Amrinone in cardiac surgical patients with left-ventricular dysfunction. A prospective, randomized placebo-controlled trial.
To evaluate the efficacy of amrinone for facilitating weaning from cardiopulmonary bypass (CPB). Prospective, randomized, double-blind, placebo-controlled trial with epinephrine as "rescue" therapy. Operating room of a large, metropolitan tertiary-care center. Thirty-nine patients with preoperative left ventricular dysfunction undergoing cardiac surgery. Thirty-three patients underwent aortocoronary bypass grafting; six patients underwent valve replacement for severe mitral or aortic regurgitation. Patients received either amrinone (1.5 mg/kg loading dose plus 10 micrograms/kg/min maintenance infusion; n = 20) or placebo (n = 19) in a randomized double-blind fashion shortly (median, 10.5 min; range, 2 to 24 min) before separation from CPB. Inotropic drugs (other than the study drug) were withheld prior to separation from CPB unless safety considerations demanded that the protocol be broken. Patients who could not be weaned from CPB, as well as those with a cardiac index of 2.2 L/min/m2 or less after weaning from CPB, received epinephrine (60 to 120 ng/kg/min) by infusion. Fourteen of 19 patients receiving placebo but only 1 of the 20 patients receiving amrinone (p = 0.00001) required epinephrine infusion to separate from bypass. The cardiac index of 4 patients receiving placebo (but no patients with amrinone) failed to exceed 2.2 L/min/m2 despite epinephrine infusion, requiring the protocol to be broken (p < 0.08). Blood concentrations of amrinone determined (only in the amrinone group) after separation from CPB confirmed that the dosage of amrinone produced an effective blood concentration. Fourteen of 19 patients receiving placebo and 17 of 20 patients receiving amrinone required an infusion of phenylephrine titrated to maintain systolic blood pressure less than 90 mm Hg. Seven patients (four with amrinone and three with placebo) required antiarrhythmic drug therapy. The outcome at 3 months was similar in the 2 groups. Amrinone by itself is an effective agent to facilitate weaning from CPB, and therapy with amrinone reduced the need for individualized titration of epinephrine. Amrinone is as effective as individualized titration of epinephrine (after CPB) to improve cardiac function. Patients in the group receiving amrinone had no greater need for vasoconstricting agents than did patients in the group receiving placebo; however, proactive administration of amrinone before separation from CPB appears to offer no greater benefit to high-risk patients than selective administration of drugs (epinephrine) only to those patients who demonstrate the need for drug support at the time of weaning.


Circulating vascular endothelial growth factor and systemic inflammatory markers in patients with stable and exacerbated chronic obstructive pulmonary disease.
The aim of the present study was to assess circulating levels of VEGF (vascular endothelial growth factor), a biomarker with prognostic significance in cardiovascular disease, and markers of systemic inflammation in patients with stable and exacerbated COPD (chronic obstructive pulmonary disease). Lung function parameters, arterial blood gas analysis and circulating levels of VEGF, IL-6 (interleukin-6), TNF-alpha (tumour necrosis factor-alpha), CRP (C-reactive protein), fibrinogen and the peripheral blood neutrophil cell count were assessed in 30 patients on admission to the hospital for acute exacerbation of COPD, in 30 age-, gender- and BMI (body mass index)-matched patients with stable COPD, and 30 matched controls with normal lung function. Patients with acute exacerbated COPD had higher circulating concentrations of VEGF (P<0.001), IL-6 (P<0.05) and CRP (P<0.01) and an increased blood neutrophil cell count (P<0.05) compared with patients with stable COPD and healthy controls. VEGF levels in exacerbated COPD correlated with systemic inflammatory markers, such as CRP (r=0.61, P<0.005), IL-6 (r=0.46; P<0.01) and fibrinogen (r=0.39, P<0.05). In patients with stable COPD, there was a significant relationship between circulating VEGF levels and the percentage of the predicted FEV(1) (forced expiratory volume in 1 s) (r=0.47, P<0.01). Recovery from the exacerbation resulted in a significant decrease in both circulating VEGF levels and markers of systemic inflammation. In conclusion, circulating levels of VEGF and markers of systemic inflammation are up-regulated in patients with acute exacerbated COPD and decrease after recovery from the exacerbation.


Bisdemethoxycurcumin Increases Sirt1 to Antagonize t-BHP-Induced Premature Senescence in WI38 Fibroblast Cells.
Curcuminoids are well known for their capabilities to combat risk factors that are associated with ageing and cellular senescence. Recent reports have demonstrated that curcuminoids can extend the lifespan of model organisms. However, the underlying mechanisms by which these polyphenic compounds exert these beneficial effects remain unknown. In this study, t-BHP-induced premature senescence model in human fibroblasts was chosen to explore the protective effects of a curcuminoid, bisdemethoxycurcumin (BDMC), on cellular senescence. The results demonstrated that BDMC attenuated oxidative stress-induced senescence-like features which include the induction of an enlarged cellular appearance, higher frequency of senescence-associated β -galactosidase staining activity, appearance of senescence-associated heterochromatic foci in nuclei, decrease in proliferation capability, and alteration in related molecules such as p16 and retinoblastoma protein. Notably, we found that BDMC treatment activated Sirt1/AMPK signaling pathway. Moreover, downregulating Sirt1 by the pharmacological inhibitor nicotianamine or small interfering RNA blocked BDMC-mediated protection against t-BHP-mediated decrease in proliferation. These results suggested that BDMC prevented t-BHP-induced cellular senescence, and BDMC-induced Sirt1 may be a mechanism mediating its beneficial effects.


Nonunions and the potential of stem cells in fracture-healing.
Recent progress in human embryonic and adult stem cell research is a cause for much enthusiasm in bone and joint surgery. Stem cells have therapeutic potential in the realm of orthopaedic surgery because of their capacity to self-renew and differentiate into various types of mature cells and tissues, including bone. Because nonunions remain a clinically important problem, there is interest in the use of cell-based strategies to augment fracture repair. Such strategies are being investigated with variations in the model systems, sources of stem cells, and methods for the application and enhancement of osseous healing, including genetic modifications and tissue-engineering. This review highlights the recent progress in the utilization of stem cells and cell-based gene therapy in promoting fracture-healing and its potential utility in the clinical setting.


Experimental evaluation of heat and moisture transfer in metal dog cage environments.
Dog cages with solid and expanded metal flooring were tested while unoccupied, occupied by a 10-kg adult male beagle, and occupied by simulated loads to represent a beagle and a greyhound. Cage performances were evaluated with no direct coupling between the room air supply and the cage, and with mechanical coupling of 50% and 100% of the room air supplied directly to the cage. At each of these conditions, the room was maintained at approximately 24 degrees C and 45% relative humidity with room air exchange rates of 5, 10, and 15 changes per hr. Results indicated significant differences existed in dry-bulb and dew-point temperatures between the cage and the room. These differences, together with significant vertical gradients of air velocity and dry-bulb and dew-point temperatures within the cage were shown to be affected by room air exchange rate, cage flooring, type of coupling, and cage load.


Selective Affinity Enrichment of Nitrotyrosine-Containing Peptides for Quantitative Analysis in Complex Samples.
Protein tyrosine nitration by oxidative and nitrate stress is important in the pathogenesis of many inflammatory or aging-related diseases. Mass spectrometry analysis of protein nitrotyrosine is very challenging because the non-nitrated peptides suppress the signals of the low-abundance nitrotyrosine (NT) peptides. No validated methods for enrichment of NT-peptides are currently available. Here we report an immunoaffinity enrichment of NT-peptides for proteomics analysis. The effectiveness of this approach was evaluated using nitrated protein standards and whole-cell lysates in vitro. A total of 1881 NT sites were identified from a nitrated whole-cell extract, indicating that this immunoaffinity-MS method is a valid approach for the enrichment of NT-peptides, and provides a significant advance for characterizing the nitrotyrosine proteome. We noted that this method had higher affinity to peptides with N-terminal nitrotyrosine relative to peptides with other nitrotyrosine locations, which raises the need for future study to develop a pan-specific nitrotyrosine antibody for unbiased, proteome-wide analysis of tyrosine nitration. We applied this method to quantify the changes in protein tyrosine nitration in mouse lungs after intranasal poly(I:C) treatment and quantified 237 NT sites. This result indicates that the immunoaffinity-MS method can be used for quantitative analysis of protein nitrotyrosines in complex samples.


Design and Evaluation Challenges of Conversational Agents in Health Care and Well-being: Selective Review Study.
Health care and well-being are 2 main interconnected application areas of conversational agents (CAs). There is a significant increase in research, development, and commercial implementations in this area. In parallel to the increasing interest, new challenges in designing and evaluating CAs have emerged. This study aims to identify key design, development, and evaluation challenges of CAs in health care and well-being research. The focus is on the very recent projects with their emerging challenges. A review study was conducted with 17 invited studies, most of which were presented at the ACM (Association for Computing Machinery) CHI 2020 conference workshop on CAs for health and well-being. Eligibility criteria required the studies to involve a CA applied to a health or well-being project (ongoing or recently finished). The participating studies were asked to report on their projects' design and evaluation challenges. We used thematic analysis to review the studies. The findings include a range of topics from primary care to caring for older adults to health coaching. We identified 4 major themes: (1) Domain Information and Integration, (2) User-System Interaction and Partnership, (3) Evaluation, and (4) Conversational Competence. CAs proved their worth during the pandemic as health screening tools, and are expected to stay to further support various health care domains, especially personal health care. Growth in investment in CAs also shows the value as a personal assistant. Our study shows that while some challenges are shared with other CA application areas, safety and privacy remain the major challenges in the health care and well-being domains. An increased level of collaboration across different institutions and entities may be a promising direction to address some of the major challenges that otherwise would be too complex to be addressed by the projects with their limited scope and budget.


