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Fibroblasts are ubiquitous cells that can adopt many functional states. As tissue-resident sentinels, they respond to acute damage signals and shape the earliest events in fibrotic and immune-mediated inflammatory diseases. Upon sensing an insult, fibroblasts produce chemokines and growth factors to organize and support the response. Depending on the size and composition of the resulting infiltrate, these activated fibroblasts may also begin to contract or relax thus changing local stiffness within the tissue. These early events likely contribute to the divergent clinical manifestations of fibrotic and immune-mediated inflammatory diseases. Further, distinct changes to the cellular composition and signaling dialogue in these diseases drive progressive fibroblasts specialization. In fibrotic diseases, fibroblasts support the survival, activation and differentiation of myeloid cells, granulocytes and innate lymphocytes, and produce most of the pathogenic extracellular matrix proteins. Whereas, in immune-mediated inflammatory diseases, sequential accumulation of dendritic cells, T cells and B cells programs fibroblasts to support local, destructive adaptive immune responses. Fibroblast specialization has clear implications for the development of effective induction and maintenance therapies for patients with these clinically distinct diseases.

Fibroblasts are ubiquitous cells that can adopt many functional states. As tissue-resident sentinels, they respond to acute damage signals and shape the earliest events in fibrotic and immune-mediated inflammatory diseases. Upon sensing an insult, fibroblasts produce chemokines and growth factors to organize and support the response. Depending on the size and composition of the resulting infiltrate, these activated fibroblasts may also begin to contract or relax thus changing local stiffness within the tissue. These early events likely contribute to the divergent clinical manifestations of fibrotic and immune-mediated inflammatory diseases. Further, distinct changes to the cellular composition and signaling dialogue in these diseases drive progressive fibroblasts specialization. In fibrotic diseases, fibroblasts support the survival, activation and differentiation of myeloid cells, granulocytes and innate lymphocytes, and produce most of the pathogenic extracellular matrix proteins. Whereas, in immune-mediated inflammatory diseases, sequential accumulation of dendritic cells, T cells and B cells programs fibroblasts to support local, destructive adaptive immune responses. Fibroblast specialization has clear implications for the development of effective induction and maintenance therapies for patients with these clinically distinct diseases.

Coal-fired power plants utilising fluidised bed technologies emit copious amounts of fly-ash, which is harmful to people owing to its particulate nature. A planned 300 MW power plant will have an electrostatic precipitator (ESP) for fly-ash emissions control, in line with power generation industry best practices. This ESP should meet a fly-ash emission limit value ≤ 50 mg/Nm3. This paper details the design process and resultant technical specifications of a cold-side, single-stage, and plate-wire dry ESP designed for the power plant. The ESP will consist of twin-chambers with quadruple-fields (2 4 315 m3) and octonary bus-sections independently energised by individual high-frequency three-phase switched integrated rectifiers (70 kV, 800 mA) to maximise ionisation. Dynamically balanced, single-impact, tumbling hammer rappers (857.5 rpm) will dislodge fly-ash from the collector plates into mass-flow wedge-shaped hoppers. A specific collection area (≥ 56.9 m2/m3/s) and an ESP index (≥ 709.2 (kV/cm)2m2/m3/s) should guarantee a collection efficiency ( ≥ 99.5 %) and the specified emission limit value at 100 % boiler capacity and normal operating conditions (gas velocity ≤ 2.4 m/s; gas temperature ≤ 137 ℃; fly-ash loading ≤ 10 000 kg/Nm3; resistivity ≤ 1010 Ω‧cm). The design was successfully verified in principle using the validation square method, in conjunction with the leading comparable historical case studies approach. It is recommended to simulate ESP designs using suitable programs like Comsol Multiphysics and construct a pilot plant before attempting scaled-up construction and commissioning. Highlights • A cold-side, single-stage plate-wire dry ESP system designed. • Theoretical collection efficiency in excess of 99.5%. • High-frequency, three-phase switched integrated rectifiers to be used for ionisation.

Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophages that express SPP1, GPNMB, FABP5, and CD63. In both human and murine hepatic and pulmonary fibrosis, these macrophages were enriched at the outside edges of scarring and adjacent to activated mesenchymal cells. Neutrophils expressing MMP9, which participates in the activation of TGF-β1, and the type 3 cytokines GM-CSF and IL-17A coclustered with these macrophages. In vitro, GM-CSF, IL-17A, and TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers. Such differentiated cells could degrade collagen IV but not collagen I and promote TGF-β1–induced collagen I deposition by activated mesenchymal cells. In murine models blocking GM-CSF, IL-17A or TGF-β1 reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis. Our work identifies a highly specific macrophage population to which we assign a profibrotic role across species and tissues. It further provides a strategy for unbiased discovery, triage, and preclinical validation of therapeutic targets based on this fibrogenic macrophage population. Fibrogenic fiend: Macrophages are key players in responding to tissue injury, and specific macrophage subsets can drive fibrosis progression or resolution. Fabre et al. showed that CD9+TREM2+ macrophages further defined by expression of SPP1, GPNMB, FABP5, and CD63 can mediate fibrosis. Analysis of human and murine hepatic and pulmonary fibrosis samples revealed accumulation of these macrophages near scar sites and proximal to activated mesenchymal cells. These macrophages also clustered with MMP9-expressing neutrophils that secreted GM-CSF and IL-17A and drove TGF-β1 activation. In vitro analysis revealed that GM-CSF, IL-17A, and TGF-β1 can promote differentiation of these macrophages, which are unable to degrade collagen I and contribute to collagen I–associated fibrosis. Blockade of GM-CSF, IL-17A, or TGF-β1 in mice was sufficient to limit fibrosis. These findings highlight a critical role for fibrogenic macrophages in this pathological process. —CNF [ABSTRACT FROM AUTHOR]

