects of corticotroph morphology. Similar but less marked effects on pituitary cell morphology and number were evident in tissue from neonatally treated rats. Our study shows that, when administered by a noninvasive process, perinatal GC treatment exerts profound effects on the adult pituitary gland, impairing the ANXA1-dependent GC regulation of ACTH release and altering the cell profile and morphology.


Transcriptome analysis of the Cryptocaryon irritans tomont stage identifies potential genes for the detection and control of cryptocaryonosis.
Cryptocaryon irritans is a parasitic ciliate that causes cryptocaryonosis (white spot disease) in marine fish. Diagnosis of cryptocaryonosis often depends on the appearance of white spots on the surface of the fish, which are usually visible only during later stages of the disease. Identifying suitable biomarkers of this parasite would aid the development of diagnostic tools and control strategies for C. irritans. The C. irritans genome is virtually unexplored; therefore, we generated and analyzed expressed sequence tags (ESTs) of the parasite to identify genes that encode for surface proteins, excretory/secretory proteins and repeat-containing proteins. ESTs were generated from a cDNA library of C. irritans tomonts isolated from infected Asian sea bass, Lates calcarifer. Clustering of the 5356 ESTs produced 2659 unique transcripts (UTs) containing 1989 singletons and 670 consensi. BLAST analysis showed that 74% of the UTs had significant similarity (E-value < 10-5) to sequences that are currently available in the GenBank database, with more than 15% of the significant hits showing unknown function. Forty percent of the UTs had significant similarity to ciliates from the genera Tetrahymena and Paramecium. Comparative gene family analysis with related taxa showed that many protein families are conserved among the protozoans. Based on gene ontology annotation, functional groups were successfully assigned to 790 UTs. Genes encoding excretory/secretory proteins and membrane and membrane-associated proteins were identified because these proteins often function as antigens and are good antibody targets. A total of 481 UTs were classified as encoding membrane proteins, 54 were classified as encoding for membrane-bound proteins, and 155 were found to contain excretory/secretory protein-coding sequences. Amino acid repeat-containing proteins and GPI-anchored proteins were also identified as potential candidates for the development of diagnostic and control strategies for C. irritans. We successfully discovered and examined a large portion of the previously unexplored C. irritans transcriptome and identified potential genes for the development and validation of diagnostic and control strategies for cryptocaryonosis.


Dynamics of the heart rate variability and oxygen saturation response to acute normobaric hypoxia within the first 10 min of exposure.
Although the heart rate variability (HRV) response to hypoxia has been studied, little is known about the dynamics of HRV after hypoxia exposure. The purpose of this study was to assess the HRV and oxygen saturation (SpO2 ) responses to normobaric hypoxia (FiO2 = 9·6%) comparing 1 min segments to baseline (normoxia). Electrocardiogram and SpO2 were recorded during a 10-min hypoxia exposure in 29 healthy male subjects aged 26·0 ± 4·9 years. Baseline HRV values were obtained from a 5-min recording period prior to hypoxia. The hypoxia period was split into 10 non-overlapping 1-min segments and time domain HRV indexes (RMSSD and SDNN) were calculated for each segment. Differences (Δ) from baseline values were calculated and transformed using natural logarithm (Ln). This study revealed that the decrease in ΔSpO2 became significant (P<0·001) in the first minute of hypoxia, the decrease in ΔLn RMSSD became significant (P = 0·002) in the second minute, and the decrease in ΔLn SDNN became significant (P = 0·001) in the third minute. Between the second and fifth minute of hypoxia, ΔSpO2 correlated with ΔLn RMSSD (r = 0·57, P<0·001) and ΔLn SDNN (r = 0·44, P<0·001). Five min after the onset of hypoxia, ΔSpO2 was significantly (P = 0·002) decreased but changes in ΔLn RMSSD (P = 0·344) and ΔLn SDNN (P = 0·558) were not significant. In conclusion, the decrease in HRV was proportional to desaturation but only during the first 5 min of hypoxia.


