Evidence-based outcomes from pulmonary rehabilitation in the chronic obstructive pulmonary disease patient.
The aim of this article is to appraise the quality of evidence reported for important outcomes in pulmonary rehabilitation using the approach of the Grading of Recommendations Assessment, Development and Evaluation Working Group. This appraisal was carried out by identifying Cochrane systematic reviews and systematic reviews that have been subsequently reported since the last Cochrane report. The focus of this appraisal was to determine the effectiveness of pulmonary rehabilitation programs versus control therapy in chronic obstructive pulmonary disease patients. This analysis did not evaluate other aspects of the pulmonary rehabilitation intervention.


The role of matrix metalloproteinase genes in glioma invasion: co-dependent and interactive proteolysis.
Matrix metalloproteinases (MMPs) are cation-dependent endopeptidases which have been implicated in the malignancy of gliomas. It is thought that the MMPs play a critical role in both metastasis and angiogenesis, and that interference with proteases might therefore deter local tumor dissemination and neovascularization. However, the attempt to control tumor-associated proteolysis will rely on better definition of the normal tissue function of MMPs, an area of study still in its infancy in the central nervous system (CNS). Understanding the role of MMP-mediated proteolysis in the brain relies heavily on advances in other areas of molecular neuroscience, most notably an understanding of extracellular matrix (ECM) composition and the function of cell adhesion molecules such as integrins, which communicate knowledge of ECM composition intracellularly. Recently, protease expression and function has been shown to be strongly influenced by the functional state and signaling properties of integrins. Here we review MMP function and expression in gliomas and present examples of MMP profiling studies in glioma tissues and cell lines by RT-PCR and Western blotting. Co-expression of MMPs and certain integrins substantiates the gathering evidence of a functional intersection between the two, and inhibition studies using recombinant TIMP-1 and integrin antisera demonstrate significant inhibition of glioma invasion in vitro. Use of promising new therapeutic compounds with anti-MMP and anti-invasion effects are discussed. These data underline the importance of functional interaction of MMPs with accessory proteins such as integrins during invasion, and the need for further studies to elucidate the molecular underpinnings of this process.


Moving forward with isoprostanes, neuroprostanes and phytoprostanes: where are we now?
Polyunsaturated fatty acids (PUFAs) are essential components in eukaryotic cell membrane. They take part in the regulation of cell signalling pathways and act as precursors in inflammatory metabolism. Beside these, PUFAs auto-oxidize through free radical initiated mechanism and release key products that have various physiological functions. These products surfaced in the early nineties and were classified as prostaglandin isomers or isoprostanes, neuroprostanes and phytoprostanes. Although these molecules are considered robust biomarkers of oxidative damage in diseases, they also contain biological activities in humans. Conceptual progress in the last 3 years has added more understanding about the importance of these molecules in different fields. In this chapter, a brief overview of the past 30 years and the recent scope of these molecules, including their biological activities, biosynthetic pathways and analytical approaches are discussed.


Analysis of naïve and memory CD4 and CD8 T cell populations in breast cancer patients receiving a HER2/neu peptide (E75) and GM-CSF vaccine.
We are conducting clinical trials of the E75 peptide as a vaccine in breast cancer (BrCa) patients. We assessed T cell subpopulations in BrCa patients before and after E75 vaccination and compared them to healthy controls. We obtained 17 samples of blood from ten healthy individuals and samples from 22 BrCa patients prior to vaccination. We also obtained pre- and post-vaccination samples of blood from seven BrCa patients who received the E75/GM-CSF vaccine. CD4, CD8, CD45RA, CD45RO, and CCR7 antibodies were used to analyze the CD4+ and CD8+ T cells by four-color flow cytometry. Compared to healthy individuals, BrCa patients have significantly more memory and less naïve T cells and more effector-memory CD8+ and less effector CD4+ T cells. Phenotypic differences in defined circulating CD4+ and CD8+ T cell subpopulations suggest remnants of an active immune response to tumor distinguished by a predominant memory T cell response and by untapped recruitment of naïve helper and cytotoxic T cells. E75 vaccination induced recruitment of both CD4+ and CD8+ naïve T cells while memory response remained stable. Additionally, vaccination induced global activation of all T cells, with specific enhancement of effector CD4+ T cells. E75 vaccination causes activation of both memory and naïve CD4+ and CD8+ T cells, while recruiting additional naïve CD4+ and CD8+ T cells to the overall immune response.


A precocious adult visual center in the larva defines the unique optic lobe of the split-eyed whirligig beetle Dineutus sublineatus.
Whirligig beetles (Coleoptera: Gyrinidae) are aquatic insects living on the water surface. They are equipped with four compound eyes, an upper pair viewing above the water surface and a lower submerged pair viewing beneath the water surface, but little is known about how their visual brain centers (optic lobes) are organized to serve such unusual eyes. We show here, for the first time, the peculiar optic lobe organization of the larval and adult whirligig beetle Dineutus sublineatus. The divided compound eyes of adult whirligig beetles supply optic lobes that are split into two halves, an upper half and lower half, comprising an upper and lower lamina, an upper and lower medulla and a bilobed partially split lobula. However, the lobula plate, a neuropil that in flies is known to be involved in mediating stabilized flight, exists only in conjunction with the lower lobe of the lobula. We show that, as in another group of predatory beetle larvae, in the whirligig beetle the aquatic larva precociously develops a lobula plate equipped with wide-field neurons. It is supplied by three larval laminas serving the three dorsal larval stemmata, which are adjacent to the developing upper compound eye. In adult whirligig beetles, dual optic neuropils serve the upper aerial eyes and the lower subaquatic eyes. The exception is the lobula plate. A lobula plate develops precociously in the larva where it is supplied by inputs from three larval stemmata that have a frontal-upper field of view, in which contrasting objects such as prey items trigger a body lunge and mandibular grasp. This precocious lobula plate is lost during pupal metamorphosis, whereas another lobula plate develops normally during metamorphosis and in the adult is associated with the lower eye. The different roles of the upper and lower lobula plates in supporting, respectively, larval predation and adult optokinetic balance are discussed. Precocious development of the upper lobula plate represents convergent evolution of an ambush hunting lifestyle, as exemplified by the terrestrial larvae of tiger beetles (Cicindelinae), in which activation of neurons in their precocious lobula plates, each serving two large larval stemmata, releases reflex body extension and mandibular grasp.


An appraisal of respiratory system compliance in mechanically ventilated covid-19 patients.
Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level. We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe CRS-calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)]-and its association with ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide. We studied 745 patients from 22 countries, who required admission to the ICU and MV from January 14 to December 31, 2020, and presented at least one value of CRS within the first seven days of MV. Median (IQR) age was 62 (52-71), patients were predominantly males (68%) and from Europe/North and South America (88%). CRS, within 48 h from endotracheal intubation, was available in 649 patients and was neither associated with the duration from onset of symptoms to commencement of MV (p = 0.417) nor with PaO2/FiO2 (p = 0.100). Females presented lower CRS than males (95% CI of CRS difference between females-males: - 11.8 to - 7.4 mL/cmH2O p < 0.001), and although females presented higher body mass index (BMI), association of BMI with CRS was marginal (p = 0.139). Ventilatory management varied across CRS range, resulting in a significant association between CRS and driving pressure (estimated decrease - 0.31 cmH2O/L per mL/cmH20 of CRS, 95% CI - 0.48 to - 0.14, p < 0.001). Overall, 28-day ICU mortality, accounting for the competing risk of being discharged within the period, was 35.6% (SE 1.7). Cox proportional hazard analysis demonstrated that CRS (+ 10 mL/cm H2O) was only associated with being discharge from the ICU within 28 days (HR 1.14, 95% CI 1.02-1.28, p = 0.018). This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV. CRS measured within 48 h from commencement of MV has marginal predictive value for 28-day mortality, but was associated with being discharged from ICU within the same period. Trial documentation: Available at https://www.covid-critical.com/study . ACTRN12620000421932.


Oral Health Status of Hospitalized Patients With Type 2 Diabetes.
Diabetes is associated with poor oral health, as well as reduced access to dental care. A large percentage of patients hospitalized in the United States carry a diagnosis of diabetes; however, the oral health status of patients with diabetes who are hospitalized is unknown. All patients meeting inclusion criteria on the general medicine service of a tertiary care hospital were invited to participate. Subjects were asked about their access to dental care and perceptions of their oral health. A dental hygienist conducted examinations, including decayed, missing, and filled teeth (DMFT) and periodontal screening and recording (PSR) indices on a subset of subjects. The 105 subjects had a mean age of 69 ± 12 years and a median A1C of 7.5 ± 2.1%. Rates of comorbidity and polypharmacy were high. The mean number of DMFT was 23.0 ± 7.2, with 10.1 ± 7.2 missing teeth. Forty- four percent of subjects had a removable prosthesis. Sixty-eight percent had a PSR index ≥4 in at least one sextant, indicating moderate periodontal disease. Rates of missing teeth, removable prostheses, and periodonal inflammation were high among hospitalized patients with diabetes, but patients did not perceive their oral health to be poor. Health care providers should be aware of the oral health risks of patients with diabetes during hospitalization, and dentists should consider screening patients with diabetes for recent hospitalization.


Age at sexual maturity, first parturition and reproductive senescence in wild lowland pacas (Cuniculus paca): Implications for harvest sustainability.
Generation length (GL) of a mammal, calculated through the age at sexual maturity, first reproduction and reproductive senescence can be used to assess the capacity of a population of a species to withstand differing amounts of hunting pressure by humans without depletion of animal numbers. Due to the lack of reproductive data for wild mammals, the GL is often difficult to determine for most species. In the present study, the GL parameters were assessed for the wild lowland paca (Cuniculus paca) from a sample of 119 female genitalia obtained during a 15-year hunter participatory program in the Amazon. The probability of female pacas being sexually active, with observable ovarian functionality or pregnancy, increased as both body and genitalia masses increased. The average body mass at puberty was 5.46 kg. Puberty was estimated to occur at 4 months of age, from which there was estimation when age at first parturition would occur 9 months after birth. Additionally, there was no indication that there was a decrease in parturition rate at more advanced ages. The estimated age of first reproduction for pacas was much less than previous estimates, most from assessments of captive animals. In addition, because there was no evidence of reproductive senescence, it is suggested that the average age of mature hunted pacas should be used to determine optimal harvesting rates of pacas by humans. The present study highlights the importance of in situ studies on reproduction of animals in their natural habitat because these will yield more accurate reproductive variable estimates than those obtained from captive animals. It is suggested that similar methods be used to accurately assess reproductive parameters of other tropical species that are hunted by humans.