Coal-fired power plants utilising fluidised bed technologies emit copious amounts of fly-ash, which is harmful to people owing to its particulate nature. A planned 300 MW power plant will have an electrostatic precipitator (ESP) for fly-ash emissions control, in line with power generation industry best practices. This ESP should meet a fly-ash emission limit value ≤ 50 mg/Nm³. This paper details the design process and resultant technical specifications of a cold-side, single-stage, and plate-wire dry ESP designed for the power plant. The ESP will consist of twin-chambers with quadruple-fields (2 4 315 m³) and octonary bus-sections independently energised by individual high-frequency three-phase switched integrated rectifiers (70 kV, 800 mA) to maximise ionisation. Dynamically balanced, single-impact, tumbling hammer rappers (857.5 rpm) will dislodge fly-ash from the collector plates into mass-flow wedge-shaped hoppers. A specific collection area (≥ 56.9 m²/m³/s) and an ESP index (≥ 709.2 (kV/cm)²m²/m³/s) should guarantee a collection efficiency (η ≥ 99.5%) and the specified emission limit value at 100% boiler capacity and normal operating conditions (gas velocity ≤ 2.4 m/s; gas temperature ≤ 137 °C; fly-ash loading ≤ 10 000 kg/Nm³; resistivity ≤ 1010 Ω‧cm). The design was successfully verified in principle using the validation square method, in conjunction with the leading comparable historical case studies approach. It is recommended to simulate ESP designs using suitable programs like Comsol Multiphysics and construct a pilot plant before attempting scaled-up construction and commissioning. [ABSTRACT FROM AUTHOR]

Objectives: Determine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.Methods: Skin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.Results: SSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.Conclusions: Skin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design. [ABSTRACT FROM AUTHOR]

Electrospray data collected demonstrate the detailed dependence of volumetric flow rate through an electrospray system upon the applied voltage. The sensitivity of nominal flow rate to applied voltage was found to be higher for lower nominal flow rates. For a volumetric flow rate ∼4 nL/s a 25% change in flow rate per kilovolt was recorded over a cone-jet mode stability range spanning ∼1.5 kV. This volumetric flow rate voltage sensitivity holds particular significance for potential colloid electrospray propulsion systems, which operate at or near minimum flow rate conditions. Analysis is presented to show that the change in flow rate due to change in voltage cannot be ascribed to evaporation from the meniscus as has been suggested by others. [ABSTRACT FROM AUTHOR]

Perivascular accumulation of lymphocytes can be a prominent histopathologic feature of various human inflammatory skin diseases. Select examples include systemic sclerosis, spongiotic dermatitis, and cutaneous lupus. Although a large body of work has described various aspects of the endothelial and vascular smooth muscle layers in these diseases, the outer adventitial compartment is poorly explored. The goal of the current study was to characterize perivascular adventitial fibroblast states in inflammatory human skin diseases and relate these states to perivascular lymphocyte accumulation. In normal skin, adventitial fibroblasts are distinguished by CD90 expression, and dense perivascular lymphocytic infiltrates are uncommon. In systemic sclerosis, this compartment expands, but lymphocyte infiltrates remain sparse. In contrast, perivascular adventitial fibroblast expression of VCAM1 is upregulated in spongiotic dermatitis and lupus and is associated with a dense perivascular T cell infiltrate. VCAM1 expression marks transitioned fibroblasts that show some resemblance to the reticular stromal cells in secondary lymphoid organs. Expanded adventitial compartments with perivascular infiltrates similar to the human settings were not seen in the inflamed murine dermis. This species difference may hinder the dissection of aspects of perivascular adventitial pathology. The altered perivascular adventitial compartment and its associated reticular network form a niche for lymphocytes and appear to be fundamental in the development of an inflammatory pattern. [ABSTRACT FROM AUTHOR]

Study design:Two randomized, double-blind, placebo-controlled trials.Objective:To evaluate the efficacy and safety of fampridine sustained-release tablets (fampridine-SR) 25 mg twice daily for moderate-to-severe spasticity in patients with chronic spinal cord injury (SCI).Setting:United States and Canada.Methods:Patients with incomplete chronic SCI were randomized to twice daily fampridine-SR 25 mg or placebo, with a 2-week single-blind placebo run-in, a 2-week titration, 12 weeks of stable dosing, 2 weeks of downward titration and 2 weeks of untreated follow-up. Co-primary end points were the change from baseline, averaged over the double-blind treatment period, for Ashworth score (bilateral knee flexors and extensors) and a 7-point Subject Global Impression of treatment (SGI; 1, terrible; 7, delighted). Secondary end points were: Penn Spasm Frequency Scale; the motor/sensory score from the International Standards for Neurological Classification of SCI; Clinician's Global Impression of Change of neurological status; and the International Index of Erectile Function (men) or the Female Sexual Function Index (women).Results:The populations were 212 and 203 patients in the two studies, respectively. Changes from baseline in Ashworth score were −0.15 (placebo) and −0.19 (fampridine-SR) in the first study, and −0.16 (placebo) and −0.28 (fampridine-SR) in the second study. The between-treatment difference was not significant for either the Ashworth score or the SGI and, with few exceptions, neither were the secondary end points. Fampridine-SR was generally well tolerated; treatment-emergent adverse events (TEAEs) and serious TEAEs were reported with similar frequency between treatments.Conclusion:Fampridine-SR was well tolerated. No significant differences were observed between treatment groups for the primary end points of Ashworth score and SGI. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is caused by mutations in the DYSTROPHIN gene. Although primarily associated with muscle wasting, a significant portion of patients (approximately 25%) are also diagnosed with autism spectrum disorder. We describe social behavioral deficits in dystrophin-deficient mice and present evidence of cerebellar deficits in cGMP production. We demonstrate therapeutic potential for selective inhibitors of the cGMP-specific PDE5A and PDE9A enzymes to restore social behaviors in dystrophin-deficient mice.