Controlled mineralisation and recrystallisation of brushite within alginate hydrogels.
Due to high solubility and fast resorption behaviour under physiological conditions, brushite (CaHPO4⋅2H2O, calcium monohydrogen phosphate dihydrate, dicalcium phosphate dihydrate) has great potential in bone regeneration applications, both in combination with scaffolds or as a component of calcium phosphate cements. The use of brushite in combination with hydrogels opens up possibilities for new cell-based tissue engineering applications of this promising material. However, published preparation methods of brushite composites, in which the mineral phase is precipitated within the hydrogel network, fail to offer the necessary degree of control over the mineral phase, content and distribution within the hydrogel matrix. The main focus of this study is to address these shortcomings by determining the precise fabrication parameters needed to prepare composites with controlled composition and properties. Composite alginate microbeads were prepared using a counter-diffusion technique, which allows for the simultaneous crosslinking of the hydrogel and precipitation of an inorganic mineral phase. Reliable nucleation of a desired mineral phase within the alginate network proved more challenging than simple aqueous precipitation. This was largely due to ion transport within the hydrogel producing concentration gradients that modified levels of supersaturation and favoured the nucleation of other phases such as hydroxyapatite and octacalcium phosphate, which would otherwise not form. To overcome this, the incorporation of brushite seed crystals resulted in good control during the mineral phase, and by adjusting the number of seeds and amount of precursor concentration, the amount of mineral could be tuned. The material was characterised with a range of physical techniques, including scanning electron microscopy, powder x-ray diffraction and Rietveld refinement, Fourier transform infrared spectroscopy, and thermogravimetric analysis, in order to assess the mineral morphology, phase and amount within the organic matrix. The mineral content of the composite material converted from brushite into hydroxyapatite when submerged in simulated body fluid, indicating possible bioactivity. Additionally, initial cell culture studies revealed that both the material and the synthesis procedure are compatible with cells relevant to bone tissue engineering.


Cyclin G-associated kinase is necessary for osteosarcoma cell proliferation and receptor trafficking.
Osteosarcoma is the most frequent primary malignant bone tumor among the children. The advent of neoadjuvant chemotherapy significantly improved the prognosis of patients with osteosarcoma in the 1980s, but it has since plateaued in the past decades. Recently, one of the most researched areas in sarcoma treatment is tyrosine kinases. Here, we describe research on a serine/threonine kinase, cyclin G-associated kinase (GAK), which has not been reported in osteosarcoma previously. In this study, a lentiviral based human shRNA library was utilized to screen for kinases in KHOS and U-2OS osteosarcoma cells. The expression of GAK was examined in osteosarcoma and the effect on cell proliferation was analyzed by GAK siRNA knockdown. The level of GAK expression and its correlation to prognosis was analyzed in osteosarcoma tissue microarray. The effect of GAK depletion on insulin-like growth factor and epidermal growth factor receptor-mediated signal transduction was analyzed by Western blot. We observed that GAK was overexpressed in both osteosarcoma cell lines and tissue samples when compared with human osteoblasts. GAK knockdown by siRNA decreased cell proliferation in both drug-sensitive and multidrug-resistant osteosarcoma cell lines. Immunohistochemistry of osteosarcoma tissue microarray revealed that overexpression of GAK was associated with poor prognosis. Finally, knockdown of GAK resulted in alterations of receptor trafficking and several downstream proteins. In conclusion, our results suggest that osteosarcoma cell proliferation and survival are dependent on GAK. These findings may lead to the development of new therapeutic options for osteosarcoma.


Catalytic alkylation of remote C-H bonds enabled by proton-coupled electron transfer.
Despite advances in hydrogen atom transfer (HAT) catalysis, there are currently no molecular HAT catalysts that are capable of homolysing the strong nitrogen-hydrogen (N-H) bonds of N-alkyl amides. The motivation to develop amide homolysis protocols stems from the utility of the resultant amidyl radicals, which are involved in various synthetically useful transformations, including olefin amination and directed carbon-hydrogen (C-H) bond functionalization. In the latter process-a subset of the classical Hofmann-Löffler-Freytag reaction-amidyl radicals remove hydrogen atoms from unactivated aliphatic C-H bonds. Although powerful, these transformations typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, because these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of carbon-carbon (C-C) bonds. Here we report an approach that overcomes these limitations by homolysing the N-H bonds of N-alkyl amides via proton-coupled electron transfer. In this protocol, an excited-state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resultant amidyl radical intermediates are shown to promote subsequent C-H abstraction and radical alkylation steps. This C-H alkylation represents a catalytic variant of the Hofmann-Löffler-Freytag reaction, using simple, unfunctionalized amides to direct the formation of new C-C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, this study demonstrates that concerted proton-coupled electron transfer can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.