Physiological identification, morphological analysis, and development of identified serotonin-proctolin containing neurons in the lobster ventral nerve cord.
Amines and peptides exert a wide range of physiological actions on both central neurons and peripheral tissues. Among these actions, serotonin and octopamine are known to trigger contrasting postures when injected into freely moving lobsters. Immunocytochemical studies of lobster ganglia have identified presumptive serotonergic neurons, their central and peripheral projections, and their terminal fields of arborization. More than 100 neurons that show serotonin-like immunoreactivity have been found in the lobster nervous system (Beltz and Kravitz, 1983). From immunocytochemical studies it appears that varicosities within peripheral neurosecretory structures and endings in certain central neuropil regions arise from the same 2 pairs of large cells located in the fifth thoracic (T5) and first abdominal (A1) ganglia. Because we believed that such cells could account for the central and peripheral actions of serotonin on the postural system, we chose to study these 2 pairs of neurons in greater detail. In the previous paper, Siwicki et al. (1987) report that these neurons contain the pentapeptide proctolin in addition to serotonin. In this communication, we report that these cells can be identified reliably in living preparations; they have large fields of innervation projecting anteriorly into at least 4 segmental ganglia; these neurons are the origin of the fibers that form the thoracic second root neurosecretory regions; they are generally spontaneously active neurons that have overshooting action potentials in their cell bodies; and the serotonin and proctolin immunoreactivities are first expressed in these cells at widely different times in development.


Highly Antibacterial and Antioxidative Carbon Nanodots/Silk Fibroin Films for Fruit Preservation.
The issues of fruit waste and safety resulting from rot have spurred a demand for improved packaging systems. Herein, we present highly antibacterial and antioxidative carbon nanodot/silk fibroin (CD/SF) films for fruit preservation. The films are composed of CDs and SF together with a small amount of glycerol via hydrogen bonding, exhibiting outstanding biosafety, transparency, and stretchability. The films effectively integrate key functionalities (atmosphere control, resistance to food-borne pathogens, and antioxidation properties) and can be manufactured in large sizes (about 20 × 30 cm), boasting a transmission rate of 13 183 cm3/m2·day for oxygen and 2860 g/m2·day for water vapor, favoring the preservation of fresh fruits. A convenient dip-coating method enables in situ fabrication of films with a thickness of approximately 14 μm directly on the fruits' surface providing comprehensive protection. Importantly, the films are washable and biodegradable. This work presents a promising technology to produce multifunctional and eco-friendly antibacterial packaging systems.


Transitioning From Thrombopoietin Agonists to the Novel SYK Inhibitor Fostamatinib: A Multicenter, Real-World Case Series.
Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor used for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Clinical and operational barriers may exist that warrant bridging or switching from thrombopoietin receptor agonists (TPO-RAs), such as volatility or unpredictability of platelets, adverse events, and quality of life or patient preference. While fostamatinib demonstrated durable platelet responses, the safety and efficacy in combination, bridging, and/or switching with TPO-RAs is not well documented. The objective of this article is to provide guidance from real-world case studies for a safe and effective strategy for the transitioning of patients from TPO-RAs to fostamatinib, with some degree of overlap between the two agents. Currently, the evidence does not exist to guide the safe and effective use of combination therapy or transition between therapies in ITP. This case series highlights the importance to further understand the complexities of managing this disease, as well as successfully combining, bridging, and/or switching patients over to fostamatinib without the need for rescue therapy or increase in adverse events. The need for real-world evidence that guides providers on the safety and efficacy of short- and long-term combination therapy of fostamatinib and TPO-RAs is crucial. The rationale for combination therapy is to target different pathways, platelet destruction, and production without added toxicities. Additionally, gradual tapering off of TPO-RAs may provide a more favorable clinical outcome when switching to fostamatinib. The need for additional data is necessary to provide clinicians with guidance when managing patients with ITP.


Gastrointestinal absorption of drugs.
In this paper, those subjects that are important to drug absorption in the gastrointestinal tract are reviewed. First the anatomy of the gastrointestinal system is discussed in some detail. This is followed by a general review of the some of the animal models that are used to study drug absorption. In later sections, the physiological factors that affect drug absorption (pH and bile fluid), different mechanisms of drug absorption (passive, facilitated, and active transport, peptide and macromolecule absorption, and lymphatic uptake), and adjuvants (promoters of drug absorption) are discussed.


Impact of inappropriate drug use on health services utilization among representative older community-dwelling residents.
There is limited objective information regarding the impact of drugs identified as inappropriate by drug utilization review (DUR) or the Beers drugs-to-avoid criteria on health service use. The goal of this study was to examine the predictive validity of DUR and the Beers criteria employed to define inappropriate drug use in representative community residents, aged >or=68 years, as determined by the relationship of these criteria to health service use in older community residents. Data came from participants in the Duke University Established Populations for Epidemiologic Studies of the Elderly seen in 1989/1990 and for whom information was also available 3 years later. Two sets of inappropriate drug use criteria were examined: (1) DUR regarding dosage, duration, duplication, and drug-drug and drug-disease interactions; and (2) the Beers criteria, applied to drug use reported in an in-home interview. Outpatient visits and nursing-home entry were determined by personal report; hospitalization information came from Medicare Part A files from the Centers for Medicare and Medicaid Services. A total of 3165 participants were available at the fourth interview in 1989/1990. The majority were aged >74 years (51.1%), white (64.8%), women (64.7%), had fair or poor health (77.0%), consistently saw the same physician (86.9%), and possessed supplemental health insurance (62.8%). Use of inappropriate drugs meeting DUR criteria, especially for drug-drug or drug-disease interaction problems, was associated with increased outpatient visits (P<0.05) but not with time to hospitalization or time to nursing home entry. The use of inappropriate drugs according to the Beers criteria was associated with reduced time to hospitalization (adjusted hazard ratio, 1.20; 95% CI, 1.04-1.39) but not to outpatient visits or nursing home entry. Our data suggest that in representative community residents aged >or=68 years, current criteria for inappropriate drug use should be used with caution in evaluating quality of care because they have minimal impact on use of health services. We found increases only in the use of outpatient services (with DUR) and more rapid use of hospitalization (with the Beers criteria).


Non-Coding RNAs in Cancer Radiosensitivity: MicroRNAs and lncRNAs as Regulators of Radiation-Induced Signaling Pathways.
Radiotherapy is a cancer treatment that applies high doses of ionizing radiation to induce cell death, mainly by triggering DNA double-strand breaks. The outcome of radiotherapy greatly depends on radiosensitivity of cancer cells, which is determined by multiple proteins and cellular processes. In this review, we summarize current knowledge on the role of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in determining the response to radiation. Non-coding RNAs modulate ionizing radiation response by targeting key signaling pathways, including DNA damage repair, apoptosis, glycolysis, cell cycle arrest, and autophagy. Additionally, we indicate miRNAs and lncRNAs that upon overexpression or inhibition alter cellular radiosensitivity. Current data indicate the potential of using specific non-coding RNAs as modulators of cellular radiosensitivity to improve outcome of radiotherapy.


Reassessing the organization of the UL42-UL43 region of the human cytomegalovirus strain AD169 genome.
A polymorphism in the UL42-UL43 region of the human cytomegalovirus genome has been characterized by nucleotide sequence analysis, revealing a 929-bp insertion following nt 54,612 relative to the published strain AD169-UK genome sequence (M.S. Chee et al., 1990, Curr. Top. Microbiol Immunol. 154, 125-170). Although AD169-UK exhibited polymorphism in this genomic region, other CMV strains (Towne, Toledo, and AD169-ATCC) carried only the newly characterized longer form. The additional sequence altered the assignment of UL42 and UL43 open reading frames. UL42 decreased in size from 157 to 125 codons, retaining 76 of the previously reported carboxyl terminal codons, and UL43 increased in size from 187 to 423 codons, retaining 185 of the previously reported amino terminal codons. This additional sequence makes UL43 a more conserved betaherpesvirus US22 family member. Only AD169-UK exhibited restriction fragment length polymorphism in this region, suggesting that a deletion occurred during the propagation of this strain in cell culture. The additional sequence should be considered a bona fide part of the cytomegalovirus genome and the AD169 genome size should be corrected to 230,283 bp.


Development and Initial Validation of a Rock Climbing Craving Questionnaire (RCCQ).
Conceptual similarities have been identified between experiences of extreme sports athletes and those with drug and behavioral addictions. Evidence suggests rock climbers experience craving and other withdrawal-like states when abstinent from their sport. However, no studies have attempted to quantitatively measure the craving experienced by participants of any extreme sports. Such a measure could allow a greater understanding of the craving experienced by extreme sports athletes and a comparison of these across sports (e.g., surfing) and activities (e.g., drug-use). Therefore, using validated craving measures as a template, the aim of the two studies outlined here was to design and preliminarily validate a subjective multidimensional inventory that could be used to measure craving in the sports of rock-climbing and mountaineering ("RCCQ"). The aim of the first study was to investigate the factor structure of a preliminary measure of craving. Climbers (n = 407) completed the RCCQ. A 3-factor model explained 53.65% of the total variance in item scores. All three factors comprised five items each, which were conceptually labeled as "urge to climb" "negative reinforcement" and "positive reinforcement." The aim of the second study was to validate the 15-item 3-factor RCCQ resulting from Study 1 using confirmatory factor analysis (CFA). Climbers (n = 254) completed the questionnaire under a climbing-related cue condition or a cue-neutral condition. CFA revealed a good model fit and that all individual parameter estimates were significant and standard errors were within reasonable limits once item 13 was removed from Factor 1. Study 1 supports the multi-dimensional nature of rock climbing craving and shows parallels with substance-related craving in reflecting intention and positive (desire) and negative (withdrawal) reinforcement. Study 2 confirms this factor structure and gives initial validation to the measure with evidence that these factors are sensitive to cue exposure. Given the preliminary nature of the data, any practical implications are tentative. However, if as shown here, craving for climbing (and potentially other extreme sports) is similar to that experienced by drug-users and addicts, there is the potential that climbing and other extreme sports could be used as a replacement therapy for drug users.