Development and assessment of a 3D pharmacophore for ligand recognition of BDZR/GABAA receptors initiating the anxiolytic response.
Benzodiazepine receptor (BDZR) ligands are structurally diverse compounds that bind to specific binding sites on GABAA receptors and allosterically modulate the effect of GABA on chloride flux. The binding of BDZR ligands to this receptor system results in activity at multiple behavioral end points including anxiolytic, sedative, hyperphagic, anticonvulsant and hyperthermic effects. In the work presented here, 17 structurally diverse BDZR ligands of the receptors initiating the anxiolytic response have been studied using a systematic computational procedure developed in our laboratory. Using this procedure, a five component 3D recognition pharmacophore was obtained consisting of two proton acceptors, a hydrophobic group, an aromatic electron accepting ring and a ring containing polar moieties, all found in a common geometric arrangement in the 15 compounds with an effect at the anxiolytic end point and absent in two control compounds. The 3D pharmacophore developed was validated by searching 3D databases and finding known BDZR ligands active at the anxiolytic end point, including 1,4-BDZ derivatives, imidazo BDZ and beta-carboline ligands.


Cerebral microarteriovenous malformations: a series of 28 cases.
Microarteriovenous malformations (micro-AVMs) are a rare subgroup of brain AVMs characterized by a nidus smaller than 1 cm. The authors' purpose in this study was to assess the clinical presentation, radiological features, therapeutic management, and outcome of these lesions. All angiography studies performed at the authors' institution since 2000 for the diagnosis of AVM were retrospectively reviewed. Clinicoradiological findings, therapeutic management, and outcome were evaluated. Twenty-eight patients had presented with AVMs having a nidus diameter smaller than 1 cm or no clearly identifiable nidus but an early draining vein. All patients, except 2, presented with intracranial hemorrhage, and 12 patients had a focal deficit. Supratentorial hematomas were large (mean volume 25 ml), and in 8 patients hematomas were evacuated urgently. In 6 patients cerebral digital subtraction angiography studies were normal. Magnetic resonance imaging and dynamic MR angiography revealed an AVM in 4 of these 6 patients. Treatment of the AVM consisted of surgery in 16 cases, radiosurgery in 6, and endovascular embolization in 2, and there were no posttreatment deficits. Four patients received no treatment because of their poor condition. The AVM was occluded at the follow-up in all patients treated with surgery or embolization and in 4 of the 6 patients treated with radiosurgery. The Glasgow Outcome Scale (GOS) score was good (GOS 4-5) in 23 patients (82%) and poor (GOS 3-2) in 5 (18%). Patients with micro-AVMs generally present with large intracranial hemorrhages and neurological deficits. If the initial angiography is negative, then delayed or superselective angiography is recommended. Magnetic resonance imaging may reveal the existence of these lesions. Surgery is the treatment of choice for superficial micro-AVMs, and radiosurgery or embolization can be considered for deep lesions.


Neuro-immune interactions in inflammation and host defense: Implications for transplantation.
Sensory and autonomic neurons of the peripheral nervous system (PNS) play a critical role in regulating the immune system during tissue inflammation and host defense. Recent studies have identified the molecular mechanisms underlying the bidirectional communication between the nervous system and the immune system. Here, we highlight the studies that demonstrate the importance of the neuro-immune interactions in health and disease. Nociceptor sensory neurons detect immune mediators to produce pain, and release neuropeptides that act on the immune system to regulate inflammation. In parallel, neural reflex circuits including the vagus nerve-based inflammatory reflex are physiological regulators of inflammatory responses and cytokine production. In transplantation, neuro-immune communication could significantly impact the processes of host-pathogen defense, organ rejection, and wound healing. Emerging approaches to target the PNS such as bioelectronics could be useful in improving the outcome of transplantation. Therefore, understanding how the nervous system shapes the immune response could have important therapeutic ramifications for transplantation medicine.


Health-related quality of life measurement in women with common benign gynecologic conditions: a systematic review.
Endometriosis, menorrhagia, chronic pelvic pain, and polycystic ovary syndrome are major sources of psychologic morbidity and can negatively affect quality of life. Although comparative studies have been published on the measurement of health-related quality of life for gynecologic malignancies, a similar review for these benign gynecologic conditions has not been conducted. Consequently, we searched the literature systematically to identify the impact of symptoms and treatments for these conditions on health status and to report on the types and psychometric properties of the instruments used. Papers were retrieved by systematically searching 6 electronic databases and hand-searching relevant reference lists and bibliographies. Forty-six studies used a questionnaire to measure health status: 34 studies (74%) used standardized instruments; of these, 23 studies (68%) used generic tools. Although a meta analysis was not possible, it appears that women with chronic pelvic pain and conditions that are associated with pelvic pain (such as endometriosis) report worse health-related quality of life. Despite the development of disease-specific questionnaires, only 2 questionnaires were generated from interviews of patients with the condition of interest, and few questionnaires are being used to evaluate the outcomes of treatment on subjective health status.


Quantifying Molecular-Level Cell Adhesion on Electroactive Conducting Polymers using Electrochemical-Single Cell Force Spectroscopy.
Single Cell Force Spectroscopy was combined with Electrochemical-AFM to quantify the adhesion between live single cells and conducting polymers whilst simultaneously applying a voltage to electrically switch the polymer from oxidized to reduced states. The cell-conducting polymer adhesion represents the non-specific interaction between cell surface glycocalyx molecules and polymer groups such as sulfonate and dodecylbenzene groups, which rearrange their orientation during electrical switching. Single cell adhesion significantly increases as the polymer is switched from an oxidized to fully reduced state, indicating stronger cell binding to sulfonate groups as opposed to hydrophobic groups. This increase in single cell adhesion is concomitant with an increase in surface hydrophilicity and uptake of cell media, driven by cation movement, into the polymer film during electrochemical reduction. Binding forces between the glycocalyx and polymer surface are indicative of molecular-level interactions and during electrical stimulation there is a decrease in both the binding force and stiffness of the adhesive bonds. The study provides insight into the effects of electrochemical switching on cell adhesion at the cell-conducting polymer interface and is more broadly applicable to elucidating the binding of cell adhesion molecules in the presence of electrical fields and directly at electrode interfaces.


Sequence dependence of branch migratory minima.
The Holliday junction is a central intermediate in the process of genetic recombination. The position of its branch-point can relocate through an isomerization known as branch migration. This migration occurs because the branch-point is flanked by homologous symmetry. All attempts at modeling the kinetics of branch migration have relied on the assumption that branch migration minima are sequence-independent. We have tested that assumption here, using a competition assay based on symmetric immobile branched junctions; these are junctions that cannot undergo branch migration, despite the fact that they are flanked by homology. The assay used is predicated on the non-association of strands displaced in the assay; we have tested this assumption, and have performed our experiments under conditions where we know that it is true. We have measured the free energy of relocating a branched junction from a fixed non-homologous sequence to all possible dimeric symmetric sequences. We find that the assumption of sequence-independence is often valid, but that it is not universally true. We find that the flanking sequences can have a marked effect on the free energy measured, both for extensions of symmetry and for reversals of flanking nucleotides. We have varied the temperature in our experiments, and have derived both enthalpies and entropies for the different sequences. The entropies are largely unfavorable, whereas the enthalpies are largely favorable; regardless of the signs of these quantities, we see that this is another system where enthalpy-entropy compensation is operative.


On the stability of interval type-2 TSK fuzzy logic control systems.
Type-2 fuzzy logic systems have recently been utilized in many control processes due to their ability to model uncertainties. This paper proposes a novel inference mechanism for an interval type-2 Takagi-Sugeno-Kang fuzzy logic control system (IT2 TSK FLCS) when antecedents are type-2 fuzzy sets and consequents are crisp numbers (A2-C0). The proposed inference mechanism has a closed form which makes it more feasible to analyze the stability of this FLCS. This paper focuses on control applications for the following cases: 1) Both plant and controller use A2-C0 TSK models, and 2) the plant uses type-1 Takagi-Sugeno (TS) and the controller uses IT2 TS models. In both cases, sufficient stability conditions for the stability of the closed-loop system are derived. Furthermore, novel linear-matrix-inequality-based algorithms are developed for satisfying the stability conditions. Numerical analyses are included which validate the effectiveness of the new inference methods. Case studies reveal that an IT2 TS FLCS using the proposed inference engine clearly outperforms its type-1 TSK counterpart. Moreover, due to the simple nature of the proposed inference engine, it is easy to implement in real-time control systems. The methods presented in this paper lay the mathematical foundations for analyzing the stability and facilitating the design of stabilizing controllers of IT2 TSK FLCSs and IT2 TS FLCSs with significantly improved performance over type-1 approaches.


Plant Response to Engineered Metal Oxide Nanoparticles.
All metal oxide nanoparticles influence the growth and development of plants. They generally enhance or reduce seed germination, shoot/root growth, biomass production and physiological and biochemical activities. Some plant species have not shown any physiological change, although significant variations in antioxidant enzyme activity and upregulation of heat shock protein have been observed. Plants have evolved antioxidant defence mechanism which involves enzymatic as well as non-enzymatic components to prevent oxidative damage and enhance plant resistance to metal oxide toxicity. The exact mechanism of plant defence against the toxicity of nanomaterials has not been fully explored. The absorption and translocation of metal oxide nanoparticles in different parts of the plant depend on their bioavailability, concentration, solubility and exposure time. Further, these nanoparticles may reach other organisms, animals and humans through food chain which may alter the entire biodiversity. This review attempts to summarize the plant response to a number of metal oxide nanoparticles and their translocation/distribution in root/shoot. The toxicity of metal oxide nanoparticles has also been considered to see if they affect the production of seeds, fruits and the plant biomass as a whole.