In patients with Duchenne muscular dystrophy (DMD), the absence of a functional dystrophin protein results in sarcolemmal instability, abnormal calcium signaling, cardiomyopathy, and skeletal muscle degeneration. Using the dystrophin-deficient sapje zebrafish model, we have identified microRNAs (miRNAs) that, in comparison to our previous findings in human DMD muscle biopsies, are uniquely dysregulated in dystrophic muscle across vertebrate species. MiR-199a-5p is dysregulated in dystrophin-deficient zebrafish, mdx5cv mice, and human muscle biopsies. MiR-199a-5p mature miRNA sequences are transcribed from stem loop precursor miRNAs that are found within the introns of the dynamin-2 and dynamin-3 loci. The miR-199a-2 stem loop precursor transcript that gives rise to the miR-199a-5p mature transcript was found to be elevated in human dystrophic muscle. The levels of expression of miR-199a-5p are regulated in a serum response factor (SRF)-dependent manner along with myocardin-related transcription factors. Inhibition of SRF-signaling reduces miR-199a-5p transcript levels during myogenic differentiation. Manipulation of miR-199a-5p expression in human primary myoblasts and myotubes resulted in dramatic changes in cellular size, proliferation, and differentiation. MiR-199a-5p targets several myogenic cell proliferation and differentiation regulatory factors within the WNT signaling pathway, including FZD4, JAG1, and WNT2. Overexpression of miR-199a-5p in the muscles of transgenic zebrafish resulted in abnormal myofiber disruption and sarcolemmal membrane detachment, pericardial edema, and lethality. Together, these studies identify miR-199a-5p as a potential regulator of myogenesis through suppression of WNT-signaling factors that act to balance myogenic cell proliferation and differentiation. [ABSTRACT FROM AUTHOR]

Objectives:To create an International Spinal Cord Injury (SCI) Skin and Thermoregulation Basic Data Set within the framework of the International SCI Data Sets.Setting:An international working group.Methods:The draft of the Data Set was developed by a working group comprising members appointed by the American Spinal Injury Association (ASIA), the International Spinal Cord Society (ISCoS) and a representative of the Executive Committee of the International SCI Standards and Data Sets. The final version of the Data Set was developed after review and comments by members of the Executive Committee of the International SCI Standards and Data Sets, the ISCoS Scientific Committee, ASIA Board, relevant and interested international organizations and societies, individual persons with specific interest and the ISCoS Council. To make the Data Set uniform, each variable and each response category within each variable have been specifically defined to promote the collection and reporting of comparable minimal data.Results:Variables included in the present Data Set are: date of data collection, thermoregulation history after SCI, including hyperthermia or hypothermia (noninfectious or infectious), as well as the history of hyperhidrosis or hypohidrosis above or below level of lesion. Body temperature and the time of measurement are included. Details regarding the presence of any pressure ulcer and stage, location and size of the ulcer(s), date of appearance of the ulcer(s) and whether surgical treatment has been performed are included. The history of any pressure ulcer during the last 12 months is also noted. [ABSTRACT FROM AUTHOR]

Objectives:To develop the International Spinal Cord Injury (SCI) Pulmonary Function Basic Data Set within the framework of the International SCI Data Sets in order to facilitate consistent collection and reporting of basic bronchopulmonary findings in the SCI population.Setting:International.Methods:The SCI Pulmonary Function Data Set was developed by an international working group. The initial data set document was revised on the basis of suggestions from members of the Executive Committee of the International SCI Standards and Data Sets, the International Spinal Cord Society (ISCoS) Executive and Scientific Committees, American Spinal Injury Association (ASIA) Board, other interested organizations and societies and individual reviewers. In addition, the data set was posted for 2 months on ISCoS and ASIA websites for comments.Results:The final International SCI Pulmonary Function Data Set contains questions on the pulmonary conditions diagnosed before spinal cord lesion,if available, to be obtained only once; smoking history; pulmonary complications and conditions after the spinal cord lesion, which may be collected at any time. These data include information on pneumonia, asthma, chronic obstructive pulmonary disease and sleep apnea. Current utilization of ventilator assistance including mechanical ventilation, diaphragmatic pacing, phrenic nerve stimulation and Bi-level positive airway pressure can be reported, as well as results from pulmonary function testing includes: forced vital capacity, forced expiratory volume in one second and peak expiratory flow. The complete instructions for data collection and the data sheet itself are freely available on the website of ISCoS (http://www.iscos.org.uk). [ABSTRACT FROM AUTHOR]