Automated segmentation of cell membranes to evaluate HER2 status in whole slide images using a modified deep learning network.
The uncontrollable growth of cells in the breast tissue causes breast cancer which is the second most common type of cancer affecting women in the United States. Normally, human epidermal growth factor receptor 2 (HER2) proteins are responsible for the division and growth of healthy breast cells. HER2 status is currently assessed using immunohistochemistry (IHC) as well as in situ hybridization (ISH) in equivocal cases. Manual HER2 evaluation of IHC stained microscopic images involves an error-prone, tedious, inter-observer variable, and time-consuming routine lab work due to diverse staining, overlapped regions, and non-homogeneous remarkable large slides. To address these issues, digital pathology offers reproducible, automatic, and objective analysis and interpretation of whole slide image (WSI). In this paper, we present a machine learning (ML) framework to segment, classify, and quantify IHC breast cancer images in an effective way. The proposed method consists of two major classifying and segmentation parts. Since HER2 is associated with tumors of an epithelial region and most of the breast tumors originate in epithelial tissue, it is crucial to develop an approach to segment different tissue structures. The proposed technique is comprised of three steps. In the first step, a superpixel-based support vector machine (SVM) feature learning classifier is proposed to classify epithelial and stromal regions from WSI. In the second stage, on classified epithelial regions, a convolutional neural network (CNN) based segmentation method is applied to segment membrane regions. Finally, divided tiles are merged and the overall score of each slide is evaluated. Experimental results for 127 slides are presented and compared with state-of-the-art handcraft and deep learning-based approaches. The experiments demonstrate that the proposed method achieved promising performance on IHC stained data. The presented automated algorithm was shown to outperform other approaches in terms of superpixel based classifying of epithelial regions and segmentation of membrane staining using CNN.


STAT5: a Target of Antagonism by Neurotropic Flaviviruses.
Flaviviruses are a diverse group of arthropod-borne viruses responsible for numerous significant public health threats; therefore, understanding the interactions between these viruses and the human immune response remains vital. West Nile virus (WNV) and Zika virus (ZIKV) infect human dendritic cells (DCs) and can block antiviral immune responses in DCs. Previously, we used mRNA sequencing and weighted gene coexpression network analysis (WGCNA) to define molecular signatures of antiviral DC responses following activation of innate immune signaling (RIG-I, MDA5, or type I interferon [IFN] signaling) or infection with WNV. Using this approach, we found that several genes involved in T cell cosignaling and antigen processing were not enriched in DCs during WNV infection. Using cis-regulatory sequence analysis, STAT5 was identified as a regulator of DC activation and immune responses downstream of innate immune signaling that was not activated during either WNV or ZIKV infection. Mechanistically, WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and interleukin-4 (IL-4), but not granulocyte-macrophage colony-stimulating factor (GM-CSF), signaling. Unexpectedly, dengue virus serotypes 1 to 4 (DENV1 to DENV4) and the yellow fever 17D vaccine strain (YFV-17D) did not antagonize STAT5 phosphorylation. In contrast to WNV, ZIKV inhibited JAK1 and TYK2 phosphorylation following type I IFN treatment, suggesting divergent mechanisms used by these viruses to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert the immune response in infected DCs.IMPORTANCE Flaviviruses are a diverse group of insect-borne viruses responsible for numerous significant public health threats. Previously, we used a computational biology approach to define molecular signatures of antiviral DC responses following activation of innate immune signaling or infection with West Nile virus (WNV). In this work, we identify STAT5 as a regulator of DC activation and antiviral immune responses downstream of innate immune signaling that was not activated during either WNV or Zika virus (ZIKV) infection. WNV and ZIKV actively blocked STAT5 phosphorylation downstream of RIG-I, IFN-β, and IL-4, but not GM-CSF, signaling. However, other related flaviviruses, dengue virus serotypes 1 to 4 and the yellow fever 17D vaccine strain, did not antagonize STAT5 phosphorylation. Mechanistically, WNV and ZIKV showed differential inhibition of Jak kinases upstream of STAT5, suggesting divergent countermeasures to inhibit STAT5 activation. Combined, these findings identify STAT5 as a target of antagonism by specific pathogenic flaviviruses to subvert antiviral immune responses in human DCs.


Biomass allocation and leaf chemical defence in defoliated seedlings of Quercus serrata with respect to carbon-nitrogen balance.
Both nutrient availability and defoliation affect the carbon-nutrient balance in plants, which in turn influences biomass allocation (e.g. shoot-to-root ratio) and leaf chemical composition (concentration of nitrogen and secondary compounds). In this study it is questioned whether defoliation alters biomass allocation and chemical defence in a similar fashion to the response to nutrient deficiency. Current-year seedlings of Quercus serrata were grown with or without removal of all leaves at three levels of nutrient availability. Plant nitrogen concentration (PNC), a measure of the carbon-nutrient balance in the plant, significantly decreased immediately after defoliation because leaves had higher nitrogen concentrations than stems and roots. However, PNC recovered to levels similar to or higher than that of control plants in 3 or 6 weeks after the defoliation. Nitrogen concentration of leaves produced after defoliation was significantly higher than leaf nitrogen concentration of control leaves. Leaf mass per plant mass (leaf mass ratio, LMR) was positively correlated with PNC but the relationship was significantly different between defoliated and control plants. When compared at the same PNC, defoliated plants had a lower LMR. However, the ratio of the leaf to root tissues that were newly produced after defoliation as a function of PNC did not differ between defoliated and control plants. Defoliated plants had a significantly lower concentration of total phenolics and condensed tannins. Across defoliated and control plants, the leaf tannin concentration was negatively correlated with the leaf nitrogen concentration, suggesting that the amount of carbon-based defensive compounds was controlled by the carbon-nutrient balance at the leaf level. Defoliation alters biomass allocation and chemical defence through the carbon-nutrient balance at the plant and at the leaf level, respectively.


Poor outcome with nonmyeloablative conditioning regimen before cord blood transplantation for patients with high-risk acute myeloid leukemia compared with matched related or unrelated donor transplantation.
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is recommended for patients with high-risk acute myeloid leukemia (AML). In many situations, a matched related (MRD) or matched unrelated donor (MUD) is lacking, in which case unrelated cord blood units (UCB) provide an alternative. We analyzed the outcome of consecutive high-risk AML patients prepared with reduced-intensity conditioning (RIC) regimens and allografted with UCB (n = 32) and compared their outcome with high-risk AML patients who underwent transplantation with MRD/MUD (n = 49) in the same period of time. Grade III to IV acute graft-versus-host disease (GVHD) occurred slightly more frequently in the UCB group (25%) than in the MRD/MUD group (8%) (P = .069). Conversely, we found a lower incidence of extensive chronic GVHD in the UCB group (6%) than in the MRD/MUD group (20%, P = .085). Nonrelapse mortality at 4 years was 16% and 22% in the UCB and MRD/MUD groups, respectively (P = .529). The cumulative incidence of relapse at 4 years was significantly higher in the UCB group (60%) than in the MRD/MUD group (27%, P = .006). Leukemia-free survival (LFS) and overall survival (OS) at 4 years were 25% and 34%, respectively, in the UCB group and 50% and 56%, respectively, in the MRD/MUD group (LFS, P = .029; OS, P = .072). Multivariate analyses adjusted by cytogenetics and disease status at the time of Allo-HSCT revealed that use of UCB remained an independent predictive factor of shorter LFS (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.6; P = .018), and was associated with a trend for shorter OS (hazard ratio, 1.7; 95% confidence interval, .9 to 3.2; P = .093). Whereas UCB provides an alternative for patients with high-risk AML lacking an MRD/MUD, the high incidence of relapse after RIC-based UCB Allo-HSCT is a concern. Attempts to improve leukemic control with UCB Allo-HSCT are warranted, as well as the evaluation of other alternative donors in this context.


Electrophysiological characterization of ivermectin triple actions on Musca chloride channels gated by l-glutamic acid and γ-aminobutyric acid.
Ivermectin (IVM) is a macrocyclic lactone that exerts antifilarial, antiparasitic, and insecticidal effects on nematodes and insects by acting on l-glutamic acid-gated chloride channels (GluCls). IVM also acts as an allosteric modulator of various other ion channels. Although the IVM binding site in the Caenorhabditis elegans GluCl was identified by X-ray crystallographic analysis, the mechanism of action of IVM in insects is not well defined. We therefore examined the action of IVM on the housefly (Musca domestica) GluCl and γ-aminobutyric acid (GABA)-gated ion channel (GABACl). For both channels, IVM induced currents by itself, potentiated currents induced by low concentrations of agonists, and inhibited currents induced by high concentrations of agonists. Despite exerting common actions on both types of channels, GluCls were more susceptible to IVM actions than GABACls, indicating that GluCls are the primary target of IVM. Substitution of an amino acid residue in the third transmembrane segment (G312M in GluCls, and G333A and G333M in GABACls) resulted in significantly reduced levels or loss of activation, potentiation, and antagonism of the channels, indicating that these three actions result from the interaction of IVM with amino acid residues in the transmembrane intersubunit crevice.


Distal acquired demyelinating symmetric neuropathy after vaccination.
Neuropathy after vaccination is a rare event. Chronic immune-mediated polyneuropathy developing in the postvaccination period is distinctly unusual and not well described. Almost all such patients have been reported as having typical chronic inflammatory demyelinating polyneuropathy. Distal acquired demyelinating symmetric neuropathy, unlike classic chronic inflammatory demyelinating polyneuropathy, is characterized by distally predominant sensory symptoms with no or mild distal weakness. We describe the clinical, laboratory, and neurophysiological findings of 2 patients who developed distal acquired demyelinating symmetric neuropathy after vaccination. Immunomodulatory therapy led to clinical improvement in both cases. The literature is reviewed with attention to the clinical features of chronic immune-mediated neuropathies that follow vaccination.


On scleroderma. Mast cells, endothelial cells, and fibroblasts.
An integrated view of the pathogenesis of scleroderma should include vascular, immunologic, and fibrotic processes. This review introduces the mast cell into this picture, emphasizing recent knowledge gained from a study of experimental chronic graft-vs-host disease and scleroderma itself. In both of these situations, increased mast cell activity occurs. A link between the activation of both endothelial cells and fibroblasts may be provided by the family of heparin-binding growth factors. These cytokines are produced by many cells and are bound, protected, and enhanced by heparin, which may be provided by the activated mast cells. These and other growth factors may be responsible for endothelial proliferation and excess collagen production by fibroblasts. This enlarged schema should provide additional points for therapeutic intervention in scleroderma.


Trigeminal neuralgia caused by nerve compression by dilated superior cerebellar artery associated with cerebellar arteriovenous malformation: case report.
Intracranial arteriovenous malformation (AVM) is a rare cause of trigeminal neuralgia (TGN). In this presented case, successful resolution of AVM-related TGN following embolization and gamma knife stereotactic radiosurgery (GKRS) was obtained. A patient suffered from TGN on the left side, which was thought to be caused by root entry zone compression by dilated superior cerebellar artery (SCA) associated with cerebellar AVM. The cerebellar vermis AVM was embolized in endovascular surgery. The AVM was reduced in size and TGN was partially relieved. The patient subsequently underwent GKRS for the residual nidus. TGN was completely resolved within one year and a half. GKRS following embolization of the nidus improved the flow-related dilation of the SCA and completely relieved TGN.