Imported human African trypanosomiasis in Europe, 2005-2009.
Physicians in Europe are likely to see more African trypanosomiasis cases because of the increasing popularity of travel to Africa. In this paper the literature on imported cases in Europe, since 2005 is reviewed. Because of the high mortality risk associated with acute Rhodesian trypanosomiasis, travellers should be informed about preventive measures and the early disease manifestations.


The LOV protein of Xanthomonas citri subsp. citri plays a significant role in the counteraction of plant immune responses during citrus canker.
Pathogens interaction with a host plant starts a set of immune responses that result in complex changes in gene expression and plant physiology. Light is an important modulator of plant defense response and recent studies have evidenced the novel influence of this environmental stimulus in the virulence of several bacterial pathogens. Xanthomonas citri subsp. citri is the bacterium responsible for citrus canker disease, which affects most citrus cultivars. The ability of this bacterium to colonize host plants is influenced by bacterial blue-light sensing through a LOV-domain protein and disease symptoms are considerably altered upon deletion of this protein. In this work we aimed to unravel the role of this photoreceptor during the bacterial counteraction of plant immune responses leading to citrus canker development. We performed a transcriptomic analysis in Citrus sinensis leaves inoculated with the wild type X. citri subsp. citri and with a mutant strain lacking the LOV protein by a cDNA microarray and evaluated the differentially regulated genes corresponding to specific biological processes. A down-regulation of photosynthesis-related genes (together with a corresponding decrease in photosynthesis rates) was observed upon bacterial infection, this effect being more pronounced in plants infected with the lov-mutant bacterial strain. Infection with this strain was also accompanied with the up-regulation of several secondary metabolism- and defense response-related genes. Moreover, we found that relevant plant physiological alterations triggered by pathogen attack such as cell wall fortification and tissue disruption were amplified during the lov-mutant strain infection. These results suggest the participation of the LOV-domain protein from X. citri subsp. citri in the bacterial counteraction of host plant defense response, contributing in this way to disease development.


Involvement of mitochondrial dysfunction and ER-stress in the physiopathology of equine osteochondritis dissecans (OCD).
Osteochondrosis (OC) is a developmental bone disorder affecting several mammalian species including the horse. Equine OC is described as a focal disruption of endochondral ossification, leading to osteochondral lesions (osteochondritis dissecans, OCD) that may release free bodies within the joint. OCD lesions trigger joint swelling, stiffness and lameness and affects about 30% of the equine population. OCD is considered as multifactorial but its physiopathology is still poorly understood and genes involved in genetic predisposition are still unknown. Our study compared two healthy and two OC-affected 18-month-old French Trotters diagnosed with OCD lesions at the intermediate ridge of the distal tibia. A comparative shot-gun proteomic analysis of non-wounded cartilage and sub-chondral bone from healthy (healthy samples) and OC-affected foals (predisposed samples) identified 83 and 53 modulated proteins, respectively. These proteins are involved in various biological pathways including matrix structure and maintenance, protein biosynthesis, folding and transport, mitochondrial activity, energy and calcium metabolism. Transmission electron microscopy revealed typical features of mitochondrial swelling and ER-stress, such as large, empty mitochondria, and hyper-dilated rough endoplasmic reticulum, in the deep zone of both OC lesions and predisposed cartilage. Abnormal fibril organization surrounding chondrocytes and abnormal features at the ossification front were also observed. Combining these findings with quantitative trait loci and whole genome sequencing results identified about 140 functional candidate genes carrying putative damaging mutations in 30 QTL regions. In summary, our study suggests that OCD lesions may result from defective hypertrophic terminal differentiation associated with mitochondrial dysfunction and ER-stress, leading to impaired cartilage and bone biomechanical properties, making them prone to fractures. In addition, 11 modulated proteins and several candidate mutations located in QTL regions were identified, bringing new insight into the molecular physiopathology and genetic basis of OCD.