Objective:To create the International Spinal Cord Injury (SCI) Female Sexual and Reproductive Function Basic Data Set within the International SCI Data Sets.Setting:An international working group.Methods:The draft of the data set was developed by an international working group consisting of members appointed by the International Spinal Cord Society (ISCoS), the American Spinal Injury Association (ASIA), and a representative from the Executive Committee of the International SCI Standards and Data Sets. The data set was developed in an iterative process with review and comments by members of the Executive Committee of the International SCI Standards and Data Sets, ISCoS Scientific Committee, ASIA Board and the ISCoS Council, as well as all interested organizations and individuals. In addition, the data set was posted for 2 months at the ISCoS and ASIA websites for comments. ISCoS and ASIA approved the final version of the data set. To make the data set uniform, each variable and each response category within each variable have been specifically designed to promote the collection and reporting of comparable minimal data.Results:Variables included in the International SCI Female Sexual and Reproductive Function Basic Data Set are as follows: date of data collection, interest in discussing sexual issues, sexual issues unrelated to spinal cord lesion, sexual dysfunction related to spinal cord lesion, psychogenic genital arousal, reflex genital arousal, orgasmic function and menstruation. Complete instruction for data collection, data sheet and training cases are available at the websites of ISCoS (http://www.iscos.org.uk) and ASIA (http://www.asia-spinalinjury.org). [ABSTRACT FROM AUTHOR]

Objective:To create the International Spinal Cord Injury (SCI) Male Sexual Function Basic Data Set within the International SCI Data Sets.Setting:An international working group.Methods:The draft of the data set was developed by an international working group consisting of members appointed by the International Spinal Cord Society (ISCoS), the American Spinal Injury Association (ASIA) and a representative from the executive committee of the International SCI Standards and Data Sets. The data set was developed in an iterative process with review and comments by the members of the executive committee of the International SCI Standards and Data Sets, ISCoS scientific committee, ASIA Board and the ISCoS Council, as well as all the interested organizations and individuals. Next, the data set was posted for 2 months at the ISCoS and ASIA's websites for comments. ISCoS and ASIA approved the final version of the data set. To make the data set uniform, each variable and each response category within each variable have been specifically defined in a way that is designed to promote the collection and reporting of comparable minimal data.Results:Variables included in the International SCI Male Sexual Function Basic Data Set are as follows: date of data collection, interest in discussing sexual issues, sexual issues unrelated to spinal cord lesion, sexual dysfunction related to spinal cord lesion, psychogenic erection, reflex erection, ejaculation and orgasmic function. Complete instructions for data collection, data sheet and training cases are available at the website of ISCoS (http://www.iscos.org.uk) and ASIA (http://www.asia-spinalinjury.org). [ABSTRACT FROM AUTHOR]

Objective:To provide recommendations regarding translation and reliability testing of International Spinal Cord Injury (SCI) Data Sets.Setting:The Executive Committee for the International SCI Standards and Data Sets.Recommendations:Translations of any specific International SCI Data Set can be accomplished by translation from the English version into the target language, and be followed by a back-translation into English, to confirm that the original meaning has been preserved. Another approach is to have the initial translation performed by translators who have knowledge of SCI, and afterwards controlled by other person(s) with the same kind of knowledge. The translation process includes both language translation and cultural adaptation, and therefore shall not be made word for word, but will strive to include conceptual equivalence. At a minimum, the inter-rater reliability should be tested by no less than two independent observers, and preferably in multiple countries. Translations must include information on the name, role and background of everyone involved in the translation process, and shall be dated and noted with a version number.Conclusion:By following the proposed guidelines, translated data sets should assure comparability of data acquisition across countries and cultures. If the translation process identifies irregularities or misrepresentation in either the original English version or the target language, the working group for the particular International SCI Data Set shall revise the data set accordingly, which may include re-wording of the original English version in order to accomplish a compromise in the content of the data set. [ABSTRACT FROM AUTHOR]

Study design:Double-blind, placebo-controlled, flexible-dose study.Objective:To evaluate the efficacy, safety and tolerability of oral sildenafil in women with female sexual arousal disorder as a result of SCI (paraplegia/tetraplegia).Setting:The study was conducted at clinical practice sites in North America (n =23), 11 European countries (n =23), Australia (n =4) and South Africa (n =2).Methods:129 women were randomized and treated with sildenafil or matching placebo. A 4-week baseline period was followed by 12 weeks of treatment, which could be increased from 50 to 100 mg or decreased to 25 mg once during the treatment period, depending on efficacy and tolerability. By use of an event log, sexual activity was monitored between screening and the end of treatment. The Sexual Function Questionnaire, the Sexual Quality of Life Questionnaire-Female, a global efficacy question and Sexual Distress Question were also assessed.Results:Sildenafil-treated women and placebo-treated women had an increase in their percentage of sexual activities throughout the course of the study, with no statistically significant difference between groups in the percentage of successful sexual activities at end of treatment versus baseline. There were also no statistically significant differences between sildenafil- and placebo-treated women on the aforementioned measures. The most common adverse events included headache and vasodilatation.Conclusion:The results of this study are similar to other reports regarding a lack of clinically meaningful benefit of sildenafil in other populations of women.Sponsorship:This study was sponsored by Pfizer Inc. [ABSTRACT FROM AUTHOR]