Stress fracture of the supracondylar process of the humerus in a professional tennis player.
The supracondylar process of the humerus is an anatomic variant present in 1% of the population associated with a fibrous band, the ligament of Struthers that attaches it to the medial epicondyle, and may serve as a proximal origin of a fascicle of the pronator teres. Fractures of the supracondylar process of the humerus are extremely rare. To the best of our knowledge, this is the first report of a stress fracture of the supracondylar process. We present the case of a professional tennis player with a stress fracture of the supracondylar process who underwent surgery to avoid possible displacement and neurovascular complications. Clinicians should consider the diagnosis of a supracondylar process fracture with or without neurovascular compression when examining athletes with otherwise unexplained arm or elbow pain. Stress fracture of the supracondylar process may be secondary to the excessive traction of the pronator teres.


The MAS4AI framework for human-centered agile and smart manufacturing.
Volatility and uncertainty of today's value chains along with the market's demands for low-batch customized products mandate production systems to become smarter and more resilient, dynamically and even autonomously adapting to both external and internal disturbances. Such resilient behavior can be partially enabled by highly interconnected Cyber-Physical Production Systems (CPPS) incorporating advanced Artificial Intelligence (AI) technologies. Multi-agent solutions can provide better planning and control, improving flexibility and responsiveness in production systems. Small modular parts can autonomously take intelligent decisions and react to local events. The main goal of decentralization and interconnectivity is to enable autonomous and cooperative decision-making. Nevertheless, a more efficient orchestration of various AI components and deeper human integration are required. In addition, global behaviors of coalitions of autonomous agents are not easily comprehensible by workers. Furthermore, it is challenging to implement an Industry 4.0 paradigm where a human should be in charge of decision-making and execution. This paper discusses a Multi-Agent System (MAS) where several software agents cooperate with smart workers to enable a dynamic and reconfigurable production paradigm. Asset Administration Shell (AAS) submodels hold smart workers' descriptions in machine-readable format, serving as an integration layer between various system's components. The self-description capability of the AAS supports the system's adaptability and self-configuration. The proposed concept supports the plug-and-produce functionality of the production modules and improves human-machine integration in the shared assembly tasks.


The Good and Bad of β-Catenin in Kidney Development and Renal Dysplasia.
Congenital renal malformations are a major cause of childhood and adult onset chronic kidney disease. Identifying the etiology of these renal defects is often challenging since disruptions in the processes that drive kidney development can result from disruptions in environmental, genetic, or epigenetic cues. β-catenin is an intracellular molecule involved in cell adhesion, cell signaling, and regulation of gene transcription. It plays essential roles in kidney development and in the pathogenesis of renal dysplasia. Here, we review the function of β-catenin during kidney development and in the genesis of renal dysplasia.


Challenges in the management of early versus late presenting congenital diaphragmatic hernia in a poor resource setting.
Despite the advances in management, congenital diaphragmatic hernia (CDH) has continued to pose a significant challenge to paediatric surgeons. This is amplified in a setting like ours where there is a dearth of facilities to cope with the problem of CDH. This study was undertaken to highlight the peculiarities of the management of CDH in a poor resource setting. All confirmed cases of CDH were prospectively documented from 2003 till date. Seven children were treated from 2003 till date. The diaphragmatic defect was on the left side in six (83.8%) and on the right side in one (17.7%). All the patients had primary closure of the defect without patch via an abdominal approach. The three patients presenting at birth died while the remaining four patients survived. With inadequate neonatal intensive care facilities, the severe early presenting CDH has a dismal prognosis. In contrast, the late presenting CDH poses more diagnostic challenges; but once identified and appropriate treatment instituted, it has an excellent prognosis. We recommend that physicians should include CDH in the differential diagnosis of patients with birth asphyxia and in patients with chronic respiratory symptoms with failure to thrive.


Efficacy of prophylactic nimodipine for delayed ischemic deficit after subarachnoid hemorrhage: a metaanalysis.
The authors report findings from a metaanalysis of all published randomized trials of prophylactic nimodipine used in patients who have experienced subarachnoid hemorrhage (SAH). Seven trials were included with a total of 1202 patients suitable for evaluation. Eight outcome measures were examined, including good versus other outcome, good or fair outcome versus other outcome, overall mortality, deficit and/or death attributed to vasospasm, infarction rate as judged by computerized tomography (CT), and deficit and/or death from rebleeding. Nimodipine improved outcome according to all measures examined. The odds of good and of good plus fair outcomes were improved by ratios of 1.86:1 and 1.67:1, respectively, for nimodipine versus control(p<0.005 for both measures). The odds of deficit and/or mortality attributed to vasospasm and CT-assessed infarction rate were reduced by ratios of 0.46:1 to 0.58:1 in the nimodipine group (p<0.008 for all measures). Overall mortality was slightly reduced in the nimodipine group, but the trend was not statistically significant. The rebleeding rate was not increased by nimodipine. A metaregression yielded findings indicating that the treatment effect of nimodipine in individual trials was positively correlated with the severity of SAH in enrolled patients. Although the majority of individual trials examined did not have statistically significant results at the p<0.01 level according to most outcome measures, the metaanalyses confirmed the significant efficacy of prophylactic nimodipine in improving outcome after SAH under the conditions used in these trials.


Analysis of excretory-secretory and somatic antigens of Gastrothylax crumenifer.
The excretory/secretory (ES) metabolic products released by Gastrothylax crumenifer (Trematoda: Digenea) during in vitro incubations and the somatic extract of the adult parasite were analysed using polyacrylamide gel electro-phoresis (PAGE). Immunogenicity of ES and somatic extracts were evaluated by immunoblotting and ELISA using sera raised against ES and somatic antigens in rabbits. The electropherograms of ES and somatic extracts have been resolved into 38 and 41 polypeptides, respectively. The apparent molecular weights of these polypeptides range from <29 to > 205 kDa. A total of 14 polypeptides were found to be common to both of the samples. The analysis of immunoblot results revealed 22 and 27 antigenic polypeptides in ES and somatic extracts respectively. Only 11 and 13 antigenic polypeptides were found specific to ES and tissue extract respectively. The molecular weights of these specific polypeptides were calculated to be <14.4, 16, 20, 25, 33, 42, 119, 125 and > 205 kDa for metabolic products and <14.4, 25, 30, 35, 78, 84 and > 205 kDa for the tissue extracts, respectively. Analysis of ELISA results revealed that a dilution of up to 1:3200 of the test sera could react with the ES product. Further, when the ES antigens were allowed to react with antisomatic extracts in hyperimmune sera the titre of IgG increased up to a dilution of 1:12800. The potential importance of these antigens in the immunodiagnosis of amphistomiasis is discussed.


Identification, spatial expression analysis and functional characterization of a pyrokinin-1 receptor in the Chagas' disease vector, Rhodnius prolixus.
The capability or capa gene, encodes a pyrokinin-related peptide (known as pyrokinin-1, PK1) that contains the consensus carboxy-terminal sequence of WFGPRL-NH(2). Although the CAPA precursor polypeptide in Rhodnius prolixus yields the anti-diuretic hormone, RhoprCAPA-α2, no function has yet been elucidated for the pyrokinin-1 peptide, RhoprCAPA-αPK1. In order to elucidate the possible physiological roles of the PK1-related peptides in R. prolixus, we have isolated and functionally characterized the PK1 receptor, RhoprPK1-R. Additionally, we have determined a set of three optimal reference genes to utilize for normalization of data obtained when carrying out spatial expression analyses via quantitative reverse transcriptase PCR (RT-qPCR) in various tissues of fifth instar R. prolixus. The RhoprPK1-R expression profile differs strikingly from the receptor for the anti-diuretic hormone RhoprCAPA-α2, which is localized mainly to gut epithelial tissues. Instead, RhoprPK1-R expression in fifth instar stage insects was identified in tissues that are not involved in osmotic and ionic balance, including the prothoracic glands, male reproductive tissues and a pooled sample composed of fat body, dorsal vessel, abdominal nerves and female reproductive tissues. Thus, this research establishes novel possibilities for the physiological roles of the pyrokinin-related peptides in this medically relevant disease vector.


Impairment of DNA in a freshwater gastropod (Lymnea luteola L.) after exposure to titanium dioxide nanoparticles.
The apoptotic and genotoxic potential of titanium dioxide nanoparticles (TiO2NPs) were evaluated in hemocyte cells of freshwater snail Lymnea luteola L. Before evaluation of the toxic potential, mean size of the TiO2NPs was determined using a transmission electron microscopy and dynamic light scattering. In this study, L. luteola were exposed to different concentrations of TiO2NPs (28, 56, and 84 μg/ml) over 96 h. Induction of oxidative stress in hemolymph was observed by a decrease in reduced glutathione and glutathione-S-transferase levels at different concentration of TiO2NPs and, in contrast, an increase in malondialdehyde and reactive oxygen species levels. Catalase activity was decreased at lower concentrations but increased at greater concentration of TiO2NPs. The extent of DNA fragmentation occurring in L. luteola due to ecotoxic impact TiO2NPs was further substantiated by alkaline single-cell gel electrophoresis assay and expressed in terms of % tail DNA and olive tail moment. The alkaline single-cell gel electrophoresis assay for L. luteola clearly shown relatively greater DNA damage at the highest concentration of TiO2NPs.The results indicate that the interaction of TiO2NPs with snail influences toxicity, which is mediated by oxidative stress according dose and in a time-dependent manner. The results of this study showed the importance of a multibiomarker approach for assessing the injurious effects of TiO2NPs to freshwater snail L. luteola, which may be vulnerable due to the continuous discharge of TiO2NPs into the aquatic ecosystems. The measurement of DNA integrity in L. luteola thus provides an early warning signal of contamination of the aquatic ecosystem by TiO2NPs.