Learned Embeddings from Deep Learning to Visualize and Predict Protein Sets.
Models from machine learning (ML) or artificial intelligence (AI) increasingly assist in guiding experimental design and decision making in molecular biology and medicine. Recently, Language Models (LMs) have been adapted from Natural Language Processing (NLP) to encode the implicit language written in protein sequences. Protein LMs show enormous potential in generating descriptive representations (embeddings) for proteins from just their sequences, in a fraction of the time with respect to previous approaches, yet with comparable or improved predictive ability. Researchers have trained a variety of protein LMs that are likely to illuminate different angles of the protein language. By leveraging the bio_embeddings pipeline and modules, simple and reproducible workflows can be laid out to generate protein embeddings and rich visualizations. Embeddings can then be leveraged as input features through machine learning libraries to develop methods predicting particular aspects of protein function and structure. Beyond the workflows included here, embeddings have been leveraged as proxies to traditional homology-based inference and even to align similar protein sequences. A wealth of possibilities remain for researchers to harness through the tools provided in the following protocols. © 2021 The Authors. Current Protocols published by Wiley Periodicals LLC. The following protocols are included in this manuscript: Basic Protocol 1: Generic use of the bio_embeddings pipeline to plot protein sequences and annotations Basic Protocol 2: Generate embeddings from protein sequences using the bio_embeddings pipeline Basic Protocol 3: Overlay sequence annotations onto a protein space visualization Basic Protocol 4: Train a machine learning classifier on protein embeddings Alternate Protocol 1: Generate 3D instead of 2D visualizations Alternate Protocol 2: Visualize protein solubility instead of protein subcellular localization Support Protocol: Join embedding generation and sequence space visualization in a pipeline.


Osseointegration of nanohydroxyapatite- or nano-calcium silicate-incorporated polyetheretherketone bioactive composites in vivo.
Polyetheretherketone (PEEK) exhibits appropriate biomechanical strength as well as good biocompatibility and stable chemical properties but lacks bioactivity and cannot achieve highly efficient osseointegration after implantation. Incorporating bioceramics into the PEEK matrix is a feasible approach for improving its bioactivity. In this study, nanohydroxyapatite (n-HA) and nano-calcium silicate (n-CS) were separately incorporated into PEEK to prepare n-HA/PEEK and n-CS/PEEK biocomposites, respectively, using a compounding and injection-molding technique, and the in vitro degradation characteristics were evaluated. Discs with a diameter of 8 mm were inserted in 8 mm full-thickness cranial defects in rabbits for 4 and 8 weeks, and implantation of pure PEEK was used as the control. Three-dimensional microcomputed tomography, histological analysis, fluorescence microscopy of new bone formation, and scanning electron microscopy were used to evaluate the osseointegration performance at the bone/implant interface. The results of the in vitro degradation study demonstrated that degradation of n-CS on the surface of n-CS/PEEK could release Ca and Si ions and form a porous structure. In vivo tests revealed that both n-CS/PEEK and n-HA/PEEK promoted osseointegration at the bone/implant interface compared to PEEK, and n-CS/PEEK exhibited higher bone contact ratio and more new bone formation compared with those of n-HA/PEEK, implying that n-CS/PEEK possessed a stronger ability to promote osseointegration. These two PEEK biocomposites are promising materials for the preparation of orthopedic or craniofacial implants.


Audiovisual biofeedback breathing guidance for lung cancer patients receiving radiotherapy: a multi-institutional phase II randomised clinical trial.
There is a clear link between irregular breathing and errors in medical imaging and radiation treatment. The audiovisual biofeedback system is an advanced form of respiratory guidance that has previously demonstrated to facilitate regular patient breathing. The clinical benefits of audiovisual biofeedback will be investigated in an upcoming multi-institutional, randomised, and stratified clinical trial recruiting a total of 75 lung cancer patients undergoing radiation therapy. To comprehensively perform a clinical evaluation of the audiovisual biofeedback system, a multi-institutional study will be performed. Our methodological framework will be based on the widely used Technology Acceptance Model, which gives qualitative scales for two specific variables, perceived usefulness and perceived ease of use, which are fundamental determinants for user acceptance. A total of 75 lung cancer patients will be recruited across seven radiation oncology departments across Australia. Patients will be randomised in a 2:1 ratio, with 2/3 of the patients being recruited into the intervention arm and 1/3 in the control arm. 2:1 randomisation is appropriate as within the interventional arm there is a screening procedure where only patients whose breathing is more regular with audiovisual biofeedback will continue to use this system for their imaging and treatment procedures. Patients within the intervention arm whose free breathing is more regular than audiovisual biofeedback in the screen procedure will remain in the intervention arm of the study but their imaging and treatment procedures will be performed without audiovisual biofeedback. Patients will also be stratified by treating institution and for treatment intent (palliative vs. radical) to ensure similar balance in the arms across the sites. Patients and hospital staff operating the audiovisual biofeedback system will complete questionnaires to assess their experience with audiovisual biofeedback. The objectives of this clinical trial is to assess the impact of audiovisual biofeedback on breathing motion, the patient experience and clinical confidence in the system, clinical workflow, treatment margins, and toxicity outcomes. This clinical trial marks an important milestone in breathing guidance studies as it will be the first randomised, controlled trial providing the most comprehensive evaluation of the clinical impact of breathing guidance on cancer radiation therapy to date. This study is powered to determine the impact of AV biofeedback on breathing regularity and medical image quality. Objectives such as determining the indications and contra-indications for the use of AV biofeedback, evaluation of patient experience, radiation toxicity occurrence and severity, and clinician confidence will shed light on the design of future phase III clinical trials. This trial has been registered with the Australian New Zealand Clinical Trials Registry (ANZCTR), its trial ID is ACTRN12613001177741 .