Objective:To create an International Spinal Cord Injury (SCI) Cardiovascular Function Basic Data Set within the framework of the International SCI Data Sets.Setting:An international working group.Methods:The draft of the data set was developed by a working group comprising members appointed by the American Spinal Injury Association (ASIA), the International Spinal Cord Society (ISCoS) and a representative of the executive committee of the International SCI Standards and Data Sets. The final version of the data set was developed after review by members of the executive committee of the International SCI Standards and Data Sets, the ISCoS scientific committee, ASIA board, relevant and interested international organizations and societies, individual persons with specific interest and the ISCoS Council. To make the data set uniform, each variable and each response category within each variable have been specifically defined in a way that is designed to promote the collection and reporting of comparable minimal data.Results:The variables included in the International SCI Cardiovascular Function Basic Data Set include the following items: date of data collection, cardiovascular history before the spinal cord lesion, events related to cardiovascular function after the spinal cord lesion, cardiovascular function after the spinal cord lesion, medications affecting cardiovascular function on the day of examination; and objective measures of cardiovascular functions, including time of examination, position of examination, pulse and blood pressure. The complete instructions for data collection and the data sheet itself are freely available on the websites of both ISCoS (http://www.iscos.org.uk) and ASIA (http://www.asia-spinalinjury.org). [ABSTRACT FROM AUTHOR]

Study design:Review by the spinal cord outcomes partnership endeavor (SCOPE), which is a broad-based international consortium of scientists and clinical researchers representing academic institutions, industry, government agencies, not-for-profit organizations and foundations.Objectives:Assessment of current and evolving tools for evaluating human spinal cord injury (SCI) outcomes for both clinical diagnosis and clinical research studies.Methods:a framework for the appraisal of evidence of metric properties was used to examine outcome tools or tests for accuracy, sensitivity, reliability and validity for human SCI.Results:Imaging, neurological, functional, autonomic, sexual health, bladder/bowel, pain and psychosocial tools were evaluated. Several specific tools for human SCI studies have or are being developed to allow the more accurate determination for a clinically meaningful benefit (improvement in functional outcome or quality of life) being achieved as a result of a therapeutic intervention.Conclusion:Significant progress has been made, but further validation studies are required to identify the most appropriate tools for specific targets in a human SCI study or clinical trial.Spinal Cord (2009) 47, 582–591; doi:10.1038/sc.2009.18; published online 21 April 2009 [ABSTRACT FROM AUTHOR]

Study design:Experts opinions consensus.Objective:To develop a common strategy to document remaining autonomic neurologic function following spinal cord injury (SCI).Background and Rationale:The impact of a specific SCI on a person's neurologic function is generally described through use of the International Standards for the Neurological Classification of SCI. These standards document the remaining motor and sensory function that a person may have; however, they do not provide information about the status of a person's autonomic function.Methods:Based on this deficiency, the American Spinal Injury Association (ASIA) and the International Spinal Cord Society (ISCoS) commissioned a group of international experts to develop a common strategy to document the remaining autonomic neurologic function.Results:Four subgroups were commissioned: bladder, bowel, sexual function and general autonomic function. On-line communication was followed by numerous face to face meetings. The information was then presented in a summary format at a course on Measurement in Spinal Cord Injury, held on June 24, 2006. Subsequent to this it was revised online by the committee members, posted on the websites of both ASIA and ISCoS for comment and re-revised through webcasts. Topics include an overview of autonomic anatomy, classification of cardiovascular, respiratory, sudomotor and thermoregulatory function, bladder, bowel and sexual function.Conclusion:This document describes a new system to document the impact of SCI on autonomic function. Based upon current knowledge of the neuroanatomy of autonomic function this paper provides a framework with which to communicate the effects of specific spinal cord injuries on cardiovascular, broncho-pulmonary, sudomotor, bladder, bowel and sexual function.Spinal Cord (2009) 47, 36–43; doi:10.1038/sc.2008.121; published online 28 October 2008 [ABSTRACT FROM AUTHOR]

Study design:This presentation was originally given as ‘The Sullivan Lecture’ at the International Spinal Cord Society Meeting in Reykjavik, Iceland on 30 June 2007.Setting:Named lecture at an international meeting.Results:The development of the autonomic component standards of the International Standards for the Neurologic Classification is described. Research pertaining to sexual responses after spinal cord injury is presented as a model for ways the impact of varying patterns of spinal cord injuries on other organ systems could be studied. Future challenges and opportunities facing the field of spinal cord injury are also discussed.Conclusion:The addition of a standard form of communicating the impact of spinal cord injury on autonomic responses should improve clinical care and research related to spinal cord injury. Using the knowledge that can be obtained from detailed assessment of persons with spinal cord injuries will help provide increased understanding of neuroanatomy in the able-bodied persons. This added value from studying persons with spinal cord injuries provides further justification for research in this area.Spinal Cord (2008) 46, 402–405; doi:10.1038/sj.sc.3102165; published online 1 April 2008 [ABSTRACT FROM AUTHOR]