Adsorption of molecular iodine on the Ag(111) surface: Phase transitions, silver reconstruction, and iodide growth.
Room temperature adsorption of molecular iodine on Ag(111) has been studied by scanning tunneling microscopy (STM), low energy electron diffraction, Auger electron spectroscopy with factor analysis, and density functional theory (DFT). At the chemisorption stage, iodine first forms a (3×3)R30° structure. Further iodine dosing leads to continuous commensurate-incommensurate phase transition, taking place via the formation of striped superheavy domain walls. As a result, the uniaxially compressed (13 ×3-R30°) phase is formed at an iodine coverage (θ) of 0.38 ML. At θ > 0.38 ML, first-order phase transition begins, leading to the formation of hexagonal moiré-like phases, which exhibit an anomalously large corrugation in STM (0.8-2.3 Å). In the range of 0.40-0.43 ML, the compression of hexagonal phases occurs, which ends at the formation of the (7 × 7)R21.8° structure at saturation. The DFT calculations allow us to explain the anomalous atomic corrugation of the hexagonal phases by the strong violation of the atomic structure of the substrate including up to ten layers of silver. Iodine dosing above 0.43 ML leads to the growth of 2D islands of silver iodide. The STM images of the silver iodide surface demonstrate a clear visible hexagonal superstructure with a periodicity of 25 Å superimposed with a quasi-hexagonal atomic modulation. DFT calculations of the atomic structure of AgI islands point to the formation of a sandwich-like double layer honeycomb structure similar to the case of I/Ag(100).


Physicians' perceptions of asymptomatic hyperuricemia in patients with chronic kidney disease: A questionnaire survey.
Hyperuricemia is associated with the development and progression of chronic kidney disease (CKD) as well as cardiovascular diseases. However, there is no consistent recommendation regarding the treatment of asymptomatic hyperuricemia (AHU) in CKD patients. Here, we surveyed Korean physicians' perceptions regarding the diagnosis and management of AHU in CKD patients. Questionnaires on the management of AHU in CKD patients were emailed to regular members registered with the Korean Society of Nephrology. A total of 158 members answered the questionnaire. Among the respondents, 49.4%/41.1% were considered hyperuricemic in male CKD patients whereas 36.7%/20.9% were considered hyperuricemic in female CKD patients when defined by serum uric acid level over 7.0/8.0 mg/dL, respectively. A total of 80.4% reported treating AHU in CKD patients. The most important reasons to treat AHU in CKD patients were renal function preservation followed by cerebro-cardiac protection. Majority of respondents (59.5%) thought that uric acid-lowering agents (ULAs) were the most effective method for controlling serum uric acid levels. Approximately 80% chose febuxostat as the preferred medication. A total of 32.3% and 31.0%, respectively, initiated ULA treatment if the serum uric acid level was more than 8.0 or 9.0 mg/dL, respectively. In addition, 39.2% and 30.4% answered that target serum uric acid levels of less than 6.0 or 7.0 mg/dL, respectively, were appropriate. The two major hurdles to prescribing ULAs were concerns of adverse reactions and the existing lack of evidence (i.e., the absence of Korean guidelines). Most Korean physicians treat AHU in CKD patients to prevent CKD progression and cerebro-cardiovascular complications.


Clonality: an R package for testing clonal relatedness of two tumors from the same patient based on their genomic profiles.
If a cancer patient develops multiple tumors, it is sometimes impossible to determine whether these tumors are independent or clonal based solely on pathological characteristics. Investigators have studied how to improve this diagnostic challenge by comparing the presence of loss of heterozygosity (LOH) at selected genetic locations of tumor samples, or by comparing genomewide copy number array profiles. We have previously developed statistical methodology to compare such genomic profiles for an evidence of clonality. We assembled the software for these tests in a new R package called 'Clonality'. For LOH profiles, the package contains significance tests. The analysis of copy number profiles includes a likelihood ratio statistic and reference distribution, as well as an option to produce various plots that summarize the results. Bioconductor (http://bioconductor.org/packages/release/bioc/html/Clonality.html) and http://www.mskcc.org/mskcc/html/13287.cfm.


Lactation-associated postpartum weight changes among HIV-infected women in Zambia.
There are concerns about effects of lactation on postpartum weight changes among HIV-infected women because low weight may increase risks of HIV-related disease progression. This analysis of postpartum maternal weight change is based on a trial evaluating the effects of shortened breastfeeding on postpartum mother-to-child transmission of HIV in Lusaka, Zambia, in which 958 HIV-infected women were randomized to breastfeed for a short duration (4 months) or for a duration of their own informed choosing (median 16 months). Among 768 women who met inclusion criteria, we compared across the two groups change in weight (kg) and the percent underweight [body mass index (BMI) <18.5] through 24 months. We also examined the effect of breastfeeding in two high-risk groups: those with low BMI and those with low CD4 counts. Overall, women in the long-duration group gained less weight compared with those in the short-duration group from 4-24 months {1.0 kg [95% confidence interval (CI): 0.3-1.7] vs 2.3 kg (95% CI: 1.6-2.9), P = 0.01}. No association was found between longer breastfeeding and being underweight (odds ratio 1.1; 95% CI: 0.8-1.6; P = 0.40). Effects of lactation in underweight women and women with low CD4 counts were similar to the effects in women with higher BMI and higher CD4 counts. Women with low baseline BMI tended to gain more weight from 4 to 24 months than those with higher BMI, regardless of breastfeeding duration (2.1 kg, 95% CI: 1.3-2.9; P < 0.01). In this study of HIV-infected breastfeeding women in a low-resource setting, the average change in weight from 4 to 24 months postpartum was a net gain rather than loss. Although longer duration breastfeeding was associated with less weight gain, breastfeeding duration was not associated with being underweight (BMI < 18.5). Weight change associated with longer breastfeeding may be metabolically regulated so that women with low BMI and at risk of wasting are protected from excess weight loss.


High-concentration sevoflurane exposure in mid-gestation induces apoptosis of neural stem cells in rat offspring.
Sevoflurane is the most commonly used volatile anesthetic during pregnancy. The viability of neural stem cells directly affects the development of the brain. However, it is unknown whether the use of sevoflurane during the second trimester affects the survival of fetal neural stem cells. Therefore, in this study, we investigated whether exposure to sevoflurane in mid-gestation induces apoptosis of neural stem cells and behavioral abnormalities. On gestational day 14, pregnant rats were anesthetized with 2% or 3.5% sevoflurane for 2 hours. The offspring were weaned at 28 days and subjected to the Morris water maze test. The brains were harvested to examine neural stem cell apoptosis by immunofluorescence and to measure Nestin and SOX-2 levels by western blot assay at 6, 24 and 48 hours after anesthesia as well as on postnatal day (P) 0, 14 and 28. Vascular endothelial growth factor (VEGF) and phosphoinositide 3-kinase (PI3K)/AKT pathway protein levels in fetal brain at 6 hours after anesthesia were assessed by western blot assay. Exposure to high-concentration (3.5%) sevoflurane during mid-gestation increased escape latency and path length to the platform, and it reduced the average duration spent in the target quadrant and platform crossing times. At 6, 24 and 48 hours after anesthesia and at P0, P14 and P28, the percentage of Nestin/terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells was increased, but Nestin and SOX-2 protein levels were decreased in the hippocampus of the offspring. At 6 hours after anesthesia, VEGF, PI3K and phospho-AKT (p-AKT) levels were decreased in the fetal brain. These changes were not observed in animals given low-concentration (2%) sevoflurane exposure. Together, our findings indicate that exposure to a high concentration of sevoflurane (3.5%) in mid-gestation decreases VEGF, PI3K and p-AKT protein levels and induces neural stem cell apoptosis, thereby causing learning and memory dysfunction in the offspring.


The attentional blink is immune to masking-induced data limits.
The attentional blink is the robust finding that processing a masked item (T1) hinders the subsequent identification of a backwards masked second item (T2), which follows soon after the first one. There has been some debate about the theoretically important relation between the difficulty of T1 processing and the ensuing blink. In Experiment 1 we manipulated the difficulty of T1 in such a way as to affect the quality of data without altering the amount of resources allocated to its identification. We found no relation between the accuracy of T1 identification and the blink. In Experiment 2, the same difficulty manipulation was applied to T2, and we observed an additive pattern with the blink. Together, this pattern of results indicates that a data-limited difficulty manipulation does not affect the blink, whether applied to T1 or T2. In Experiment 3 we used an individual differences methodology to show that performance in the traditional "stream"-like presentation (rapid serial visual presentation) was highly correlated with performance in our modified "target mask, target mask" paradigm, thus allowing for comparisons beyond the present methodology to much of the previous literature that has used the stream paradigm.


Assessing the Functions of Non-Suicidal Self-Injury: Factor Analysis of Functional Assessment of Self-Mutilation among Adolescents.
Objective: The aim of this cross sectional study was to assess the factor analysis of Functional Assessment of Self-Mutilation (FASM) among Iranian adolescents with non-suicidal self-injury. Method: In this study, 646 high school students, with the mean age of 16.55 ± 0.7, were selected using a multistage cluster sampling method; they completed FASM and the demographic form. Data were analyzed using the descriptive statistics, chi-square (χ2), independent sample t test, MANOVA, and confirmatory factor analyses (CFA). Results: Of the participants, 178 reported at least 1 episode of NSSI during the previous year. The mean age of the participants when they first harmed themselves was 14.64 (±1.71). Most of them reported to engage in NSSI impulsively (39.32%) and experienced little (31.5%) or moderate physical pain (31.5%) There were no significant differences between males and females in severity of NSSI, frequency of NSSI, thinking about NSSI prior to engaging in the act, and age of onset. The results of the confirmatory factor analysis supported the 4-factor model of NSSI functions suggested by Nock and Prinstine [Χ2/df = 1.84; RMSEA = 0.07; GFI = 0.82; AGFI = 0.77]. The most frequent function for engaging in NSSI was Automatic Negative Reinforcement. Conclusion: Findings of this study supported the structural validity of the FASM; thus, this tool can be useful in treatment and research contexts as a measure of NSSI functions. Moreover, this study found that adolescents engage in non-suicidal self-injury because of 4 distinct reinforcement processes. The study findings have important implications for the assessment and treatment of NSSI.