The randomized controlled trial of Head Start REDI: Sustained effects on developmental trajectories of social-emotional functioning.
This study assessed the sustained effects of Head Start REDI (Research-based, Developmentally Informed), a randomized controlled preschool preventive intervention, on children's developmental trajectories of social-emotional functioning into elementary school. Twenty-five Head Start centers with 44 classrooms were randomly assigned to deliver Head Start REDI or Head Start as usual. Head Start REDI featured an integrated language-emergent literacy and social-emotional skills curriculum and enhanced support for positive teaching practices. The 356 4-year-old children (54% girls; 25% African American; 17% Latino; 70% living in poverty) in those centers and classrooms were followed for 5 years (from preschool through third grade; 91% retention rate). Each year, teachers rated multiple domains of social-emotional functioning. Person-oriented latent class growth models were used to identify the different developmental trajectories of social-emotional functioning that children followed. Tests of proportions revealed that children who had been in the Head Start REDI intervention were statistically significantly more likely than children in the control condition to follow the most optimal developmental trajectories of social competence, aggressive-oppositional behavior, learning engagement, attention problems, student-teacher closeness, and peer rejection (odds ratio = 1.60-1.93). These findings suggest that enriching Head Start with evidence-based curriculum components and teaching practices can have long-lasting benefits for children's social-emotional functioning. These findings elucidate how high-quality preschool experiences promote core competencies that are critical to the school success of children living in poverty.


A Device for the Functional Evaluation of the VOR in Clinical Settings.
We developed the head impulse testing device (HITD) based on an inertial sensing system allowing to investigate the functional performance of the rotational vestibulo-ocular reflex (VOR) by testing its gaze stabilization ability, independently from the subject's visual acuity, in response to head impulses at different head angular accelerations ranging from 2000 to 7000 deg/s(2). HITD was initially tested on 22 normal subjects, and a method to compare the results from a single subject (patient) with those from controls was set up. As a pilot study, we tested the HITD in 39 dizzy patients suffering, non-acutely, from different kinds of vestibular disorders. The results obtained with the HITD were comparable with those from the clinical head impulse test (HIT), but an higher number of abnormalities was detectable by HITD in the central vestibular disorders group. The HITD appears to be a promising tool for detecting abnormal VOR performance while providing information on the functional performance of the rotational VOR, and can provide a valuable assistance to the clinical evaluation of patients with vestibular disorders.


Marine natural products.
This review covers the marine natural products literature for the year 2000 and is organized phylogenetically, with sections on marine microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates. echinoderms and miscellaneous marine organisms. There is an emphasis on new structures, stressing their biological activities, source organisms and countries of origin, and also syntheses that confirm the structures of known compounds. The review contains 869 structures and 592 references, of which 434 appeared between January and December 2000.


Androgenic and spermatogenic activity of alkylamide-rich ethanol solution extract of Anacyclus pyrethrum DC.
Anacyclus pyrethrum (A. pyrethrum) has been used as Vajikaran Rasayana (aphrodisiac) in traditional Indian ayurvedic medicine to treat male sexual dysfunction, including infertility. Aphrodisiac activity may be due to an increase in the production or effect of androgens, so this study sought to evaluate the androgenic and spermatogenic potential of the alkylamide-rich ethanol solution extract. Male Wistar strain rats weighing between 150 and 180 g were completely randomized divided into five groups. The ethanol solution extract of A. pyrethrum was administered to groups of rats in 50, 100, and 150 mg/kg doses for a period of 28 days, and the action was compared with control and testosterone-treated rats. Thirteen N-alkylamides were detected in the extract by using HPLC/UV/electrospray ionization mass spectrometry method. Extract administration at all the doses produced significant increase in body weight, sperm count, motility, and viability along with serum testosterone, luteinizing hormone, and follicle-stimulating hormone concentrations. Histoarchitecture of testis revealed increased spermatogenic activities. Seminal fructose content was also significantly increased after 28 days of treatment. Our results suggest that the ethanol solution extract of the roots of A. pyrethrum has androgenic potential and may improve male fertility by enhancing spermatogenesis.


A randomized trial investigating an exercise program to prevent reduction of bone mineral density and impairment of motor performance during treatment for childhood acute lymphoblastic leukemia.
Reduced bone mineral density (BMD), altered body composition, impaired motor performance and passive ankle dorsiflexion are side effects of acute lymphoblastic leukemia (ALL) treatment. We performed a randomized study investigating whether an exercise program could prevent these side effects. At diagnosis we randomized 51 ALL patients (median age: 5.4 years) into a group receiving a 2-year exercise program or a control group receiving standard care. BMD of total body (BMD(TB)), lumbar spine (BMD(LS)) and body composition were measured using dual energy X-ray absorptiometry, motor performance with Bayley Scales of Infant Development or Movement-ABC, and passive ankle dorsiflexion with a goniometer. The investigator was blinded to the randomization. Body fat increased equally during treatment in both groups. One year after cessation of therapy more rapid decline of excessive body fat was observed in the intervention group than in the controls (P = 0.01). Lean body mass, BMD(TB) and BMD(LS) of both groups decreased equally during treatment and increased equally thereafter. Both groups showed a similar decrease in passive ankle dorsiflexion and motor performance during treatment. Adherence to the intervention program varied considerably. Adherence to intervention: 11% of children exercised daily, 37% > once a week, 16% once weekly, 36% < once a week. The exercise program was not more beneficial than standard care in preventing reduction in BMD, motor performance and passive ankle dorsiflexion than standard care, most likely due to unsatisfactory compliance. Increased BMI and body fat in the intervention group normalized faster after cessation of chemotherapy.


A remarkable diversity of bone-eating worms (Osedax; Siboglinidae; Annelida).
Bone-eating Osedax worms have proved to be surprisingly diverse and widespread. Including the initial description of this genus in 2004, five species that live at depths between 25 and 3,000 m in the eastern and western Pacific and in the north Atlantic have been named to date. Here, we provide molecular and morphological evidence for 12 additional evolutionary lineages from Monterey Bay, California. To assess their phylogenetic relationships and possible status as new undescribed species, we examined DNA sequences from two mitochondrial (COI and 16S rRNA) and three nuclear genes (H3, 18S and 28S rRNA). Phylogenetic analyses identified 17 distinct evolutionary lineages. Levels of sequence divergence among the undescribed lineages were similar to those found among the named species. The 17 lineages clustered into five well-supported clades that also differed for a number of key morphological traits. Attempts to determine the evolutionary age of Osedax depended on prior assumptions about nucleotide substitution rates. According to one scenario involving a molecular clock calibrated for shallow marine invertebrates, Osedax split from its siboglinid relatives about 45 million years ago when archeocete cetaceans first appeared and then diversified during the late Oligocene and early Miocene when toothed and baleen whales appeared. Alternatively, the use of a slower clock calibrated for deep-sea annelids suggested that Osedax split from its siboglinid relatives during the Cretaceous and began to diversify during the Early Paleocene, at least 20 million years before the origin of large marine mammals. To help resolve uncertainties about the evolutionary age of Osedax, we suggest that the fossilized bones from Cretaceous marine reptiles and late Oligocene cetaceans be examined for possible trace fossils left by Osedax roots. Regardless of the outcome, the present molecular evidence for strong phylogenetic concordance across five separate genes suggests that the undescribed Osedax lineages comprise evolutionarily significant units that have been separate from one another for many millions of years. These data coupled with ongoing morphological analyses provide a solid foundation for their future descriptions as new species.


Genetically altering organismal metabolism by leptin-deficiency benefits a mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that causes death of motor neurons. ALS patients and mouse models of familial ALS display organismal level metabolic dysfunction, which includes increased energy expenditure despite decreased lean mass. The pathophysiological relevance of abnormal energy homeostasis to motor neuron disease remains unclear. Leptin is an adipocyte-derived hormone that regulates whole-animal energy expenditure. Here, we report that placing mutant superoxide dismutase 1 (SOD1) mice in a leptin-deficient background improves energy homeostasis and slows disease progression. Leptin-deficient mutant SOD1 mice possess increased bodyweight and fat mass, as well as decreased energy expenditure. These observations coincide with enhanced survival, improved strength and decreased motor neuron loss. These results suggest that altering whole-body energy metabolism in mutant SOD1 mice can mitigate disease progression. We propose that manipulations that increase fat mass and reduce energy expenditure will be beneficial in the setting of motor neuron disease.


Renal impairment after spontaneous bacterial peritonitis: incidence and prognosis.
Spontaneous bacterial peritonitis (SBP) is an important complication in cirrhotic patients. The aim of the present study was to assess the incidence, predictive factors and prognosis for renal impairment (RI) after SBP in cirrhotic patients from southern Brazil. Of the 1030 hospitalizations evaluated, 114 episodes of SBP were diagnosed in 94 patients (mean age 49 years; 76.59% men). SBP diagnosis was established when the ascitic fluid polymorphonuclear cell count was equal to or greater than 250 cells/mm3. Five cases were excluded. The variables assessed as possible predictors of steady or progressive RI were blood urea nitrogen and creatinine levels before the diagnosis of SBP; type of infection, antibiotic prophylaxis, first episode or recurrent SBP, presence of gastrointestinal bleeding and hepatic encephalopathy during hospitalization, SBP resolution, Child-Pugh classification, levels of blood pressure, ascitic fluid and blood polymorphonuclear cell count, bacteriological data (positive and negative ascitic fluid culture), albumin, bilirubin, sodium and prothrombin time at the moment of diagnosis. The incidence of SBP was 11.07%. In 61 (55.96%) episodes, SBP was associated with RI (transient in 57.37%; steady in 19.67%; and progressive in 22.95%). The mortality rate associated with progressive RI was 100%; 58.33% with steady RI; and 2.85% with transient RI. The mortality rate in patients with or without RI was 36.07% and 6.25%, respectively (P<0.001). The level of creatinine (greater than or equal to 1.3mg/dL) before the diagnosis of SBP and the rate of infection resolution were the only predictors of RI in the multivariate analysis. RI after SBP is a common complication, and indicates a poor prognosis for this infection. High levels of creatinine before infection and the rate of infection resolution are independent predictors of RI.