Eotaxins (CCL11, CCL24, CCL26) originating from airway epithelial cells and leukocytes have been detected in bronchoalveolar lavage of asthmatics. Although the alveolar epithelium is the destination of uncleared allergens and other inflammatory products, scanty information exists on their contribution to the generation and regulation of the eotaxins. We envisioned a state whereby alveolar type II cells, a known source of other inflammatory proteins, could be involved in both the production and regulation of CCL24 and CCL26. Herein, we demonstrated that all three eotaxins are constitutively expressed in A549 cells. IL-4 and IL-13 stimulated a concentration-dependent secretion of CCL24 and CCL26. The cytokines did not act synergistically. Cycloheximide and actinomycin D abrogated IL-4- and IL13-dependent CCL26 but not CCL24 secretion. Both IL-13 and IL-4 stimulated CCL26 synthesis that was inhibited in a concentration-dependent manner by CCL26 but not CCL24. Only CCL26 reduced expression of CCR3 receptors by 30-40%. On the other hand, anti-CCR3 pretreatment reduced IL-4+IL-13-dependent CCL26 secretion, implying autoregulation. A CCR3-specific antagonist (SB328437) significantly decreased IL-4-dependent synthesis and release of CCL26. Eosinophils treated with medium from IL-4-stimulated A549 cells preincubated with anti-CCL26 showed a marked decrease of superoxide anion production compared with anti-CCL24 treated. These results suggest that CCL26 is a major eotaxin synthesized and released by alveolar epithelial cells and is involved in autoregulation of CCR3 receptors and other eotaxins. This CCL26-CCR3 ligand-receptor system may be an attractive target for development of therapeutics that limits progress of inflammation in airway disease. [ABSTRACT FROM AUTHOR]

In a double-blind comparative trial of sulpiride (600-1,800 mg/day) and trifluoperazine (15-45 mg/day) in 38 chronic schizophrenic patients, ratings of therapeutic results and unwanted effects were made at two-weekly interviews during the six weeks treatment period. The results show that sulpiride has neuroleptic properties and a spectrum of therapeutic activity similar to that of trifluoperazine. There was an association between plasma sulpiride levels and therapeutic response after four weeks' treatment. [ABSTRACT FROM AUTHOR]

Two patients developed an extrapyramidal syndrome after therapy with lithium carbonate. Although the clinical features of this syndrome were indistinguishable from those of drug-induced parkinsonism, it was made worse by the anti-parkinsonian drug, orphenadrine. These findings were reproduced later under laboratory conditions when extrapyramidal symptoms and physiological tremor were recorded before and after challenge doses of orphenadrine. This unwanted effect of lithium carbonate may be explained by selective blockade of dopamine receptors. [ABSTRACT FROM AUTHOR]

The inter-situational, inter-rater and temporal reliability of a schedule for rating personality disorders is described. In an initial study with a simplified form of the schedule in patients from different wards of a psychiatric hospital inter-situational reliability between raters was higher for patients with personality disorders than with no personality disorder. Using the full schedule, inter-rater reliability, using audiotaped and separate interviews, and temporal reliability at interviews conducted a mean of 12.5 months apart all reached a satisfactory level, suggesting that the schedule may be a useful instrument for measuring deviant personality traits. The interview may be used with a subject or an informant but agreement between ratings made with informants and psychiatric patients during illness was low, and the schedule is not recommended for use with patients alone during acute episodes of illness. [ABSTRACT FROM AUTHOR]

Lung-resident memory B cells (BRM cells) are elicited after influenza infections of mice, but connections to other pathogens and hosts - as well as their functional significance - have yet to be determined. We postulate that BRM cells are core components of lung immunity. To test this, we examined whether lung BRM cells are elicited by the respiratory pathogen pneumococcus, are present in humans, and are important in pneumonia defense. Lungs of mice that had recovered from pneumococcal infections did not contain organized tertiary lymphoid organs, but did have plasma cells and noncirculating memory B cells. The latter expressed distinctive surface markers (including CD69, PD-L2, CD80, and CD73) and were poised to secrete antibodies upon stimulation. Human lungs also contained B cells with a resident memory phenotype. In mice recovered from pneumococcal pneumonia, depletion of PD-L2+ B cells, including lung BRM cells, diminished bacterial clearance and the level of pneumococcus-reactive antibodies in the lung. These data define lung BRM cells as a common feature of pathogen-experienced lungs and provide direct evidence of a role for these cells in pulmonary antibacterial immunity. [ABSTRACT FROM AUTHOR]

Study Design: Cross-sectional study., Objectives: To assess whether T11-L2 sensation is significantly associated with perception of bladder filling and whether S3-S5 sensation is significantly associated with potential for voluntary voiding after spinal cord injury (SCI)., Setting: Alabama, United States., Methods: A total of 79 men and women with SCI, and 40 able-bodied (AB) subjects, ages 19-60, seen in an outpatient academic medical center clinic, underwent International Standards for Neurological Classification of SCI (ISNCSCI) assessment along with urodynamic testing to assess lower urinary tract (LUT) function. X 2 test was performed to compare: (1) bladder sensation across T11-L2 groups classified by total sensory scores and (2) ability to voluntarily void across S3-S5 scores., Results: Persons with greater ability to perceive pinprick and light touch sensation in the T11-L2 dermatomes were more likely to perceive bladder filling both via self-report and by urodynamics. However, persons with greater sensation at T6-T9 and S3-5 also had a greater likelihood of perceiving bladder filling. Subjects with greater preservation of sensation in S3-5 reported greater ability to initiate and control voiding., Conclusion: Findings suggest ISNCSCI results along with self-report can be used to predict potential for bladder control., Sponsorship: National Institute of Disability and Rehabilitation Research.