Barley morphology, genetics and hormonal regulation of internode elongation modelled by a relational growth grammar.
A multiscaled ecophysiological model of barley (Hordeum vulgare) development is presented here. The model is based on the new formalism of relational growth grammars (RGG), an extension of L-systems, and implemented using the new modelling language XL. It is executable in the interactive modelling platform GroIMP. The model consists of a set of morphogenetic rules, combined with a metabolic regulatory network, which simulates the biosynthesis of gibberellic acid (GA1). GA1 and two of its metabolic precursors are transported along the developing simulated structure. Local concentrations of GA1 determine internode elongation. Furthermore, virtual barley individuals are chosen interactively from a population, based on genotype, and (sexual or asexual) reproduction is simulated. Genotype and phenotype of the population are visualized. Seven Mendelian genes have been implemented in the model so far; some of these directly influence the GA-regulation network. The model exemplifies and validates the new formalism and modelling language. RGG have the capability to represent genetic, metabolic and morphological aspects of plant development and reproduction, all within the same framework.


[Autism, epilepsy and mitochondrial disease: points of contact].
Autism is a neurodevelopmental disorder with unknown etiology, although several different specific organic conditions have been found to be associated with autism in about 10 to 37% of cases. Autism with regression has been reported in one third of autistic children with previously normal development. Epilepsy is quite common in autism spectrum disorders. The rate of comorbidity varies between 20-30% of cases, depending upon the age and type of disorder. Major risk factors for epilepsy in autistic children are mental retardation and additional neurological disorders, as well as some specific associated medical conditions like chromosomal abnormalities, phakomatosis and inherited metabolic disorders. To review the possible linkage between autism, epilepsy and mitochondrial dysfunction. The hypothesis of a disturbed bioenergetic metabolism underlying autism has been suggested by the detection of high lactate levels in some patients. Although the mechanism of hyperlactacidemia remains unknown, a likely possibility involves mitochondrial oxidative phosphorylation dysfunction in neuronal cells. Reduced levels of respiratory mitochondrial enzymes, ultraestructural mitochondrial abnormalities and a broad range of mitochondrial DNA mutations suggest a linkage between autism, epilepsy and mitochondrial disorders. Though mitochondrial disorders are a rare cause of autism in children, we must keep in mind this etiology in autistic patients with epilepsy and associated signs of neurologic and/or systemic dysfunction. Finding biochemical or structural mitochondrial abnormalities in an autistic child does not necessarily imply a primary mitochondrial disorder but can also be secondary to technical inaccuracies or another genetic disorder.


CYP17A1 Maintains the Survival of Glioblastomas by Regulating SAR1-Mediated Endoplasmic Reticulum Health and Redox Homeostasis.
Cytochrome P450 (CYP) 17A1 is an important steroidogenic enzyme harboring 17α-hydroxylase and performing 17,20 lyase activities in multiple steps of steroid hormone synthesis, including dehydroepiandrosterone (DHEA) biosynthesis. Previously, we showed that CYP17A1-mediated DHEA production clearly protects glioblastomas from temozolomide-induced apoptosis, leading to drug resistance. Herein, we attempt to clarify whether the inhibition of CYP17A1 has a tumor-suppressive effect, and to determine the steroidogenesis-independent functions of CYP17A1 in glioblastomas. Abiraterone, an inhibitor of CYP17A1, significantly inhibits the proliferation of A172, T98G, and PT#3 (the primary glioblastoma cells) by inducing apoptosis. In parallel, abiraterone potently suppresses tumor growth in mouse models through transplantation of PT#3 cells to the back or to the brain. Based on evidence that abiraterone induces endoplasmic reticulum (ER) stress, followed by the accumulation of reactive oxygen species (ROS), CYP17A1 is important for ER health and redox homeostasis. To confirm our hypothesis, we showed that CYP17A1 overexpression prevents the initiation of ER stress and attenuates ROS production by regulating SAR1a/b expression. Abiraterone dissociates SAR1a/b from ER-localized CYP17A1, and induces SAR1a/b ubiquitination, leading to degradation. Furthermore, SAR1 overexpression rescues abiraterone-induced apoptosis and impairs redox homeostasis. In addition to steroid hormone synthesis, CYP17A1 associates with SAR1a/b to regulate protein processing and maintain ER health in glioblastomas.


Lumbar puncture and post-dural puncture headaches: implications for the emergency physician.
Lumbar puncture is a diagnostic procedure commonly performed by emergency physicians. Post-dural puncture headaches occur frequently after this procedure and can be associated with significant morbidity and, occasionally, even death. There is also a lot of variation in how post-dural puncture headaches are treated once they occur. This article seeks to examine the science behind post-dural puncture headaches, their prevention and treatment.


Cruciferous vegetable consumption is associated with a reduced risk of total and cardiovascular disease mortality.
Asian populations habitually consume a large amount of cruciferous vegetables and other plant-based foods. Few epidemiologic investigations have evaluated the potential health effects of these foods in Asian populations. We aimed to examine the associations of cruciferous vegetables, noncruciferous vegetables, total vegetables, and total fruit intake with risk of all-cause and cause-specific mortality. The analysis included 134,796 Chinese adults who participated in 2 population-based, prospective cohort studies: the Shanghai Women's Health Study and the Shanghai Men's Health Study. Dietary intakes were assessed at baseline through in-person interviews by using validated food-frequency questionnaires. Deaths were ascertained by biennial home visits and linkage with vital statistics registries. We identified 3442 deaths among women during a mean follow-up of 10.2 y and 1951 deaths among men during a mean follow-up of 4.6 y. Overall, fruit and vegetable intake was inversely associated with risk of total mortality in both women and men, and a dose-response pattern was particularly evident for cruciferous vegetable intake. The pooled multivariate hazard ratios (95% CIs) for total mortality across increasing quintiles of intake were 1 (reference), 0.91 (0.84, 0.98), 0.88 (0.77, 1.00), 0.85 (0.76, 0.96), and 0.78 (0.71, 0.85) for cruciferous vegetables (P < 0.0001 for trend) and 0.88 (0.79, 0.97), 0.88 (0.79, 0.98), 0.76 (0.62, 0.92), and 0.84 (0.69, 1.00) for total vegetables (P = 0.03 for trend). The inverse associations were primarily related to cardiovascular disease mortality but not to cancer mortality. Our findings support recommendations to increase consumption of vegetables, particularly cruciferous vegetables, and fruit to promote cardiovascular health and overall longevity.


Vitamin E protects against monosodium glutamate-induced acute liver injury and hepatocyte ultrastructural alterations in rats.
Food additives such as nitrates and nitrites, and monosodium glutamate (MSG) used in the food industry increase the risk of certain cancers and inflict damage to vital organs. We sought to determine whether the antioxidant vitamin E can protect against liver injuries induced by a toxic dose of MSG in a rat model of MSG-induced acute liver injury. The model group of rats received a daily dose of MSG (4 gm/kg) for 7 days, whereas the protective groups were either received a 100 mg/kg vitamin E plus MSG or 300 mg/kg vitamin E plus MSG for 7 days. Rats were then sacrificed at day 8. Transmission and light microscopy images revealed substantial liver tissue damage induced by MSG in the model group as demonstrated by apoptotic hepatocytes with Pyknotic nuclei and irregular nuclear membrane, and cytoplasm displayed many vacuoles, swollen mitochondria, dilated endoplasmic reticulum, dilated blood sinusoids and bundles of collagen fibers in extracellular space. Treatment of the model group with vitamin E showed a substantial protection of liver tissue and hepatocellular architecture by 300 mg/kg vitamin E compared to a partial protection by 100 mg/kg vitamin E. In addition, MSG significantly (p < .05) modulated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), superoxide dismutase (SOD), and glutathione peroxidase (GPx), which were significantly (p < .05) protected with vitamin E. Thus, vitamin E at 300 mg/kg effectively protects against MSG-induced acute liver injury in rats, possibly via the inhibition of inflammation, and up-regulation of endogenous antioxidants.


Effect of Resistance Training Programs With Equated Power on Older Adults' Functionality and Strength: A Randomized Controlled Trial.
Fraga-Germade, E, Carballeira, E, and Iglesias-Soler, E. Effect of resistance training programs with equated power on older adults' functionality and strength: a randomized controlled trial. J Strength Cond Res 38(1): 153-163, 2024-This study aimed to compare the effect of 2 training programs of equated power but differing in load intensity on older adults' functionality, strength, performance, and body composition. Forty-four active (23 female) older adults (66.3 ± 4.5 years) were randomly assigned to low-load high-velocity (LL-HV), high-load low-velocity (HL-LV), and control (CON) groups. Low-load high-velocity and HL-LV performed, twice weekly for 5 weeks, a resistance training program at 95% of their individual peak power (PP) but with different load intensities for 3 exercises: chest press (CHP), leg press (LP), and seated row (SR). Before and after the intervention, body composition, functional performance, maximal voluntary isokinetic force (MVF), PP, and a relative load-power profile (L-PP) were evaluated for every exercise. PP similarly improved in the experimental groups for SR and LP (p < 0.05). Both groups increased their MVF for the 3 exercises (p < 0.05). Positive effects on L-PP were observed in LL-HV for SR (p = 0.009) and HL-LV for LP (p < 0.001). CON decreased its global power performance in SR (p = 0.009) and CHP (p = 0.031) compared with the baseline. Both experimental groups improved Timed Up and Go performance (p < 0.05), but only HL-LV increased 6-minute walking performance (pre: 514.3 ± 89.0 m, post: 552.6 ± 65.4 m; p < 0.05). In conclusion, adding short-term power training (i.e., 10 sessions throughout 5 weeks) with loads slightly above the optimal load to nonsupervised multicomponent training might improve active older adults' functional performance and cardiovascular endurance.