The outcome of patients requiring multiple extracorporeal membrane oxygenation: how many runs of ECMO is reasonable?
Extracorporeal membrane oxygenation (ECMO) has been proven effective in life support for patients with refractory cardiopulmonary failure. Deteriorating patients who have removed their first ECMO support and required second or more courses of ECMO support have rarely been discussed. All the records of the patients who experienced at least 2 courses of ECMO during single admission were retrieved. Survival was defined as survival to discharge. Demographic data and clinical information were compared between survival and nonsurvival groups. There were 86 patients who received at least 2 courses of ECMO in the 20-year database, and 27 (31.3%) were <18 years old. Of them, 87.3% received 2 runs of ECMO, 10.4% 3 runs, and 2.3% 4 runs. Overall survival rate was 30.2%. The survival rate for patients with 2 runs of ECMO was 33.3% (25 out of 75), 11.1% (1 out of 9) for 3 runs, and 0% (0 out of 2) for 4 runs. Multivariate analysis revealed that only ARF with hemodialysis was the independent risk factor. The decision to perform repeated ECMO implantation is a complex and difficult process. Despite the arguments debating the consumption of resources and increased complications, there are still nearly 1 out of 3 patients who will survive to discharge. More than 2 courses of ECMO may be carefully considered for further rescue.


Neurocognitive function and joint attention ability in young children with autism spectrum disorder versus developmental delay.
Studies have shown that young children with autism are not impaired on prefrontal tasks relative to what would be expected for their mental age, raising questions about the executive dysfunction hypothesis of autism. These studies did not include ventromedial prefrontal tasks, however. The present study examined whether young children with autism spectrum disorder (ASD) are impaired on ventromedial prefrontal tasks, and whether performance on such tasks is correlated with a core autism symptom, joint attention ability. Seventy-two 3- to 4-year-old children with ASD, 34 3- to 4-year-old developmentally delayed children, and 39 12- to 46-month-old typically developing children, matched on mental age, were administered ventromedial and dorsolateral prefrontal tasks and joint attention tasks. Children with ASD performed similarly to comparison groups on all executive function tasks, indicating that at this early age, there is no autism-specific pattern of executive dysfunction. Ventromedial, but not dorsolateral, prefrontal task performance was strongly correlated with joint attention ability, however. The ventromedial prefrontal cortex is hypothesized to play a role in the development of joint attention and possibly some aspects of the autistic syndrome.


A moving bump in a continuous manifold: a comprehensive study of the tracking dynamics of continuous attractor neural networks.
Understanding how the dynamics of a neural network is shaped by the network structure and, consequently, how the network structure facilitates the functions implemented by the neural system is at the core of using mathematical models to elucidate brain functions. This study investigates the tracking dynamics of continuous attractor neural networks (CANNs). Due to the translational invariance of neuronal recurrent interactions, CANNs can hold a continuous family of stationary states. They form a continuous manifold in which the neural system is neutrally stable. We systematically explore how this property facilitates the tracking performance of a CANN, which is believed to have clear correspondence with brain functions. By using the wave functions of the quantum harmonic oscillator as the basis, we demonstrate how the dynamics of a CANN is decomposed into different motion modes, corresponding to distortions in the amplitude, position, width, or skewness of the network state. We then develop a perturbation approach that utilizes the dominating movement of the network's stationary states in the state space. This method allows us to approximate the network dynamics up to an arbitrary accuracy depending on the order of perturbation used. We quantify the distortions of a gaussian bump during tracking and study their effects on tracking performance. Results are obtained on the maximum speed for a moving stimulus to be trackable and the reaction time for the network to catch up with an abrupt change in the stimulus.


Engineered tendon with decellularized xenotendon slices and bone marrow stromal cells: an in vivo animal study.
The purpose of this study was to investigate an engineered composite of multilayer acellular tendon slices seeded with bone marrow stromal cells (BMSCs) as a possible solution for tendon reconstruction. BMSCs were harvested from 15 rabbits and infraspinatus tendons were harvested from 17 dogs. The decellularized tendons were sectioned in longitudinal slices with a thickness of 50 µm. The BMSCs were seeded on the slices and then the slices were bundled into one composite. The composite was implanted into a rabbit patellar tendon defect. Tendon slices without BMSCs were implanted into the contralateral patellar tendon as a control. The composites were evaluated by histology and qRT-PCR. The viability of BMSCs was assessed using a fluorescent marker. Histology showed viable cells between the collagen fibres on the cell-seeded side. Analysis by qRT-PCR showed higher tenomodulin, collagen type III, MMP3 and MMP13 expressions and lower collagen type I expression in the cell-seeded composite than in the tendon slices without BMSCs. We conclude that BMSCs can survive in a multilayer composite, express a tendon phenotype and enhance the metabolism of tendon in vivo. This in vivo study suggests a potential utility of this composite in tendon reconstruction.


Preliminary observations on responses of embryonic and larval Pacific herring, Clupea pallasi, to neutral fraction biodegradation products of weathered Alaska North Slope oil.
Weathered Alaska North Slope crude oil (ANS 521) was subjected to biodegradation in vigorously stirred incubations for 14 days at 15 +/- 1 degrees C in 20/1000 salinity sterilized seawater, amended with nutrients and inoculated with a hydrocarbon-degrading microorganism (EI2V) isolated from an oil-contaminated beach in Prince William Sound, Alaska. A total of 13.7 mg/L water-soluble neutral fraction (WSF) was recovered from the incubation of weathered ANS 521. Toxicity/ teratogenicity tests were conducted with WSF recovered from the biodegradation system using embryonic and larval Pacific herring, Clupea pallasi. Exposures were begun at 4, 48, and 96 h postfertilization of herring eggs. Exposure concentrations were 1, 10, and 100% of the original concentration of WSF recovered from incubations (redissolved in 20/1000 salinity sterile seawater at 15 +/- 1 degrees C). Sterile 20/1000 salinity seawater without the addition of redissolved neutral fraction was used as a control. Significant (p < or = 0.05) embryo mortality or teratogenic responses were observed at WSF concentrations of 10 and 100%. On days 5 through 8 of embryogenesis, counts of heart contraction rates were significantly lower (p < or = 0.05) at the 100% WSF concentration for embryos exposed beginning at 4 and 48 h postfertilization. Grow-out of larvae from selected exposures was conducted. High mortality was noted in larvae exposed to the 10% WSF concentration beginning at 4 and 48 h postfertilization. Most of these larvae died 5 to 8 days after hatching when they elicited vertebral displacements at a time concurrent with the onset of feeding behavior.


Characterization and reconstruction of planar sources that generate identical intensity distributions in the Fraunhofer zone.
A general explicit form of the correlation functions of all the partially coherent quasi-monochromatic sources that generate identical intensity distributions at the far (Fraunhofer) zone is given. The common characteristic part of all of these correlation functions is pointed out. Also, the possibility is shown for reconstructing (in unique way), from intensity data at the far zone, any source whose correlation function at some region Omega depends on the coordinate difference only.


Protective effect of an L-type calcium channel blocker, amlodipine, on paracetamol-induced hepatotoxicity in rats.
Paracetamol (P), one of the most popular and commonly used analgesic and antipyretic agents, causes hepatotoxicity in overdoses. Amlodipine (AML), an L-type calcium channel blocker, has been shown to have anti-inflammatory activity by reversing the effect of calcium in the inflammation pathogenesis. In this study, the hepatoprotective activity of AML on P-induced hepatotoxicity was evaluated. Thirty male albino Wistar rats were divided into five groups: (1) control, (2) 2 g/kg of P, (3) 2 g/kg of P + 5 mg/kg of AML, (4) 2 g/kg of P + 10 mg/kg of AML, and (5) 10 mg/kg of AML. Some liver enzymes, oxidative parameters, cytokine mRNA expressions, histopathology, and immunohistochemical studies were performed in liver and blood samples. The serum levels of alanine aminotransferase and aspartate aminotransferase and the mRNA expression of tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta in the liver tissues were significantly increased in the group treated with P. The superoxide dismutase and glutathione parameters decreased and malondialdehyde levels increased in the livers of the rats treated with P. All these parameters were increased with both doses of the AML similar to the control group. A histopathological examination of the liver showed that AML administration ameliorated the P-induced inflammatory liver damage. In immunohistochemical staining, the expression of TNF-α in the cytoplasm of the hepatocytes was increased in the P group but not in other treatment groups when compared to the control. In conclusion, AML treatment showed significant protective effects against P-induced hepatotoxicity by increasing the activity of antioxidants and reducing inflammatory cytokines.


Unhealthy Food and Beverage Consumption in Children and Risk of Overweight and Obesity: A Systematic Review and Meta-Analysis.
This WHO-commissioned review contributed to the update of complementary feeding recommendations, synthesizing evidence on effects of unhealthy food and beverage consumption in children on overweight and obesity. We searched PubMed (Medline), Cochrane CENTRAL, and Embase for articles, irrespective of language or geography. Inclusion criteria were: 1) randomized controlled trials (RCTs), non-RCTs, cohort studies, and pre/post studies with control; 2) participants aged ≤10.9 y at exposure; 3) studies reporting greater consumption of unhealthy foods/beverages compared with no or low consumption; 4) studies assessing anthropometric and/or body composition; and 5) publication date ≥1971. Unhealthy foods and beverages were defined using nutrient- and food-based approaches. Risk of bias was assessed using the ROBINS-I (risk of bias in nonrandomized studies of interventions version I) and RoB2 [Cochrane RoB (version 2)] tools for nonrandomized and randomized studies, respectively. Narrative synthesis was complemented by meta-analyses where appropriate. Certainty of evidence was assessed using Grading of Recommendations Assessment, Development, and Evaluation. Of 26,542 identified citations, 60 studies from 71 articles were included. Most studies were observational (59/60), and no included studies were from low-income countries. The evidence base was low quality, as assessed by ROBINS-I and RoB2 tools. Evidence synthesis was limited by the different interventions and comparators across studies. Evidence indicated that consumption of sugar-sweetened beverages (SSBs) and unhealthy foods in childhood may increase BMI/BMI z-score, percentage body fat, or odds of overweight/obesity (low certainty of evidence). Artificially sweetened beverages and 100% fruit juice consumption make little/no difference to BMI, percentage body fat, or overweight/obesity outcomes (low certainty of evidence). Meta-analyses of a subset of studies indicated a positive association between SSB intake and percentage body fat, but no association with change in BMI and BMI z-score. High-quality epidemiological studies that are designed to assess the effects of unhealthy food consumption during childhood on risk of overweight/obesity are needed to contribute to a more robust evidence base upon which to design policy recommendations. This protocol was registered at https://www.crd.york.ac.uk/PROSPERO as CRD42020218109.