Orthophosphate-P in the nutrient impacted River Taw and its catchment (SW England) between 1990 and 2013.
Excess dissolved phosphorus (as orthophosphate-P) contributes to reduced river water quality within Europe and elsewhere. This study reports results from analysis of a 23 year (1990-2013) water quality dataset for orthophosphate-P in the rural Taw catchment (SW England). Orthophosphate-P and river flow relationships and temporal variations in orthophosphate-P concentrations indicate the significant contribution of sewage (across the catchment) and industrial effluent (upper R. Taw) to orthophosphate-P concentrations (up to 96%), particularly during the low flow summer months when maximum algal growth occurs. In contrast, concentrations of orthophosphate-P from diffuse sources within the catchment were more important (>80%) at highest river flows. The results from a 3 end-member mixing model incorporating effluent, groundwater and diffuse orthophosphate-P source terms suggested that sewage and/or industrial effluent contributes ≥50% of the orthophosphate-P load for 27-48% of the time across the catchment. The Water Framework Directive (WFD) Phase 2 standards for reactive phosphorus, introduced in 2015, showed the R. Taw to be generally classified as Poor to Moderate Ecological Status, with a Good Status occurring more frequently in the tributary rivers. Failure to achieve Good Ecological Status occurred even though, since the early-2000s, riverine orthophosphate-P concentrations have decreased (although the mechanism(s) responsible for this could not be identified). For the first time it has been demonstrated that sewage and industrial effluent sources of alkalinity to the river can give erroneous boundary concentrations of orthophosphate-P for WFD Ecological Status classification, the extent of which is dependent on the proportion of effluent alkalinity present. This is likely to be a European - wide issue which should be examined in more detail.


Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria.
The single-dose pharmacokinetics of 100 mg of orally administered artesunate (AS) were studied in 6 patient volunteers with uncomplicated falciparum malaria and in 6 healthy volunteers. Plasma concentrations of both the parent drug, AS, and its major metabolite, dihydroartemisinin (DHA), were measured simultaneously by high-performance liquid chromatography (HPLC) with electrochemical detection (ECD). The antimalarial activity of each plasma sample measured by an in vitro bioassay (BA) was used to derive activity concentrations. Artesunate was absorbed rapidly and then almost completely hydrolyzed to DHA in patients, whereas hydrolysis was incomplete in healthy volunteers. The mean +/- standard deviation (SD) maximum concentration (Cmax) of AS was 296+/-110 nmol/L, the time to peak blood level (tmax was 0.71+/-0.66 hr, the half-life (t1/2,z) was 0.41+/-0.34 hr, and the bioavailability over 12 hr (area under the curve [AUC](0-12)) was 253+/-185 nmol hr/L. Measured by HPLC, the Cmax and AUC(0-12) values of DHA in patients with malaria were significantly greater than in volunteers (1,948+/-772 and 1,192+/-315 nmol/L; 4,024+/-1,585 and 1,763+/-607 nmol hr/L, respectively; P < or = 0.05). These differences were even greater when measured by BA. The Cmax for patients with malaria was 2,894+/-2,497 and 795+/-455 nmol/L for volunteers, and AUC(0-12) was 5,970+/-3,625 and 1,307+/-391 nmol hr/L, respectively (P < or = 0.05). In contrast, DHA parameter estimates for t1/2,z and tmax were similar between patients and healthy volunteers, with values of 0.80+/-0.30 versus 0.87+/-0.06 hr and 1.50+/-0.55 versus 1.13+/-0.52 hr, respectively (P > 0.5). Both drug metabolism and tissue protein binding could contribute to the differences between the antimalarial activity of artemisinin drugs in healthy volunteers and malaria infected patients.