Rab11FIP proteins link endocytic recycling vesicles for cytoskeletal transport and tethering.
Regulated trafficking of internalised integrins and growth factor receptors enables polarisation of morphology and motility and enables lumen formation in multicellular structures. Recycling vesicles marked with Rab11 direct internalised cargo back to the plasma membrane to affect biological processes such as polarised trafficking and cancer cell invasion. A recent study by Ji and colleagues, provides insight into how the trafficking protein Rab11FIP2 links with the actin-based motor myo5b and the small GTPase Rab11 to regulate vesicle tethering and transport along actin filaments [1]. The authors used biochemical methods to demonstrate that Rab11a binds directly to the tail of myo5b and that Rab11FIP2 also forms direct interactions with both Rab11a and myo5b tails. These proteins essentially compete for binding to similar regions and thus can regulate the association and activity of each other. Ji and colleagues further demonstrate that Rab11a activates myo5b by binding to its globular tail and relieving a head-tail autoinhibition. Due to differing affinities between Rab11 and myo5b or Rab11FIP2, they propose that Rab11FIP2 mediates the association of myo5b with cargo vesicles, while Rab11a regulates the motor activity of myo5b. The present study thus elucidates how myo5b is regulated by its interactions with Rab11a and Rab11FIP2 and proposes a model for coordination of recycling vesicle tethering and motor activity. The present study has implications for how cells control polarity and motility in health and disease and suggests how Rab11FIP proteins might control motor protein activity and engagement for transport.


Prognostic significance of β-human chorionic gonadotropin and PAX8 expression in anaplastic thyroid carcinoma.
Anaplastic thyroid carcinoma (ATC) is a rare, aggressive malignancy with a median survival of five months. Multimodality treatment is associated with some improvement in survival, but patients are only infrequently curable. Although β-hCG secretion has been reported in many neoplasms, it has never been described in ATC. The objectives of this study were to report a case of β-hCG-secreting ATC and to study the expression and significance of β-hCG and PAX8 in an institutional cohort of ATC. The sentinel case was characterized and then immunohistochemistry was performed for β-hCG and PAX8 on 30 ATC patients. Clinical follow-up was obtained by chart review. The sentinel patient with β-hCG-secreting ATC had a dramatic response to chemotherapy and radiation. After surgical excision of residual disease, the patient developed a regional recurrence of differentiated thyroid carcinoma at 18 months. However, she is now, 30 months after initial therapy, with no evidence of disease and no detectable serum β-hCG or thyroglobulin. Five of the 30 (17%) total ATCs were positive for β-hCG and 18 (60%) for PAX8. Outcomes for the β-hCG-positive cases were not significantly different from those for negative ones. However, none of the other four β-hCG-positive ATC patients received treatment with either chemotherapy or radiation. Interestingly, PAX8 positivity correlated with statistically significantly better overall survival (p=0.019). β-hCG is expressed in a minority of ATCs. Although only a single case in the study had diffuse immunohistochemical expression, the response it showed to aggressive multimodality therapy and the resulting favorable outcome suggest that β-hCG-positive ATC may be a unique tumor subtype, or possibly even a unique entity. PAX8 is a useful marker of ATC and may be helpful in the differential diagnosis with other malignant neoplasms.


Effects of Physical Exercise on Cerebral Blood Velocity in Older Adults: A Systematic Review and Meta-Analysis.
As the older population grows, there is an increasing interest in understanding how physical exercise can counteract the changes seen with aging. The benefits of exercise to general health, and especially to the cardiovascular system, have been a topic of discussion for decades. However, there is still a need to elucidate the effects of training programs on the cerebrovascular blood velocity in older people. This systematic review and meta-analysis aimed to investigate the effect of physical exercise on the cerebral blood velocity in older people (PROSPERO CRD42019136305). A search was performed on PubMed, Web of Science, EBSCO, ScienceDirect, and Scopus from the inception of this study to October 2023, retrieving 493 results, of which 26 were included, analyzing more than 1000 participants. An overall moderate risk of bias was found for the studies using the Cochrane risk-of-bias tools for randomized and non-randomized clinical trials. The pooled results of randomized trials showed that older people who underwent physical exercise presented a statistically significant increase in cerebral blood velocity (3.58; 95%CI = 0.51, 6.65; p = 0.02). This result indicates that physical exercise is important to help maintain cerebral health in older adults.


Absence of association between individual thymidine analogues or nonnucleoside analogues and lipid abnormalities in HIV-1-infected persons on initial therapy.
Changes in levels of triglycerides and cholesterol during antiretroviral therapy raise concerns regarding an increased future risk of atherogenic disease and may precede the appearance of fat redistribution. Hypotheses regarding the impact of nucleoside analogues on adipocytes provide a possible explanation for metabolic and clinical fat disturbances. It is unclear whether the choice of nucleoside analogue combination or coadministration of nonnucleoside agents influences change in lipids. We performed a cross-sectional analysis of 135 persons receiving their first nucleoside analogue plus nonnucleoside-based combination antiretroviral regimen for at least 1 month and for whom cholesterol and triglyceride values were available on therapy. Univariate and multivariate regression models were used to explore the relation between cholesterol and triglycerides, as continuous variables with other variables. Both significant and nonsignificant variables from univariate analyses were evaluated in multivariate models to limit possible confounders. No association with drug choice was observed, either when comparing thymidine analogues (stavudine or zidovudine), all nucleoside analogue combinations or choice of either efavirenz or nevirapine as nonnucleoside. Age and triglyceride levels were found in a multivariate analysis to be associated with higher cholesterol. Only higher cholesterol was associated with higher triglyceride levels. In conclusion, no differences were observed between choice of drug or combination on cholesterol or triglyceride values during therapy. Older individuals may be more likely to have elevated cholesterol values.


Shaping the development of complex social behavior.
Early life experiences can have an enduring impact on the brain and behavior, with implications for stress reactivity, cognition, and social behavior. In particular, the neural systems that contribute to the expression of social behavior are altered by early life social environments. However, paradigms that have been used to alter the social environment during development have typically focused on exposure to stress, adversity, and deprivation of species-typical social stimulation. Here, we explore whether complex social environments can shape the development of complex social behavior. We describe lab-based paradigms for studying early life social complexity in rodents that are generally focused on enriching the social and sensory experiences of the neonatal and juvenile periods of development. The impact of these experiences on social behavior and neuroplasticity is highlighted. Finally, we discuss the degree to which our current approaches for studying social behavior outcomes give insight into "complex" social behavior and how social complexity can be better integrated into lab-based methodologies.


Smoke extract stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activity.
Inflammatory cells accumulate within the lungs of cigarette smokers. Current concepts suggest that these cells can induce protease-antiprotease and/or oxidant-antioxidant imbalance(s), which may damage the normal lung alveolar and interstitial structures. Because type II pneumocytes line the alveolar space, and because the inflammatory cells migrate and reside at the alveolus, we postulated that the type II pneumocytes might release chemotactic activity for neutrophils and monocytes in response to smoke extract. To test this hypothesis, A549 cells were cultured and the supernatant fluids were evaluated for the neutrophil and monocyte chemotactic activity (NCA and MCA) by a blind-well chamber technique. A549 cells released NCA and MCA in response to smoke extract in a dose- and time-dependent manner (P < 0.05). Checkerboard analysis showed that the activity was chemotactic. Partial characterization of NCA and MCA revealed that the activity was partly heat labile, trypsin sensitive, and ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of NCA and MCA. Molecular sieve column chromatography showed multiple peaks for both NCA and MCA. NCA was inhibited by anti-human-interleukin (IL)-8 antibody, granulocyte colony-stimulating factor (G-CSF) antibody, or leukotriene (LT)B4 receptor antagonist. Monocyte chemoattractant protein (MCP)-1 antibody or LTB4 receptor antagonist inhibited MCA. Immunoreactive IL-8, G-CSF, MCP-1, and LTB4 significantly increased in the supernatant fluids in response to smoke extract. These data suggest that the type II pneumocytes may release NCA and MCA and modulate the inflammatory cell recruitment into the lung.


Nuclear envelope composition determines the ability of neutrophil-type cells to passage through micron-scale constrictions.
Neutrophils are characterized by their distinct nuclear shape, which is thought to facilitate the transit of these cells through pore spaces less than one-fifth of their diameter. We used human promyelocytic leukemia (HL-60) cells as a model system to investigate the effect of nuclear shape in whole cell deformability. We probed neutrophil-differentiated HL-60 cells lacking expression of lamin B receptor, which fail to develop lobulated nuclei during granulopoiesis and present an in vitro model for Pelger-Huët anomaly; despite the circular morphology of their nuclei, the cells passed through micron-scale constrictions on similar timescales as scrambled controls. We then investigated the unique nuclear envelope composition of neutrophil-differentiated HL-60 cells, which may also impact their deformability; although lamin A is typically down-regulated during granulopoiesis, we genetically modified HL-60 cells to generate a subpopulation of cells with well defined levels of ectopic lamin A. The lamin A-overexpressing neutrophil-type cells showed similar functional characteristics as the mock controls, but they had an impaired ability to pass through micron-scale constrictions. Our results suggest that levels of lamin A have a marked effect on the ability of neutrophils to passage through micron-scale constrictions, whereas the unusual multilobed shape of the neutrophil nucleus is less essential.


Association of neutrophil-to-lymphocyte ratio and microalbuminuria in patients with normal eGFR.
The aim of this study was to evaluate the association between neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and microalbuminuria in patients with normal estimated glomerular filtration rate (eGFR). 174 patients who had eGFR ≥ 60 mL/min/1.73 m2 were studied. Patients were divided into two groups according to the urinary albumin excretion as microalbuminuric group (n = 105) and normoalbuminuric group (n = 69). NLR and PLR levels were calculated. NLR was significantly higher (p < 0.05) in microalbuminuric patients (1.91 ± 0.70) compared with normoalbuminuric patients (1.63 ± 0.53). A positive correlation was found between urine albumin excretion and NLR in the whole study group (r = 0.214, p < 0.005). Higher NLR levels were found in microalbuminuric patients with normal eGFR. Also a significant positive correlation was observed between albuminuria and NLR.


Synthesis and characterization of [Fe(BPMEN)ACC]SbF₆: a structural and functional mimic of ACC-oxidase.
A mononuclear Fe(II) complex bearing 1-aminocyclopropane-1-carboxylic acid (ACCH) was synthesized and characterized. X-ray crystallography demonstrated that ACC binds to the Fe(II) ion in a bidentate mode constituting the first structural mimic of the expected binding of ACC to the Fe(II) center of the ethylene forming enzyme ACC-oxidase (ACCO). [Fe(BPMEN)ACC]SbF6 also constitutes a functional biomimetic complex of ACCO, as it reacts with hydrogen peroxide producing ethylene.