Objective: To describe the changes made to the international spinal cord injury (SCI) skin and thermoregulation function basic data set in version 1.1., Setting: International., Methods: An international working group reviewed suggested changes to the international SCI skin and thermoregulation function basic data set version 1.0. These changes were discussed and the agreed changes were made. Subsequently, the recommended adjustments were circulated for review to the International Spinal Cord Society (ISCoS) Executive and Scientific Committees, the American Spinal Injury Association (ASIA) Board, around 40 national and international societies, and to interested individuals who had signed up wishing to have the opportunity to review. In addition, the suggested changes were displayed at the ISCoS and ASIA websites for at least a month for possible comments., Results: The recommendation 'largest diameter, including undermining' is changed to: 'Largest undermining', and a description of how to measure this is inserted. The 'smallest opening diameter' is changed to: 'Width' as the maximum dimension perpendicular to the length axis. In the literature, there is a tendency to replace 'grades' or 'stages' with 'categories'; therefore, the word 'category' is used instead of 'grade' or 'stage'., Conclusions: Impracticable measurements have been adjusted and new terminology adopted. All are to be found on ISCoS website: http://www.iscos.org.uk/international-sci-skin-and-thermoregulation-function-data-sets.

Tissue injury triggers the activation and differentiation of multiple cell types to minimize damage and initiate repair processes. In systemic sclerosis, these repair processes appear to run unchecked, leading to aberrant remodeling and fibrosis of the skin and multiple internal organs, yet the fundamental pathological defect remains unknown. We describe herein a transition wherein the abundant CD34(+) dermal fibroblasts present in healthy human skin disappear in the skin of systemic sclerosis patients, and CD34(-), podoplanin(+), and CD90(+) fibroblasts appear. This transition is limited to the upper dermis in several inflammatory skin diseases, yet in systemic sclerosis, it can occur in all regions of the dermis. In vitro, primary dermal fibroblasts readily express podoplanin in response to the inflammatory stimuli tumor necrosis factor and IL-1β. Furthermore, we show that on acute skin injury in both human and murine settings, this transition occurs quickly, consistent with a response to inflammatory signaling. Transitioned fibroblasts partially resemble the cells that form the reticular networks in organized lymphoid tissues, potentially linking two areas of fibroblast research. These results allow for the visualization and quantification of a basic stage of fibroblast differentiation in inflammatory and fibrotic diseases in the skin., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: To report a case with isolated, nontraumatic bilateral fourth nerve palsy as the first clinical sign of a metastatic lung carcinoma., Methods: Case report. A 56-year-old man presented with isolated, nontraumatic bilateral fourth nerve palsy. Magnetic resonance imaging (MRI) of the brain and orbits and, subsequently, chest x-ray and a computer tomographic (CT)-scan of the thorax, the abdomen, and the pelvis were performed., Results: Magnetic resonance imaging confirmed the presence of a midline brain stem lesion in the region of decussation of the trochlear nerves. Computed tomographic scan of the chest revealed that the lesion was caused by a metastatic lung carcinoma., Conclusion: The findings of isolated bilateral fourth nerve palsy in the absence of trauma should alert the clinician to the possibility of a posterior fossa lesion in the region of the trochlear nerves. Besides urgent scanning of the dorsal midbrain, investigations should be directed to search for the primary tumor.

Mass spectrometry combined with liquid chromatography (LC/MS) has become an important analytical methodology in both pharmaceutical and biomolecule analyses. LC/MS, especially with reversed-phase HPLC (RP-LC), is extensively used in the separation and structural identification of pharmaceutical samples. However, many parameters have to be considered when a new LC/MS method is developed for either separation and structural analysis of unknown mixtures or quantitative analysis of a set of known compounds in an assay. The optimization of a new LC/MS method can be a time-consuming process. A novel kit-LC/MS performance test mix-composed of aspartame, cortisone, reserpine, and dioctyl phthalate has been developed to accelerate the process of establishing a new RP-LC/MS method. The LC/MS mix makes the evaluation and validation of an LC/MS method more efficient and easier. It also simplifies the quality control procedure for an LC/MS method in use.

In a continuing evaluation of the aniline-substituted enaminones, the synthesis of additional para-substituted analogs has been made in an attempt to further quantify the electronic (sigma) and lipophilic (pi) requirements for anticonvulsant activity in this series. In addition, meta- and ortho-substituted and polysubstituted compounds have been synthesized and evaluated for anticonvulsant activity. In the para-substituted series, 4-cyano analogs (32 and 33) (+ sigma, - pi), which were highly active via intraperitoneal (ip) injection in mice, were inactive on oral (po) administration in rats. The para-substituted trifluoromethoxy (+ sigma, + pi) analog (8) had significant potency by both routes. Meta substitution limited the activity due to steric factors. Bromo and iodo substituents produced active para-substituted analogs (5 and 17) but were inactive when substituted in the meta position (37 and 41, respectively). Ortho substitution provided no clear relationship due to nonparametric deviations. Neither 1, the prototype enaminone, nor 2, the putative metabolite, produced significant nephrotoxicity or hepatotoxicity. Sodium channel binding of 1 and 8 indicated that 8 displayed relatively potent sodium channel binding but 1 showed weaker effects with IC50 values of 489 and 170 microM respectively against [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTX-B).