The heritability of cause-specific mortality: a correlated gamma-frailty model applied to mortality due to respiratory diseases in Danish twins born 1870-1930.
The genetic influence on susceptibility to diseases of the respiratory system and all-cause mortality was studied using data for identical (MZ) and fraternal (DZ) twins. Data from the Danish Twin Register include 1344 MZ and 2411 DZ male twin pairs and 1470 MZ and 2730 DZ female twin pairs born between 1870 and 1930, where both individuals were alive on 1 011943. We used the correlated gamma-frailty model. Proportions of variance in frailty attributable to genetic and environmental factors were assessed using the structural equation model approach. For all-cause mortality the correlation coefficients of frailty for MZ twins tend to be higher than for DZ twins. For mortality with respect to respiratory diseases this effect was only seen in females, whereas males showed the opposite effect. Five standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best fitting biometric model heritability for cause of death was found to be 0.58 (0.07) for all-cause mortality (AE-model) and zero for diseases of the respiratory system for males. Heritability was 0.63 (0.11) for all-cause mortality (DE-model) and 0.18 (0.09) for diseases of the respiratory system (DE-model) for females. The analysis confirms the presence of a strong genetic influence on individual frailty associated with all-cause mortality. For respiratory diseases, no genetic influence was found in males and only weak genetic influence in females. The nature of genetic influences on frailty with respect to all-cause mortality is probably additive in males and dominant in females, whereas for frailty with respect to deaths caused by respiratory diseases in females, there are genetic factors present which are caused by dominance. Environmental influences are non-shared with exception of frailty with respect to respiratory diseases in males, where the shared environment plays an important role.


Molecular cloning, in vitro expression and bioactivity of quail BAFF.
B cell activating factor (BAFF), belonging to the TNF (tumor necrosis factor) family, is critical for B cell survival and maturation. In the present study, a quail BAFF cDNA, named qBAFF, was amplified from quail spleen by RT-PCR and RACE (rapid amplification of cDNA ends) strategies. The open reading frame (ORF) of qBAFF cDNA encodes a protein consisting of 288-amino acid. The deduced amino acid sequence contains a predicted transmembrane domain and a putative furin protease cleavage site like other identified BAFF homologues. The qBAFF shows 96, 93, 93, 53 and 51% amino acid sequence identity with chicken (cBAFF), goose (gBAFF), duck (dBAFF), human (hBAFF) and mouse BAFF (mBAFF), respectively, with the functional soluble parts of qBAFF is 98, 99, 98, 78 and 71%, respectively. RT-PCR showed that BAFF is expressed in many tissues in the quail, including bursa, spleen, liver, brain, heart, intestine, kidney, thymus and muscle. Recombinant soluble qBAFF (qsBAFF) fused with His(6) tag was efficiently expressed in Escherichia coli BL21 (DE3) and its molecular weight of approximately 19kDa was identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. In vitro, purified qsBAFF was able to promote the survival of quail bursa B cells. Our results suggest that qBAFF plays an important role in survival of quail B cells cultured in vitro.


Hearing of microwave pulses by humans and animals: effects, mechanism, and thresholds.
The hearing of microwave pulses is a unique exception to the airborne or bone-conducted sound energy normally encountered in human auditory perception. The hearing apparatus commonly responds to airborne or bone-conducted acoustic or sound pressure waves in the audible frequency range. But the hearing of microwave pulses involves electromagnetic waves whose frequency ranges from hundreds of MHz to tens of GHz. Since electromagnetic waves (e.g., light) are seen but not heard, the report of auditory perception of microwave pulses was at once astonishing and intriguing. Moreover, it stood in sharp contrast to the responses associated with continuous-wave microwave radiation. Experimental and theoretical studies have shown that the microwave auditory phenomenon does not arise from an interaction of microwave pulses directly with the auditory nerves or neurons along the auditory neurophysiological pathways of the central nervous system. Instead, the microwave pulse, upon absorption by soft tissues in the head, launches a thermoelastic wave of acoustic pressure that travels by bone conduction to the inner ear. There, it activates the cochlear receptors via the same process involved for normal hearing. Aside from tissue heating, microwave auditory effect is the most widely accepted biological effect of microwave radiation with a known mechanism of interaction: the thermoelastic theory. The phenomenon, mechanism, power requirement, pressure amplitude, and auditory thresholds of microwave hearing are discussed in this paper. A specific emphasis is placed on human exposures to wireless communication fields and magnetic resonance imaging (MRI) coils.