Canine neurogenic Keratoconjunctivitis sicca: 11 cases (2006-2010).
To describe the clinical data of dogs with neurogenic Keratoconjunctivitis sicca (KCS) and an ipsilateral dry nose without other neurologic deficits. The retrospective case study included 11 dogs diagnosed with neurogenic KCS and an ipsilateral dry nose between 2006 and 2010. Medical records were reviewed for breed, age, sex, history, suspected cause of neurogenic KCS, clinical signs, and treatment modalities. Follow-up information was obtained by re-examination of patients or completion of a telephone survey with the referring veterinarian or the owners. Mean age of the dogs was 6.6 ± 4.5 years. Neurogenic KCS was diagnosed in three females, five spayed females, one male, and two castrated males representing 10 different breeds. Ophthalmic signs of KCS (mean Schirmer tear test [STT] value of 1.9 ± 2.9 mm/min) combined with an ipsilateral dry nose were diagnosed in seven left and four right eyes. The suspected cause of neurogenic KCS was idiopathic in nine and trauma in two cases. Systemic therapy consisted of oral pilocarpine 1-2% eye drops combined with case-specific topical treatment with cyclosporine 0.2% and tear substitutes. Duration of systemic treatment with pilocarpine until healing was 125 days (range 84-204, median 98 days) for five dogs. One dog was lost to follow-up, and the remaining five dogs are still under systemic treatment with pilocarpine. Neurogenic KCS with an ipsilateral dry nose seems to be a predominantly idiopathic disease of middle-aged female dogs without breed predisposition, which may be self-limiting in some cases.


Identification and characterization of epizootic hemorrhagic disease virus serotype 6 in cattle co-infected with bluetongue virus in Trinidad, West Indies.
Epizootic hemorrhagic disease virus (EHDV) is an economically important virus that can cause severe clinical disease in deer and to a lesser extent cattle. This study set out to determine and characterize which EHDV serotypes were circulating in Trinidad. Serum and whole blood samples were collected monthly for six months from a cohort of cattle imported to Trinidad from the USA. Results revealed that all the cattle seroconverted to EHDV within six months of their arrival, with EHDV RNA being detected in the samples just prior to antibodies, as expected. Serotyping assays revealed that a single serotype (EHDV-6) was circulating in the cattle. Sequencing of the surface viral protein (VP2) of EHDV-6, followed by phylogenetic analysis, revealed that the Trinidad EHDV-6 strain was closely related to EHDV-6 viruses found in Guadeloupe (2010), Martinique (2010) and USA (2006), with 96-97.2% nucleotide identity. The Trinidad EHDV-6 VP-2 shared 97.2% identity with the Australian EHDV-6 prototype strain, classifying it within the eastern topotype clade. Bayesian coalescent analysis support Australia as the most probable source for the EHDV-6 VP2 sequences in the Americas and Caribbean region and suggests that the they diverged from the Australian prototype strain around 1966 (95% HPD 1941-1979).


STRUCTURAL BIOLOGY. A Cas9-guide RNA complex preorganized for target DNA recognition.
Bacterial adaptive immunity uses CRISPR (clustered regularly interspaced short palindromic repeats)-associated (Cas) proteins together with CRISPR transcripts for foreign DNA degradation. In type II CRISPR-Cas systems, activation of Cas9 endonuclease for DNA recognition upon guide RNA binding occurs by an unknown mechanism. Crystal structures of Cas9 bound to single-guide RNA reveal a conformation distinct from both the apo and DNA-bound states, in which the 10-nucleotide RNA "seed" sequence required for initial DNA interrogation is preordered in an A-form conformation. This segment of the guide RNA is essential for Cas9 to form a DNA recognition-competent structure that is poised to engage double-stranded DNA target sequences. We construe this as convergent evolution of a "seed" mechanism reminiscent of that used by Argonaute proteins during RNA interference in eukaryotes.


A novel meiotic drive locus almost completely distorts segregation in mimulus (monkeyflower) hybrids.
We report the discovery, mapping, and characterization of a meiotic drive locus (D) exhibiting nearly 100% nonrandom transmission in hybrids between two species of yellow monkeyflowers, outcrossing Mimulus guttatus and selfing M. nasutus. Only 1% of F(2) hybrids were M. nasutus homozygotes at the marker most tightly linked to D. We used a set of reciprocal backcrosses to distinguish among male-specific, female-specific, and zygote-specific sources of transmission ratio distortion. Transmission was severely distorted only when the heterozygous F(1) acted as the female parent in crosses to either parental species, ruling out pollen competition and zygote mortality as potential sources of drive. After four generations of backcrossing to M. nasutus, nearly isogenic lines were still >90% heterozygous at markers linked to D, suggesting that heterozygosity at the drive locus alone is sufficient for nonrandom transmission. A lack of dramatic female fitness costs in these lines rules out alternatives involving ovule or seed mortality and points to a truly meiotic mechanism of drive. The strength and direction of drive in this system is consistent with population genetic theory of selfish element evolution under different mating systems. These results are the first empirical demonstration of the strong female-specific drive predicted by new models of selfish centromere turnover.


An envisioning about the caring in listening.
The purpose of this article is to make visible further dimensions and uncover an envisioning about the caring in listening in the field of caring science, which may improve the care for the suffering human being, the patient. Eriksson's caritative theory of caring constitutes the starting point for this search for knowledge, while the research method is realised by a hermeneutic reading based on the philosopher of hermeneutics, Gadamer's thought. The research is realised by a reading of Fyodor Dostoyevsky's literary works. The literary characters Sonia in Crime and Punishment and Alyosha in The Brothers Karamazov, uncovers patterns of meaning-bearing units towards the caring and the interpretation of a more profound envisioning about the caring in listening. The uncovering and interpretation show that patients in their suffering long to meet a caregiver who listens without the least condemnation in their eyes and demeanour. Patients need a listening caregiver who shows compassion and who has the courage to remain in the struggle of suffering and to carry the patients through insupportable pain, guilt and shame. Through listening, it is possible to reawaken a numb heart, to take individuals who have gone through a good deal of suffering, from darkness, degradation, unendurable pain to the light and to awaken their zest for life and joy to live. Listening renews, delivers and transforms human beings so that they can begin to find a new direction in life and start living a life in accordance with their own fundamental order, purpose, essential decision and individuality. Listening takes patients out of their loneliness and unbearable suffering into communion and a life worth living.


Symmetrically glass-clad photonic crystal nanocavities with ultrahigh quality factors.
We design and fabricate ultra-high-quality (Q) photonic nanocavities in a symmetrically glass-clad silicon (Si) two-dimensional (2D) photonic crystal (PhC) structure. We theoretically investigate the dependence of the refractive index of the glass on the Q factors for asymmetric and symmetric structures. We show that the index-symmetric distribution of the glass is a critical factor to realize ultrahigh Q factors for glass-clad 2D PhC structures. We fabricate symmetrically glass-clad Si PhC nanocavities and achieve a record Q factor of 1×10(6), comparable with the highest Q factors of nanocavities in air-bridge structures.


MHC-linked and un-linked class I genes in the wallaby.
MHC class I antigens are encoded by a rapidly evolving gene family comprising classical and non-classical genes that are found in all vertebrates and involved in diverse immune functions. However, there is a fundamental difference between the organization of class I genes in mammals and non-mammals. Non-mammals have a single classical gene responsible for antigen presentation, which is linked to the antigen processing genes, including TAP. This organization allows co-evolution of advantageous class Ia/TAP haplotypes. In contrast, mammals have multiple classical genes within the MHC, which are separated from the antigen processing genes by class III genes. It has been hypothesized that separation of classical class I genes from antigen processing genes in mammals allowed them to duplicate. We investigated this hypothesis by characterizing the class I genes of the tammar wallaby, a model marsupial that has a novel MHC organization, with class I genes located within the MHC and 10 other chromosomal locations. Sequence analysis of 14 BACs containing 15 class I genes revealed that nine class I genes, including one to three classical class I, are not linked to the MHC but are scattered throughout the genome. Kangaroo Endogenous Retroviruses (KERVs) were identified flanking the MHC un-linked class I. The wallaby MHC contains four non-classical class I, interspersed with antigen processing genes. Clear orthologs of non-classical class I are conserved in distant marsupial lineages. We demonstrate that classical class I genes are not linked to antigen processing genes in the wallaby and provide evidence that retroviral elements were involved in their movement. The presence of retroviral elements most likely facilitated the formation of recombination hotspots and subsequent diversification of class I genes. The classical class I have moved away from antigen processing genes in eutherian mammals and the wallaby independently, but both lineages appear to have benefited from this loss of linkage by increasing the number of classical genes, perhaps enabling response to a wider range of pathogens. The discovery of non-classical orthologs between distantly related marsupial species is unusual for the rapidly evolving class I genes and may indicate an important marsupial specific function.


Genome analysis and genetic transformation of a water surface-floating microalga Chlorococcum sp. FFG039.
Microalgal harvesting and dewatering are the main bottlenecks that need to be overcome to tap the potential of microalgae for production of valuable compounds. Water surface-floating microalgae form robust biofilms, float on the water surface along with gas bubbles entrapped under the biofilms, and have great potential to overcome these bottlenecks. However, little is known about the molecular mechanisms involved in the water surface-floating phenotype. In the present study, we analysed the genome sequence of a water surface-floating microalga Chlorococcum sp. FFG039, with a next generation sequencing technique to elucidate the underlying mechanisms. Comparative genomics study with Chlorococcum sp. FFG039 and other non-floating green microalgae revealed some of the unique gene families belonging to this floating microalga, which may be involved in biofilm formation. Furthermore, genetic transformation of this microalga was achieved with an electroporation method. The genome information and transformation techniques presented in this study will be useful to obtain molecular insights into the water surface-floating phenotype of Chlorococcum sp. FFG039.


Biocompatible organic charge transfer complex nanoparticles based on a semi-crystalline cellulose template.
Using a bio-inspired cellulose template, new charge transfer (CT) nanoparticles (NPs) with unique and intriguing emission properties are reported. Pyrene-modified 2,3-di-O-methyl cellulose formed CT complexes with small molecule acceptors, e.g. 7,7,8,8-tetracyanoquinodimethane (TCNQ), and exhibited aggregation-induced emission (AIE) in aqueous medium upon nanoparticle formation. The TCNQ-CT NPs showed multicolor fluorescence emissions at 370-400 nm, 602 nm and 777 nm, when excited at 330 nm, 485 nm and 620 nm respectively. The cellulose-TCNQ NPs are biocompatible and demonstrate an advance in the use of the CT mechanism for biomedical imaging applications both in vitro and in vivo.