1H nuclear magnetic resonance (NMR) spectra of enaminones were determined and compared to the anticonvulsant activity of the compounds. Although the precise employment of the NMR data to predict anticonvulsant activity of the enaminones could not be established, general inferences were made. The NMR data confirmed that the enaminones existed predominantly in the amino tautomer, and no evidence was found for the imino tautomer. The ketamine form of the enaminones was supported by the observed spin-spin splittings of the NH with the alpha-protons on certain enaminones. The NH of secondary enaminones was very important in conferring anticonvulsant activity to the enaminones. The peak for the NH proton which could be seen between delta (ppm) 4.50 and 9.70 was present in all of the active enaminones. The tertiary enaminones, which were devoid of the NH proton, were uniformly inactive. It appeared that a combination of steric and electronic effects, lipophilicity, and hydrogen bonding were necessary for the anticonvulsant activity of the enaminones. The cyclic enaminones existed in the trans-S-trans fixed conformation, and the NMR data supported our hypothesis that enantioselectivity is retained in synthesizing enaminones from cyclic, diasteriomeric 1,3-diketones. In addition, the AB system and many unique features were observed in some enaminones. The para, meta, and ortho substituted patterns were observed for monosubstituted phenyl protons, and the NMR patterns for di- and trisubstituted phenyl groups were elucidated.

Oligodendroglia-glioma hybrid cells (ROC-1) subjected to inhibition of glycolytic and oxidative ATP synthesis undergo a sequence of changes, including ATP depletion, parallel processes of cell swelling and blebbing, and finally plasma membrane disruption and cell death. The morphological and biochemical changes that follow ATP depletion were studied in the presence and absence of polyethylene glycol (M(r) 8,000), a nonpermeant oncotic agent. Polyethylene glycol prevented cell swelling and membrane blebbing. It significantly delayed, but did not prevent, the release of lactate dehydrogenase into the medium; it did not affect the fall in [ATP]. These results suggest that osmotic cell swelling may be a contributing factor in the loss of cell viability when ROC-1 cells are depleted of ATP.

A controlled release (CR) formulation of remoxipride (Roxiam(®), Astra) given once-daily was compared to immediate release (IR) remoxipride given twice-daily, with respect to efficacy and tolerability, in a 4-week multicentre parallel-group dose titration (200-600 mg/day) study with acutely ill schizophrenic patients. Forty- three patients received remoxipride CR (mean dose 344 mg/day) and 49 patients received remoxipride IR (mean dose 346 mg/day). Efficacy was assessed using the Kolakowska version of the Brief Psychiatric Rating Scale (BPRS score of ≥ 18 points at entry) and the Clinical Global Impression scale (CGI), while extrapyramidal symptoms were rated using the Simpson and Angus scale. Both formulations of remoxipride produced clinical improvement, with the BPRS median total score falling from 35 at baseline to 16 at last rating in the remoxipride CR group, and from 33 to 12.5 in the remoxipride IR group. More than 70% of the patients in both groups were assessed as 'much improved' or 'very much improved' according to the CGI scale. Both formulations of remoxipride were well-tolerated, with a low incidence of treatment-emergent adverse symptoms, including extrapyramidal side effects. No statistically significant differences were detected between the treatment groups with regard to efficacy, safety or tolerability.

The morphological and biochemical changes that occur during chemical hypoxic injury in a neural cell line were studied in the presence and absence of calcium. Oligodendroglial-glioma hybrid cells (ROC-1) were subjected to inhibitors of glycolytic and oxidative ATP synthesis (chemical hypoxia). Complete respiratory inhibition depleted [ATP] to less than 5% of control by 4 min. Blebs appeared on the cell surfaces and cells began to swell within a few minutes of ATP depletion. A 200% increase in cell volume and bleb coalescence preceded irreversible cell injury (lactate dehydrogenase release) which began at approximately 20 min with 50% cell death by 40 min. In energized cells an equivalent degree of osmotic swelling induced by ouabain inhibition of the Na+, K(+)-ATPase pump did not produce blebbing or cell death. Partial inhibition of respiration decreased [ATP] to approximately 10% of control by 40 min. Blebbing and swelling began at 40 min and bleb coalescence preceded plasma membrane disruption which began at approximately 55 min. ATP depletion, blebbing, swelling, and death followed similar time courses in the presence or absence of extracellular calcium ([Ca2+]e). Intracellular calcium ([Ca2+]i) was measured using fura-2. In calcium-containing medium metabolic inhibition caused a transient increase in resting [Ca2+]i (100 +/- 17 nM) followed by a low steady-state level preceding plasma membrane disruption. Following deenergization in calcium-free medium, [Ca2+]i remained below 60 nM throughout injury and death. These data suggest that decreased ATP initiates a sequence of events including bleb formation and cell swelling that lead to irreversible cell injury in the absence of large increases in [Ca2+]i.

Reduced left lower lobe ventilation (V) in patients with enlarged hearts has been commonly observed on routine isotope ventilation-perfusion lung scanning, and there is evidence to show that this reduction is dependent on posture. Clinically, it may have a role in posture-dependent dyspnea and postoperative left lower lobe changes in cardiomegaly. Previous studies have shown improvement in left lower lobe V in the prone compared with the supine position. In 11 patients showing this phenomenon in krypton 81m V scanning, a mean relative reduction in V of 53 percent occurred at the left base. No significant change in perfusion or in the signal from preinjected technetium 99m macroaggregated albumin was observed between the two positions. No significant change in ventilatory turnover (measured with intravenous xenon 133) was seen either, suggesting that no air trapping takes place. By combining the data from the intravenous 133Xe (which gives the ratio, V/lung volume) and continuously inhaled 81mKr (which reflects regional V), an index of relative volume between the two sides was derived and shown to be significantly reduced at the left base on moving from the prone to supine positions (a mean reduction of 40 percent; p less than 0.02 by Wilcoxon signed rank test). Thus, the mechanism of postural left lower lobe hypoventilation in cardiomegaly is predominantly a regional loss of alveolar volume.