Lack of uniformity in diagnostic labeling of shoulder pain: time for a different approach.
Diagnostic labels for shoulder pain (e.g., frozen shoulder, impingement syndrome) are widely used in international research and clinical practice. However, about 10 years ago it was shown that the criteria to define those labels were not uniform. Since an ongoing lack of uniformity seriously hampers communication and does not serve patients, we decided to evaluate the uniformity in definitions. Therefore, we compared the selection criteria of different randomised controlled trials (RCTs). This comparison revealed some corresponding criteria, but no uniform definition could be derived for any of the diagnostic labels. Besides the lack of uniformity, the currently used labels have only a fair to moderate interobserver reproducibility and in systematic reviews none of the separate trials using a diagnostic label show a large benefit of treatment. This, altogether, seems sufficient reason to reconsider their use. Therefore, we strongly suggest to abolish the use of these labels and direct future research towards undivided populations with "general" shoulder pain. Possible subgroups with a better prognosis and/or treatment result, based on common characteristics that are easily and validly reproducible, can then be identified within these populations.


Autonomous Sensory Meridian Response (ASMR): a flow-like mental state.
Autonomous Sensory Meridian Response (ASMR) is a previously unstudied sensory phenomenon, in which individuals experience a tingling, static-like sensation across the scalp, back of the neck and at times further areas in response to specific triggering audio and visual stimuli. This sensation is widely reported to be accompanied by feelings of relaxation and well-being. The current study identifies several common triggers used to achieve ASMR, including whispering, personal attention, crisp sounds and slow movements. Data obtained also illustrates temporary improvements in symptoms of depression and chronic pain in those who engage in ASMR. A high prevalence of synaesthesia (5.9%) within the sample suggests a possible link between ASMR and synaesthesia, similar to that of misophonia. Links between number of effective triggers and heightened flow state suggest that flow may be necessary to achieve sensations associated with ASMR.


Dynamic analysis of dark-light changes of the anterior chamber angle with anterior segment OCT.
To describe the use of anterior segment optical coherence tomography (OCT) in studying the dynamic dark-light changes of the anterior chamber angle. Thirty-seven normal subjects with open angles on dark-room gonioscopy and 18 subjects with narrow angles were analyzed. The dynamic dark-light changes of the anterior-chamber angle were captured with real-time video recording. The angle opening distance (AOD500) and trabecular iris space area (TISA500) of the nasal angle and the pupil diameter in each of the representative serial images were measured. Linear regression analysis was performed to investigate the association between AOD500/TISA500 and pupil diameter. Demographic and biometry measurements associated with the AOD difference (AOD500((light)) - AOD500((dark))) and TISA difference (TISA500((light)) - TISA500((dark))) were analyzed with univariate and multivariate regression models. The AOD500/TISA500 measured in the light in the open-angle and the narrow-angle groups were 694 +/- 330 microm/0.24 +/- 0.10 mm(2) and 265 +/- 78 microm/0.10 +/- 0.03 mm(2), respectively. These values were significantly greater than the AOD500/TISA500 measured in the dark (492 +/- 265 microm/0.16 +/- 0.08 mm(2) and 119 +/- 82 microm/0.05 +/- 0.04 mm(2), respectively, all with P < 0.001). The ranges of the AOD/TISA difference were 13 to 817 microm/0.011 to 0.154 mm(2), with an average of 180 microm/0.073 mm(2). Multivariate regression analysis identified a positive correlation between anterior chamber depth and the AOD/TISA difference. Fifty eyes showed significant correlations between AOD/TISA and pupil diameter, whereas one eye showed no association. Four eyes in the narrow angle group developed appositional angle closure in the dark. The dynamic dark-light changes of the anterior chamber angle can be imaged and analyzed with anterior segment OCT. Although the angle width generally decreased linearly with increasing pupil diameter, the differences of the angle width measured in the dark and in the light varied substantially among individuals.