Combined androgen deprivation therapy and radiation therapy for locally advanced prostate cancer: a randomised, phase 3 trial.
Whether the addition of radiation therapy (RT) improves overall survival in men with locally advanced prostate cancer managed with androgen deprivation therapy (ADT) is unclear. Our aim was to compare outcomes in such patients with locally advanced prostate cancer. Patients with: locally advanced (T3 or T4) prostate cancer (n=1057); or organ-confined disease (T2) with either a prostate-specific antigen (PSA) concentration more than 40 ng/mL (n=119) or PSA concentration more than 20 ng/mL and a Gleason score of 8 or higher (n=25), were randomly assigned (done centrally with stratification and dynamic minimisation, not masked) to receive lifelong ADT and RT (65-69 Gy to the prostate and seminal vesicles, 45 Gy to the pelvic nodes). The primary endpoint was overall survival. The results presented here are of an interim analysis planned for when two-thirds of the events for the final analysis were recorded. All efficacy analyses were done by intention to treat and were based on data from all patients. This trial is registered at controlledtrials.com as ISRCTN24991896 and Clinicaltrials.gov as NCT00002633. Between 1995 and 2005, 1205 patients were randomly assigned (602 in the ADT only group and 603 in the ADT and RT group); median follow-up was 6·0 years (IQR 4·4-8·0). At the time of analysis, a total of 320 patients had died, 175 in the ADT only group and 145 in the ADT and RT group. The addition of RT to ADT improved overall survival at 7 years (74%, 95% CI 70-78 vs 66%, 60-70; hazard ratio [HR] 0·77, 95% CI 0·61-0·98, p=0·033). Both toxicity and health-related quality-of-life results showed a small effect of RT on late gastrointestinal toxicity (rectal bleeding grade >3, three patients (0·5%) in the ADT only group, two (0·3%) in the ADT and RT group; diarrhoea grade >3, four patients (0·7%) vs eight (1·3%); urinary toxicity grade >3, 14 patients (2·3%) in both groups). The benefits of combined modality treatment--ADT and RT--should be discussed with all patients with locally advanced prostate cancer. Canadian Cancer Society Research Institute, US National Cancer Institute, and UK Medical Research Council.


The natural history of insomnia: acute insomnia and first-onset depression.
While many studies have examined the association between insomnia and depression, no studies have evaluated these associations (1) within a narrow time frame, (2) with specific reference to acute and chronic insomnia, and (3) using polysomnography. In the present study, the association between insomnia and first-onset depression was evaluated taking into account these considerations. A mixed-model inception design. Academic research laboratory. Fifty-four individuals (acute insomnia [n = 33], normal sleepers [n = 21]) with no reported history of a sleep disorder, chronic medical condition, or psychiatric illness. N/A. Participants were assessed at baseline (2 nights of polysomnography and psychometric measures of stress and mood) and insomnia and depression status were reassessed at 3 months. Individuals with acute insomnia exhibited more stress, poorer mood, worse subjective sleep continuity, increased N2 sleep, and decreased N3 sleep. Individuals who transitioned to chronic insomnia exhibited (at baseline) shorter REM latencies and reduced N3 sleep. Individuals who exhibited this pattern in the transition from acute to chronic insomnia were also more likely to develop first-onset depression (9.26%) as compared to those who remitted from insomnia (1.85%) or were normal sleepers (1.85%). The transition from acute to chronic insomnia is presaged by baseline differences in sleep architecture that have, in the past, been ascribed to Major Depression, either as heritable traits or as acquired traits from prior episodes of depression. The present findings suggest that the "sleep architecture stigmata" of depression may actually develop over the course transitioning from acute to chronic insomnia.


A real-time fMRI-based spelling device immediately enabling robust motor-independent communication.
Human communication entirely depends on the functional integrity of the neuromuscular system. This is devastatingly illustrated in clinical conditions such as the so-called locked-in syndrome (LIS), in which severely motor-disabled patients become incapable to communicate naturally--while being fully conscious and awake. For the last 20 years, research on motor-independent communication has focused on developing brain-computer interfaces (BCIs) implementing neuroelectric signals for communication (e.g., [2-7]), and BCIs based on electroencephalography (EEG) have already been applied successfully to concerned patients. However, not all patients achieve proficiency in EEG-based BCI control. Thus, more recently, hemodynamic brain signals have also been explored for BCI purposes. Here, we introduce the first spelling device based on fMRI. By exploiting spatiotemporal characteristics of hemodynamic responses, evoked by performing differently timed mental imagery tasks, our novel letter encoding technique allows translating any freely chosen answer (letter-by-letter) into reliable and differentiable single-trial fMRI signals. Most importantly, automated letter decoding in real time enables back-and-forth communication within a single scanning session. Because the suggested spelling device requires only little effort and pretraining, it is immediately operational and possesses high potential for clinical applications, both in terms of diagnostics and establishing short-term communication with nonresponsive and severely motor-impaired patients.


Super-Photostable Phosphole-Based Dye for Multiple-Acquisition Stimulated Emission Depletion Imaging.
As stimulated emission depletion (STED) microscopy can provide structural details of cells with an optical resolution beyond the diffraction limit, it has become an indispensable tool in cell biology. However, the intense STED laser beam usually causes rapid photobleaching of the employed fluorescent dyes, which significantly limits the utility of STED microscopy from a practical perspective. Herein we report a new design of super-photostable dye, PhoxBright 430 (PB430), comprising a fully ring-fused π-conjugated skeleton with an electron-accepting phosphole P-oxide unit. We previously developed a super-photostable dye C-Naphox by combining the phosphole unit with an electron-donating triphenylamine moiety. In PB430, removal of the amino group alters the transition type from intramolecular charge transfer character to π-π* transition character, which gives rise to intense fluorescence insensitive to molecular environment in terms of fluorescence colors and intensity, and bright fluorescence even in aqueous media. PB430 also furnishes high solubility in water, and is capable of labeling proteins with maintaining high fluorescence quantum yields. This dye exhibits outstanding resistance to photoirradiation even under the STED conditions and allows continuous acquisition of STED images. Indeed, using a PB430-conjugated antibody, we succeed in attaining a 3-D reconstruction of super-resolution STED images as well as photostability-based multicolor STED imaging of fluorescently labeled cytoskeletal structures.


Inhaled corticosteroids and hip fracture: a population-based case-control study.
There is accumulating evidence that the use of inhaled corticosteroids is associated with a dose-related reduction in bone mineral density. Whether this translates to an increase in fracture is unclear. We have used the General Practice Research Database to perform a case-control analysis, including 16,341 cases of hip fracture (mean age of 79 years, 79% female, median period prescribing data 2.7 years) and 29,889 control subjects, individually matched by age, sex, and general practice. Data for all prescriptions for corticosteroids and for potential confounders, including other drug use and comorbid illnesses, were extracted, and the impact of inhaled corticosteroid exposure was analyzed using conditional logistic regression. The risk of hip fracture was associated with exposure to inhaled corticosteroids with an odds ratio of 1.26 (95% confidence interval, 1.17 to 1.36). This odds ratio was reduced after adjusting the model for annual courses of oral corticosteroids, the only confounder of note (OR 1.19; 95% CI, 1.10 to 1.28). There was a dose-response relationship between inhaled corticosteroid use and hip fracture even after adjusting for the annual number of courses of oral corticosteroids (p trend = 0.007). In older subjects, the recent use of inhaled corticosteroids is associated with a dose-related increase in hip fracture.


A Simple Method for Discovering Druggable, Specific Glycosaminoglycan-Protein Systems. Elucidation of Key Principles from Heparin/Heparan Sulfate-Binding Proteins.
Glycosaminoglycans (GAGs) affect human physiology and pathology by modulating more than 500 proteins. GAG-protein interactions are generally assumed to be ionic and nonspecific, but specific interactions do exist. Here, we present a simple method to identify the GAG-binding site (GBS) on proteins that in turn helps predict high specific GAG-protein systems. Contrary to contemporary thinking, we found that the electrostatic potential at basic arginine and lysine residues neither identifies the GBS consistently, nor its specificity. GBSs are better identified by considering the potential at neutral hydrogen bond donors such as asparagine or glutamine sidechains. Our studies also reveal that an unusual constellation of ionic and non-ionic residues in the binding site leads to specificity. Nature engineers the local environment of Asn45 of antithrombin, Gln255 of 3-O-sulfotransferase 3, Gln163 and Asn167 of 3-O-sulfotransferase 1 and Asn27 of basic fibroblast growth factor in the respective GBSs to induce specificity. Such residues are distinct from other uncharged residues on the same protein structure in possessing a significantly higher electrostatic potential, resultant from the local topology. In contrast, uncharged residues on nonspecific GBSs such as thrombin and serum albumin possess a diffuse spread of electrostatic potential. Our findings also contradict the paradigm that GAG-binding sites are simply a collection of contiguous Arg/Lys residues. Our work demonstrates the basis for discovering specifically interacting and druggable GAG-protein systems based on the structure of protein alone, without requiring access to any structure-function relationship data.


Denosumab: A Review in Postmenopausal Osteoporosis.
Denosumab (Prolia®; Pralia®) is a human monoclonal antibody targeting the key bone resorption mediator RANKL. The drug is administered via subcutaneous injection once every 6 months and is approved for various indications, including the treatment of postmenopausal (PM) women with osteoporosis at increased/high risk of fracture or failure/intolerance of other osteoporosis therapies (indications featured in this review). Denosumab showed benefit in several phase 3 or 4 studies in PM women with osteoporosis or low bone mineral density (BMD), including the pivotal 3-year double-blind FREEDOM trial and its 7-year open-label extension. Denosumab reduced the risk of vertebral, nonvertebral and hip fractures and increased BMD across skeletal sites versus placebo in FREEDOM, with these benefits maintained over up to 10 years' therapy in the extension. The drug was also more effective in improving BMD than bisphosphonates, including in women switched from a bisphosphonate regimen, in 1-year trials; however, whether these differences translate into differences in anti-fracture efficacy is unclear. Denosumab was generally well tolerated over up to 10 years' treatment, although an increased risk of multiple vertebral fractures was observed after discontinuation of the drug. Thus, denosumab is a key treatment option for PM women with osteoporosis who have an increased/high risk of fracture or failure/intolerance of other osteoporosis therapies, although the potential for multiple vertebral fractures to occur after discontinuation of the drug requires consideration of subsequent management options.