Human neutrophil elastase does not bind to alpha 1-protease inhibitor that has been exposed to activated human neutrophils.
The effect of leukocyte-derived oxidants on the elastase-inhibitory capacity of alpha 1-protease inhibitor was examined in an in vitro system using cells and purified proteins from human sources. The exposure of alpha 1-protease inhibitor to the myeloperoxidase-hydrogen peroxide-halide system resulted in a nearly complete loss of its ability to bind and inactivate purified human neutrophil elastase. A similar loss of binding to and inactivation of human neutrophil elastase was observed on exposure of alpha 1-protease inhibitor to human neutrophils in the presence of a halide and the neutrophil-activating agent, phorbol myristate acetate. This loss of elastase binding activity was abrogated by the addition of azide or catalase but not superoxide dismutase or heated catalase. The data suggest oxidative inactivation of alpha 1-protease inhibitor by secreted myeloperoxidase and hydrogen peroxide. Thus, the reported effects of leukocyte oxidants, especially the myeloperoxidase system, on alpha 1-protease inhibitor have been confirmed using the most pathophysiologically relevant protease, human neutrophil elastase, as the test enzyme. The role of the neutrophil in the pathogenesis of emphysema may, therefore, include the secretion of both elastase and oxidants that impair antielastase defenses.


Characteristics, treatment and outcomes for all emergency department patients fulfilling criteria for septic shock: a prospective observational study.
Most published data on emergency department (ED) patients with septic shock have been generated from studies examining the effect of early protocolised resuscitation in selected cohorts. Consequently, these data do not generally represent patients falling outside trial inclusion criteria or judged unsuitable for aggressive treatment. Our aim was to determine the characteristics, treatment and outcomes for all ED patients fulfilling the criteria for septic shock. Septic shock patients were identified from a prospective database of consecutive ED patients admitted with infection. Descriptive data were compared with those from previous studies and associations between ED processes of care and mortality were determined. A total of 399 septic shock patients were identified, with a 30-day mortality of 19.5%. The median ED length of stay was 9.2 h. Rates of vasopressor use (22.6%) and ICU admission (37.3%) were low. Subgroups fulfilling the lactate criteria alone, hypotension criteria alone and both criteria represented distinct shock phenotypes with increasing severity of illness and mortality. Mortality for patients with limitations to treatment determined in the ED was 65.6% and 6.1% for those without limitations. Greater volumes of intravenous fluid and early vasopressor therapy for appropriate patients were associated with survival. Median length of stay over 9 hours may have enhanced identification of patients with limitations to treatment and fluid responders, reducing invasive therapies and ICU admissions. Distinct shock phenotypes were apparent, with implications for revision of septic shock definitions and future trial design. Liberal fluids and early vasopressor use in appropriate patients were associated with survival.


Combination of Coenzyme Q10 Intake and Moderate Physical Activity Counteracts Mitochondrial Dysfunctions in a SAMP8 Mouse Model.
Aging skeletal muscles are characterized by a progressive decline in muscle mass and muscular strength. Such muscular dysfunctions are usually associated with structural and functional alterations of skeletal muscle mitochondria. The senescence-accelerated mouse-prone 8 (SAMP8) model, characterized by premature aging and high degree of oxidative stress, was used to investigate whether a combined intervention with mild physical exercise and ubiquinol supplementation was able to improve mitochondrial function and preserve skeletal muscle health during aging. 5-month-old SAMP8 mice, in a presarcopenia phase, have been randomly divided into 4 groups (n = 10): untreated controls and mice treated for two months with either physical exercise (0.5 km/h, on a 5% inclination, for 30 min, 5/7 days per week), ubiquinol 10 (500 mg/kg/day), or a combination of exercise and ubiquinol. Two months of physical exercise significantly increased mitochondrial damage in the muscles of exercised mice when compared to controls. On the contrary, ubiquinol and physical exercise combination significantly improved the overall status of the skeletal muscle, preserving mitochondrial ultrastructure and limiting mitochondrial depolarization induced by physical exercise alone. Accordingly, combination treatment while promoting mitochondrial biogenesis lowered autophagy and caspase 3-dependent apoptosis. In conclusion, the present study shows that ubiquinol supplementation counteracts the deleterious effects of physical exercise-derived ROS improving mitochondrial functionality in an oxidative stress model, such as SAMP8 in the presarcopenia phase.


Decision making in the critically ill patient.
In the preceding discussion we have attempted to set forth some realistic guidelines for the primary care physician in the critical care area. We feel that he is of utmost importance in setting the tone for his patient's care. He is the first physician to be called when his patient becomes critically ill. He decides whether or not consultation is needed immediately. He should choose appropriate consultants, trying to provide required expertise and compatible personalities to relate with his patient and the patient's family. His work does not end with establishing roles and delivering care. He is the single most important physician when difficult ethical and medicolegal decisions must be made. He is the physician who knows the patient and the patient's family best. They look to him for guidance and decision making about their health care. He is best able to discuss the wishes and desires of the patient if the patient becomes unable to decide for himself. The primary care physician can be extremely helpful when the appropriate medical decision is to withhold therapy. He can comfort and console the family and help them realize that the proper decisions have been made. His previous close relationship with the patient and family makes difficult decisions much easier to accept. He is also of primary importance when trying to provide care to a patient who ostensibly refuses such care. The trust he has earned in the past because of the care he was provided allows him to be much more forceful than the subspecialist who may have been on the case for 1 or 2 days. He can be the difference between survival and death merely by his presence and advice. Other difficult decisions are always made easier by a primary physician who can relate to the consultants as well as the patient and his family. In conclusion, we feel that the technologic advances of the past 30 years have tended to drive the primary care physician away from the critical care unit. This is mostly because of a need for particular expertise to run the machines of medicine. One cannot be expected to become or remain an expert in primary care and critical care medicine. The primary care physician should not feel or be excluded from the critical care area. His knowledge of general medicine and his expertise in interpersonal and family relationships allow him to provide the much needed "high touch" component of "high tech" critical care medicine.


The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle.
The discovery of functional classes of long noncoding RNAs (lncRNAs) has expanded our understanding of the variety of RNA species that exist in cells. In the heart, lncRNAs have been implicated in the regulation of development, ischemic and dilated cardiomyopathy, and myocardial infarction. Nevertheless, there is a limited description of expression profiles for these transcripts in human subjects. We obtained left ventricular tissue from human patients undergoing cardiac surgery and used RNA sequencing to describe an lncRNA profile. We then identified a list of lncRNAs that were differentially expressed between pairs of samples before and after the ischemic insult of cardiopulmonary bypass. The expression of some of these lncRNAs correlates with ischemic time. Coding genes in close proximity to differentially expressed lncRNAs and coding genes that have coordinated expression with these lncRNAs are enriched in functional categories related to myocardial infarction, including heart function, metabolism, the stress response, and the immune system. We describe a list of lncRNAs that are differentially expressed after ischemia in the human heart. These genes are predicted to function in pathways consistent with myocardial injury. As a result, lncRNAs may serve as novel diagnostic and therapeutic targets for ischemic heart disease. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00985049.


Using zebrafish larval models to study brain injury, locomotor and neuroinflammatory outcomes following intracerebral haemorrhage.
Intracerebral haemorrhage (ICH) is a devastating condition with limited treatment options, and current understanding of pathophysiology is incomplete. Spontaneous cerebral bleeding is a characteristic of the human condition that has proven difficult to recapitulate in existing pre-clinical rodent models. Zebrafish larvae are frequently used as vertebrate disease models and are associated with several advantages, including high fecundity, optical translucency and non-protected status prior to 5 days post-fertilisation. Furthermore, other groups have shown that zebrafish larvae can exhibit spontaneous ICH. The aim of this study was to investigate whether such models can be utilised to study the pathological consequences of bleeding in the brain, in the context of pre-clinical ICH research. Here, we compared existing genetic (bubblehead) and chemically inducible (atorvastatin) zebrafish larval models of spontaneous ICH and studied the subsequent disease processes. Through live, non-invasive imaging of transgenic fluorescent reporter lines and behavioural assessment we quantified brain injury, locomotor function and neuroinflammation following ICH. We show that ICH in both zebrafish larval models is comparable in timing, frequency and location. ICH results in increased brain cell death and a persistent locomotor deficit. Additionally, in haemorrhaged larvae we observed a significant increase in macrophage recruitment to the site of injury. Live in vivo imaging allowed us to track active macrophage-based phagocytosis of dying brain cells 24 hours after haemorrhage. Morphological analyses and quantification indicated that an increase in overall macrophage activation occurs in the haemorrhaged brain. Our study shows that in zebrafish larvae, bleeding in the brain induces quantifiable phenotypic outcomes that mimic key features of human ICH. We hope that this methodology will enable the pre-clinical ICH community to adopt the zebrafish larval model as an alternative to rodents, supporting future high throughput drug screening and as a complementary approach to elucidating crucial mechanisms associated with ICH pathophysiology.


[The combined use of functional biocontrol and acupuncture reflexotherapy in children with the spastic forms of infantile cerebral palsy].
An optimal method of rehabilitation is outlined for children with movement disorders due to spastic cerebral paralysis. It implies combined use of functional biocontrol and acupuncture. In drug intolerance the treatment acquires special significance. The effectiveness of these two modalities comes from mutual potentiation effect on central regulation of motor functions as shown by electrophysiological findings. Marked positive shifts in clinical and electrophysiological patterns develop within 15 training procedures with the external feedback in addition to 11 sessions of acupuncture.


Comparing multiple ChIP-sequencing experiments.
New high-throughput sequencing technologies can generate millions of short sequences in a single experiment. As the size of the data increases, comparison of multiple experiments on different cell lines under different experimental conditions becomes a big challenge. In this paper, we investigate ways to compare multiple ChIP-sequencing experiments. We specifically studied epigenetic regulation of breast cancer and the effect of estrogen using 50 ChIP-sequencing data from Illumina Genome Analyzer II. First, we evaluate the correlation among different experiments focusing on the total number of reads in transcribed and promoter regions of the genome. Then, we adopt the method that is used to identify the most stable genes in RT-PCR experiments to understand background signal across all of the experiments and to identify the most variable transcribed and promoter regions of the genome. We observed that the most variable genes for transcribed regions and promoter regions are very distinct. Gene ontology and function enrichment analysis on these most variable genes demonstrate the biological relevance of the results. In this study, we present a method that can effectively select differential regions of the genome based on protein-binding profiles over multiple experiments using real data points without any normalization among the samples.