Public health genomics: the interface with public health intelligence and the role of public health observatories.
Public health genomics is a new field that brings the findings of research in genetic and molecular technologies together with public health. The purpose of this paper is to examine the interface between this new emerging field and that of public health intelligence. We describe the possible areas of integration between genomics and public health, suggesting a future potential role for the Public Health Observatories. A small group comprising of a public health geneticist and representatives from Public Health Observatories met and discussed the ways in which the public health information and intelligence community might contribute to the developing agenda of public health genomics. The results of the deliberations are presented in this paper, and a combination of short, medium and longer term possibilities are described. Also, necessary changes and additions to routinely collected data are proposed. The emerging field of public health genomics has implications for the collection, management and analysis of routine data. The benefits of this will accrue over time, but changes need to be made now in order to make the best use of these developments. A possible supporting action plan for the development of public health genomics within Public Health Observatories is proposed.


Distribution of xanthine oxidase activity in a Nigerian population.
Xanthine oxidase (XO) is one of the two interconvertible forms of xanthine oxidoreductase and well-studied for its role in purine catabolism and that of other purine analogues, drugs especially. Our study investigated the incidence of polymorphism in phenotypes along with the influence of gender and age on enzyme activity in a Nigerian population. Caffeine (110 mg) was administered to each of 129 healthy, unrelated subjects who were nonsmokers. Urine voided within 7 h after dosing was collected for a high-performance liquid chromatographic analysis of metabolites, and the urinary molar ratio of metabolites was used as marker for enzyme activity. Statistical analysis of data was carried out to identify the prevalent phenotypes and also assessed the influence of age and sex on enzyme activity. A sevenfold variation in XO activity with a population mean (± SD) molar ratio of 0.43 ± 0.15 and median (interquartile range) of 0.42 (0.16) was observed. Distinctly higher enzyme activity was also recorded in 8% of the study population, and there was no correlation (P > 0.05) between enzyme activity and the studied covariates. Our study confirmed the existence of polymorphism in xanthine oxidase activity in Nigerians and also the incidence of individuals with distinctly higher XO activity in the population.


Tight junctional changes upon microwave and x-ray irradiation.
Tight junctions (zonulae occludentes, ZO) are cellularly regulated dynamic structures sensitive to environmental stress agents including ionizing radiation. Radiation induced pathological alterations of the small intestine (gastrointestinal radiation syndrome) are related to altered ZO-mediated paracellular transport. We carried out a quantitative morphological evaluation of the murine jejunal epithelial tight junctional structure in freeze fracture replicas as changed upon whole body X-ray irradiation and low energy microwave exposition. X-ray treatment (4 Gy, 1, 24 h) brought about a partial dearrangement of the ZO strand network which regenerated only partially by 24 h. This observation is in line with data on paracellular permeability increases and ZO-bound calcium drop caused by X-ray irradiation. On the other hand, microwave treatment (16 Hz-modulated 2.45 GHz wave, 1 mW/cm2 power density, I h exposition, samples at I and 3 h after exposition) did not cause dearrangement but, rather an increase in the integration of thight junctional structure, which is in agreement with an increase in cytochemically detectable ZO-bound calcium.


Removing spurious interactions in complex networks.
Identifying and removing spurious links in complex networks is meaningful for many real applications and is crucial for improving the reliability of network data, which, in turn, can lead to a better understanding of the highly interconnected nature of various social, biological, and communication systems. In this paper, we study the features of different simple spurious link elimination methods, revealing that they may lead to the distortion of networks' structural and dynamical properties. Accordingly, we propose a hybrid method that combines similarity-based index and edge-betweenness centrality. We show that our method can effectively eliminate the spurious interactions while leaving the network connected and preserving the network's functionalities.


TORC1-regulated protein kinase Npr1 phosphorylates Orm to stimulate complex sphingolipid synthesis.
The evolutionarily conserved Orm1 and Orm2 proteins mediate sphingolipid homeostasis. However, the homologous Orm proteins and the signaling pathways modulating their phosphorylation and function are incompletely characterized. Here we demonstrate that inhibition of nutrient-sensitive target of rapamycin complex 1 (TORC1) stimulates Orm phosphorylation and synthesis of complex sphingolipids in Saccharomyces cerevisiae. TORC1 inhibition activates the kinase Npr1 that directly phosphorylates and activates the Orm proteins. Npr1-phosphorylated Orm1 and Orm2 stimulate de novo synthesis of complex sphingolipids downstream of serine palmitoyltransferase. Complex sphingolipids in turn stimulate plasma membrane localization and activity of the nutrient scavenging general amino acid permease 1. Thus activation of Orm and complex sphingolipid synthesis upon TORC1 inhibition is a physiological response to starvation.