Lightning strike fusion: extreme reduction and metal-silicate liquid immiscibility.
A glassy fulgurite, formed recently on a morainal ridge in southeastern Michigan, contains micrometer- to centimeter-sized metallic globules rich in native silicon, which unmixed from a silica-rich liquid. The unusual character of these globules and their potential for elucidating conditions of fulgurite formation prompted further study. Thermodynamic calculations indicate that temperatures in excess of 2000 K and reducing conditions approaching those of the SiO(2)-Si buffer were needed to form the coexisting metallic and silicate liquids. The phases produced are among the most highly reduced naturally occurring materials known. Some occurrences of other highly reduced minerals may also be due to lightning strike reduction. Extreme reduction and volatilization may also occur during high-temperature events such as lightning strikes in presolar nebulae and impacts of extraterrestrial bodies. As a result of scavenging of platinum-group elements by highly reduced metallic liquids, geochemical anomalies associated with the Cretaceous-Tertiary boundary may have a significant terrestrial component even if produced through bolide impact.


Injuries in Swedish floorball: a cost analysis.
The epidemiology of sport injuries is well documented. However, the costs are rarely discussed. Previous studies have presented such costs in specific sports or localization. No study has investigated the costs related to injuries in elite floorball. Thus, the aim of this study was to estimate cost of injuries in Swedish elite floorball players. During 1 year, 346 floorball players were prospectively followed. All time-loss injures were recorded. The injured players were asked to complete a questionnaire regarding their costs tied to the injury. Mean costs were calculated by multiplying the total resource use with the collected unit costs and dividing these total costs with the number of injuries as well as players. The results showed that the average cost per injury increased with the level of severity and ranged from 332 to 2358 Euros. The mild and moderate overuse injuries were costlier than the corresponding traumatic injuries. However, the severe traumatic injuries were associated with higher costs than overuse injuries. Knee injuries were the costliest. Our results indicate that there are costs to be saved, if floorball injuries can be avoided. They should be of interest to decision makers deciding whether to invest in preventive interventions.


Effect of global system for mobile communication (GSM) microwave exposure on blood-brain barrier permeability in rat.
We investigated the effects of global system for mobile communication (GSM) microwave exposure on the permeability of the blood-brain barrier using a calibrated microwave exposure system in the 900 MHz band. Rats were restrained in a carousel of circularly arranged plastic tubes and sham-exposed or microwave irradiated for a duration of 4 h at specific brain absorption rates (SAR) ranging from 0.3 to 7.5 W/kg. The extravasation of proteins was assessed either at the end of exposure or 7 days later in three to five coronal brain slices by immunohistochemical staining of serum albumin. As a positive control two rats were subjected to cold injury. In the brains of freely moving control rats (n = 20) only one spot of extravasated serum albumin could be detected in one animal. In the sham-exposed control group (n = 20) three animals exhibited a total of 4 extravasations. In animals irradiated for 4 h at SAR of 0.3, 1.5 and 7.5 W/kg (n = 20 in each group) five out of the ten animals of each group killed at the end of the exposure showed 7, 6 and 14 extravasations, respectively. In the ten animals of each group killed 7 days after exposure, the total number of extravasations was 2, 0 and 1, respectively. The increase in serum albumin extravasations after microwave exposure reached significance only in the group exposed to the highest SAR of 7.5 W/kg but not at the lower intensities. Histological injury was not observed in any of the examined brains. Compared to other pathological conditions with increased blood-brain barrier permeability such as cold injury, the here observed serum albumin extravasations are very modest and, moreover, reversible. Microwave exposure in the frequency and intensity range of mobile telephony is unlikely to produce pathologically significant changes of the blood-brain barrier permeability.


The pediatric burden of disease from lead exposure at toxic waste sites in low and middle income countries.
The impact of lead from toxic waste sites on children in low and middle income countries has not been calculated due to a lack of exposure data. We sought to calculate this impact in Disability Adjusted Life Years (DALYs). Using an Integrated Exposure Uptake Biokinetic (IEUBK) model, we converted soil and drinking water lead levels from sites in the Blacksmith Institute's Toxic Sites Identification Program (TSIP) into mean blood lead levels (BLLs). We then calculated the incidence of mild mental retardation (MMR) and DALYs resulting from these BLLs. The TSIP included 200 sites in 31 countries with soil (n=132) or drinking water (n=68) lead levels, representing 779,989 children younger than 4 years of age potentially exposed to lead. Environmental lead levels produced a range of BLLs from 1.56 to 104.71 µg/dL. These BLLs equated to an estimated loss of 5.41-8.23 IQ points, resulting in an incidence of MMR of 6.03 per 1000 population and 76.1 DALYs per 1000 population. Soil and water lead levels at toxic waste sites predict BLLs that lower the intelligence quotient (IQ), with the resulting MMR potentially limiting individual- and country-level development. The preventable burden of disease produced by these sites highlights the need for toxic waste sites to be systematically identified, evaluated, and remediated.


IQ predicts biological motion perception in autism spectrum disorders.
Biological motion is easily perceived by neurotypical observers when encoded in point-light displays. Some but not all relevant research shows significant deficits in biological motion perception among those with ASD, especially with respect to emotional displays. We tested adults with and without ASD on the perception of masked biological motion and the perception of direction from coherent and scrambled biological motion. Within the autism spectrum group, there was a large and statistically significant relationship between IQ and the ability to perceive directionality in masked biological motion. There were no group differences in sensitivity to biological motion or the ability to identify the direction of motion. Possible explanations are discussed, including the possible use of compensatory strategies in high IQ ASD.


Safety and immunogenicity study of a new purified chick embryo cell rabies vaccine Vaxirab-N (Pitman-Moore strain) manufactured in India.
Zydus Cadila Health care, India developed a new purified chick embryo cell rabies vaccine (PCECV, Vaxirab-N; 1 mL) by adapting Pitman-Moore strain of virus on to the chick embryo fibroblast cell line in 2006. During 2007-10, a series of safety and immunogenicity studies were conducted as per ICH-GCP guidelines after obtaining permission from Drug Controller General of India. In the first study, Vaxirab-N was administered to 35 healthy adult volunteers by intramuscular (IM) route using pre exposure regimen. The geometric mean concentration (GMC) of rabies virus neutralizing antibody (RvnAb) of 7.5 IU/mL on day 35. In the second study, Vaxirab-N was administered to 35 healthy adult volunteers using simulated post- exposure prophylaxis regimen by IM route. A GMC of 6.3 IU/mL on day 14, 13.2 IU/mL on day 28 and 8.6 IU/mL on day 90 was obtained. In the third study, Vaxirab-N administered by intradermal (ID) route using Updated Thai Red Cross (TRC) regimen in 36 healthy adult volunteers showed GMC of 7.8 IU/mL on day 14, 11.5 IU/mL on day 28 and 6.0 IU/mL on day 90. The 4th study was multi centric and Vaxirab-N was administered to 129 animal bite cases by IM route using post-exposure Essen regimen. The GMC following this schedule was 8.2 IU/mL on day 14, 13.01 IU/mL on day 28, 7.92 IU/mL on day 90 and 3.72 IU/mL on day 180. Mild to moderate adverse events were reported to Vaxirab-N but no serious adverse events were reported in any of these studies. In conclusion, Vaxirab-N developed by Zydus Cadila was found to be safe and immunogenic by both intramuscular and intradermal route and is recommended for rabies prophylaxis (CTRI No. 2010/091/000055 and 2010/091/000509).


Cepharanthin, a multidrug resistant modifier, is a substrate for P-glycoprotein.
P-glycoprotein modulators are respected to be multidrug resistance reversing agents in cancer chemotherapy. Some calcium channel blockers, calmodulin inhibitors or immunosuppressive agents have been used in clinical studies, although the dose of these drugs required to test in vitro experimental data might cause potent pharmacological effects which are not desirable in patients. By using LLC-GA5-COL150 cells that express P-glycoprotein specifically on the apical membranes, we examined the transport of anticancer drugs mediated by P-glycoprotein. Cepharanthin, a biscoclaurine alkaloid, potently inhibits the transport of vinblastine and daunorubicin, both commonly used anticancer agents. The 50% inhibitory concentration of cepharanthin on daunorubicin transport was 2.06 microM. Combined inhibitory effects on daunorubicin transport were observed when cepharanthin was used together with cyclosporin A, a potent immunosuppressive agent and P-glycoprotein modulator. Cepharanthin itself was transported by P-glycoprotein. Transcellular transport of cepharanthin across LLC-GA5-COL150 cell monolayers was saturable when its concentration was under 5 microM, and the transport was inhibited by P-glycoprotein modulators. These results indicate that cepharanthin can reverse multidrug resistance, and proper combination with other P-glycoprotein modulators could potentiate its inhibitory effect on expelling the anticancer drugs out of the cell via P-glycoprotein.


Influence of Access, Anticoagulant, and Bleeding Definition on Outcomes of Primary Percutaneous Coronary Intervention: Early Experience of an US Academic Center.
Background We aimed to carry out comparison of different bleeding avoidance strategies in doing primary percutaneous coronary intervention (PPCI) using either radial or femoral as access of choice and either bivalirudin or unfractionated heparin as anticoagulant of choice. In this analysis, we analyzed the influence of major bleeding definition on bleeding outcomes as well. Methods We did a retrospective analysis of 139 patients with ST-segment elevation myocardial infarction (STEMI) who had PPCI in our academic center from January 2010 till October 2013. The primary outcome at 30 days was a composite of death from any cause or stent thrombosis or non-coronary artery bypass grafting (CABG) related major bleeding (CathPCI Registry definition) and secondary outcomes were individual components of primary outcome and the hospital length of stay. Results There was no significant difference among different access/anticoagulant combinations with regards to primary outcome (22% in radial/bivalirudin vs. 5% in radial/heparin vs. 17% in femoral/bivalirudin vs. 28% in femoral/heparin group; p = 0.2) as well as its individual components except the hospital length of stay (2.56 vs. 3 vs. 3.97 vs. 4.4 days each; p < 0.0001). The overall rate of major bleeding was 11.5%. When we use HORIZON-AMI bleeding definition, it went up to 25 % due to one particular component (p < 0.004). Conclusions This single center observational study doing PPCI did not show any superiority of one bleeding avoidance strategy over others with regard to primary outcome and its individual components except the hospital length of stay. It also shows the importance of bleeding definition on bleeding outcomes.


Sputum eosinophilia and short-term response to prednisolone in chronic obstructive pulmonary disease: a randomised controlled trial.
Some patients with chronic obstructive pulmonary disease (COPD) respond to corticosteroid therapy. Whether these patients have different airway pathology from other COPD patients is unclear. We tested the hypothesis that response to prednisolone is related to the presence of eosinophilic airway inflammation. We did a randomised, double-blind, crossover trial. Patients who had COPD treated with bronchodilators only were assigned placebo and 30 mg prednisolone daily for 2 weeks each, in a random order, separated by a 4-week washout period. Before and after each treatment period, we assessed patients with spirometry, symptom scores, the chronic respiratory disease questionnaire (CRQ), incremental shuttle walk test, and induced sputum. Analysis was done by intention to treat. 83 patients were recruited, of whom 67 were randomised. The geometric mean sputum eosinophil count fell significantly after prednisolone (from 2.4% to 0.4%; mean difference six-fold [95% CI 3.1-11.4]) but not after placebo. Other sputum cell counts did not change. After stratification into tertiles by baseline eosinophil count, postbronchodilator forced expiratory volume in 1 s (FEV1) and total scores on the CRQ improved progressively after prednisolone from the lowest to the highest eosinophilic tertile, compared with placebo. The mean change in postbronchodilator FEV1, total CRQ score, and shuttle walk distance with prednisolone compared with placebo in the highest tertile was 0.19 L (0.06-0.32), 0.62 (0.31-0.93), and 20 m (5-35), respectively. Our findings suggest that eosinophilic airway inflammation contributes to airflow obstruction and symptoms in some patients with COPD and that the short-term effects of prednisolone are due to modification of this feature of the inflammatory response. The possibility that sputum eosinophilia identifies a subgroup of patients who particularly respond to long-term treatment with inhaled corticosteroids should be investigated.


Species-related differences in the mechanism of apoptosis during structural luteolysis.
Luteolysis is defined as the loss of function and subsequent involution of the luteal structure. The luteolytic process is usually subdivided, whereby the decline in progesterone is described as functional luteolysis and the structural involution is described as structural luteolysis. After the corpus luteum ceases to produce progesterone, it decreases in size, experiences a loss of cellular integrity, and then disappears from the ovary as a result of apoptosis of luteal cells. However, the control mechanisms responsible for initiating and mediating apoptosis during structural luteolysis seem more complex than originally envisioned. Furthermore, efforts to elucidate the apoptotic mechanisms have been complicated by the fact that different mammalian species have different mechanisms for controlling luteal function. Therefore, it is of interest to know whether different mammalian species have different apoptotic mechanisms. The goal of this review was to focus on species-related differences in the mechanism of apoptosis during structural luteolysis in rodents, cattle and humans, the species that are used most for luteolysis research.


Experimental models of melatonin-deficient hypertension.
Melatonin secreted by the pineal gland plays an important role in the regulation of blood pressure (BP) and its administration reduces hypertension both in animals and humans. There are two experimental models of melatonin-deficient hypertension: one induced by pinealectomy and another by continuous 24 hour exposure to light. Both models cause melatonin deficiency and prevent darkness-mediated nocturnal melatonin secretion and are associated with increased BP and myocardial, vascular and renal dysfunction. These models also lead to neurohumoral activation of the renin-angiotensin system, sympathetic nervous system, adrenocorticotrophin-glucocorticoid axis and cause insulin resistance. Together, these alterations contribute to rise in blood pressure by vasoconstrictive or circulatory fluid volume overload. The light induced hypertension model mimics the melatonin deficiency in patients with insufficient nocturnal BP decline, in those who have night shift or who are exposed to environmental light pollution. For this reason, this model is useful in development of anti-hypertensive drugs.


Consistent View of Protein Fluctuations from All-Atom Molecular Dynamics and Coarse-Grained Dynamics with Knowledge-Based Force-Field.
It is widely recognized that atomistic Molecular Dynamics (MD), a classical simulation method, captures the essential physics of protein dynamics. That idea is supported by a theoretical study showing that various MD force-fields provide a consensus picture of protein fluctuations in aqueous solution [Rueda, M. et al. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 796-801]. However, atomistic MD cannot be applied to most biologically relevant processes due to its limitation to relatively short time scales. Much longer time scales can be accessed by properly designed coarse-grained models. We demonstrate that the aforementioned consensus view of protein dynamics from short (nanosecond) time scale MD simulations is fairly consistent with the dynamics of the coarse-grained protein model - the CABS model. The CABS model employs stochastic dynamics (a Monte Carlo method) and a knowledge-based force-field, which is not biased toward the native structure of a simulated protein. Since CABS-based dynamics allows for the simulation of entire folding (or multiple folding events) in a single run, integration of the CABS approach with all-atom MD promises a convenient (and computationally feasible) means for the long-time multiscale molecular modeling of protein systems with atomistic resolution.


Genetics of recurrent early-onset major depression (GenRED): significant linkage on chromosome 15q25-q26 after fine mapping with single nucleotide polymorphism markers.
The authors studied a dense map of single nucleotide polymorphism (SNP) DNA markers on chromosome 15q25-q26 to maximize the informativeness of genetic linkage analyses in a region where they previously reported suggestive evidence for linkage of recurrent early-onset major depressive disorder. In 631 European-ancestry families with multiple cases of recurrent early-onset major depressive disorder, 88 SNPs were genotyped, and multipoint allele-sharing linkage analyses were carried out. Marker-marker linkage disequilibrium was minimized, and a simulation study with founder haplotypes from these families suggested that linkage scores were not inflated by linkage disequilibrium. The dense SNP map increased the information content of the analysis from around 0.7 to over 0.9. The maximum evidence for linkage was the Z likelihood ratio score statistic of Kong and Cox (Z(LR))=4.69 at 109.8 cM. The exact p value was below the genomewide significance threshold. By contrast, in the genome scan with microsatellite markers at 9 cM spacing, the maximum Z(LR) for European-ancestry families was 3.43 (106.53 cM). It was estimated that the linked locus or loci in this region might account for a 20% or less populationwide increase in risk to siblings of cases. This region has produced modestly positive evidence for linkage to depression and related traits in other studies. These results suggest that DNA sequence variations in one or more genes in the 15q25-q26 region can increase susceptibility to major depression and that efforts are warranted to identify these genes.


Should a colonoscopy be recommended for healthy individuals with increased carcinoembryonic antigen levels? A case-control study.
Despite the limitations of screening or early diagnosis of colorectal cancers (CRC), carcinoembryonic antigen (CEA) is frequently measured in practice and during health promotion programs. The aim of this study was to evaluate the role of colonoscopy in healthy individuals with elevated CEA levels. From January 2003 to November 2008, 117,731 healthy persons underwent an opportunistic screening program in two health promotion centers; 1,497 subjects (1.3%) showed an elevated CEA level (>5 ng/ml). Among them, 174 patients were recruited to undergo a colonoscopy to determine if colorectal malignancies were present. A total of 372 age- and sex-matched persons were selected as controls from among the healthy subjects who had a normal level of CEA and had received surveillance colonoscopy. The primary outcome was the incidences of CRC in elevated CEA and normal CEA groups. The secondary outcome was the predictive factors of CRC in the elevated CEA group. The incidence of CRC was higher in the group with higher CEA-levels than in the group with normal CEA levels (4.6 vs. 1.3%; P=0.031). In the CEA-elevated group, patients with CRCs were diagnosed at more advanced stages than were those in the CEA-normal group. The incidence of colorectal polyps was not different between the two groups. In the CEA-elevated group, anemia was an independent predictive factor of CRCs by multivariate analysis (P=0.002). Anemia itself is not a predictive factor of CRC in the entire population, but is an independent predictive factor of CRC in healthy individuals with an elevated level of CEA. Therefore, colonoscopy should be recommended for healthy subjects with an elevated level of CEA accompanied with anemia in the absence of other adenocarcinomas to evaluate the presence of colorectal malignancy.


Psychiatric sequelae in atomic bomb survivors in Hiroshima and Nagasaki two decades after the explosions.
Atomic bomb exposure was an extraordinarily stressful event. Although little epidemiological research has been performed on the psychiatric effects of the bombings, many medical descriptions of the survivors suggest that there was an increase of various symptoms that implied autonomic ataxia or neurosis-like disorders. The psychiatric effects of exposure to the atomic bomb explosions in Hiroshima and Nagasaki were assessed in this study. From a self-administered medical questionnaire completed between 1962 and 1965 by 9421 informed and consenting Adult Health Study subjects, some questions congruent with the DSM-IV diagnostic criteria for generalized anxiety disorder and somatization disorder were selected and used as indicators of anxiety symptoms and somatization symptoms. The prevalence of psychiatric symptoms in relation to age, sex, city (Hiroshima vs. Nagasaki), acute radiation symptoms, exposure status (in city or not in city), ground distance from hypocenter, disease history, and death of family members were analyzed. A higher prevalence of anxiety symptoms (odds ratio, 1.73) and somatization symptoms (odds ratio, 1.99) was observed in those with acute radiation symptoms than in those without them. The prevalence of anxiety symptoms and somatization symptoms among people who were in the city at the time of the explosion was significantly higher than among those who were not in the city. Among the former, prevalence was lower among proximally exposed people than among distally exposed people. Symptom prevalences were also affected by age, sex, and city. Although disease history such as neurotic disorder and ulcer were risk factors for anxiety symptoms and somatization symptoms, the increased prevalence of anxiety symptoms and somatization symptoms in association with atomic bomb exposure was independent of disease history and the death of family members. The prevalence of anxiety symptoms and somatization symptoms was elevated in atomic bomb survivors even 17-20 years after the bombings had occurred, indicating the long-term nature of the psychiatric effects of the experience. Psychiatric sequelae were independent of physical sequelae.