Spermatogonial kinetics in humans

The human spermatogonial compartment is essential for daily production of millions of sperm. Despite this crucial role, the molecular signature, kinetic behavior and regulation of human spermatogonia are poorly understood. Using human testis biopsies with normal spermatogenesis and by studying marker protein expression, we have identified for the first time different subpopulations of spermatogonia. MAGE-A4marks all spermatogonia, KITmarks all Bspermatogonia and UCLH1 all Apale-dark (Ap-d) spermatogonia. We suggest that at the start of the spermatogenic lineage there are Ap-d spermatogonia that are GFRA1High, likely including the spermatogonial stem cells. Next, UTF1 becomes expressed, cells become quiescent and GFRA1 expression decreases. Finally, GFRA1 expression is lost and subsequently cells differentiate into B spermatogonia, losing UTF1 and acquiring KIT expression. Strikingly, most human Ap-d spermatogonia are out of the cell cycle and even differentiating type B spermatogonial proliferation is restricted. A novel scheme for human spermatogonial development is proposed that will facilitate further research in this field, the understanding of cases of infertility and the development of methods to increase sperm output

Lower pneumonia risk in COPD patients initiating fixed dose combination (FDC) inhaler comprising extrafine beclometasone dipropionate versus fluticasone

Grant support: This study was funded by Chiesi Farmaceutici S.p.A. David Price has grants and unrestricted funding for investigator-initiated studies (conducted through Observational and Pragmatic Research Institute Pte Ltd) from AstraZeneca, Boehringer Ingelheim, Chiesi, Mylan, Novartis, Regeneron Pharmaceuticals, Respiratory Effectiveness Group, Sanofi Genzyme, Theravance and UK National Health Service; is a peer reviewer for grant committees of the UK Efficacy and Mechanism Evaluation programme, and Health Technology Assessment; and was an expert witness for GlaxoSmithKline.Peer reviewe

Risk of pneumonia in patients with COPD initiating fixed dose inhaled corticosteroid (ICS) / long-acting bronchodilator (LABD) formulations containing extrafine beclometasone dipropionate versus patients initiating LABD without ICS

Professor Dave Singh is supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC). Jaco Voorham is acknowledged for his contribution to protocol development. We would also like to acknowledge Ms. Shilpa Suresh (MSc) of the Observational and Pragmatic Research Institute (OPRI), Singapore, for editorial and formatting assistance which supported the development of this publication. This study was conducted by the Observational and Pragmatic Research Institute (OPRI) Pte Ltd and was funded by Chiesi Farmaceutici S.p.A.Peer reviewedPublisher PD

Adaptive robot training for the treatment of incoordination in Multiple Sclerosis

<p>Abstract</p> <p>Background</p> <p>Cerebellar symptoms are extremely disabling and are common in Multiple Sclerosis (MS) subjects. In this feasibility study, we developed and tested a robot therapy protocol, aimed at the rehabilitation of incoordination in MS subjects.</p> <p>Methods</p> <p>Eight subjects with clinically defined MS performed planar reaching movements while grasping the handle of a robotic manipulandum, which generated forces that either reduced (error-reducing, ER) or enhanced (error-enhancing, EE) the curvature of their movements, assessed at the beginning of each session. The protocol was designed to adapt to the individual subjects' impairments, as well as to improvements between sessions (if any). Each subject went through a total of eight training sessions. To compare the effect of the two variants of the training protocol (ER and EE), we used a cross-over design consisting of two blocks of sessions (four ER and four EE; 2 sessions/week), separated by a 2-weeks rest period. The order of application of ER and EE exercises was randomized across subjects. The primary outcome measure was the modification of the Nine Hole Peg Test (NHPT) score. Other clinical scales and movement kinematics were taken as secondary outcomes.</p> <p>Results</p> <p>Most subjects revealed a preserved ability to adapt to the robot-generated forces. No significant differences were observed in EE and ER training. However over sessions, subjects exhibited an average 24% decrease in their NHPT score. The other clinical scales showed small improvements for at least some of the subjects. After training, movements became smoother, and their curvature decreased significantly over sessions.</p> <p>Conclusions</p> <p>The results point to an improved coordination over sessions and suggest a potential benefit of a short-term, customized, and adaptive robot therapy for MS subjects.</p

ICS/formoterol in the management of asthma in the clinical practice of pulmonologists: an international survey on GINA strategy

Background: The treatment with short-acting beta-2 agonists (SABA) alone is no longer recommended due to safety issues. Instead, the current Global Initiative for Asthma (GINA) Report recommends the use of the combination of inhaled corticosteroids (ICS) with the rapid/long-acting beta-2 agonist formoterol, although the use in steps 1 and 2 is still off-label in the EU and in many countries. It is important to understand clinicians' knowledge and opinions on the issue with the ultimate goal to encourage the implementation of the new approach in clinical practice. Methods: We performed an international survey, directed to pulmonologists interested in the management of patients with asthma. Results: Most participants reported that SABA alone should not be used in GINA Step 1 asthma treatment. As-needed low-dose ICS/formoterol combination to patients in step 1, and as-needed low-dose ICS/formoterol as reliever therapy in any step were found to be of current use prescribed in their real-life settings. SABA alone was still prescribed to a proportion of patients, although the pulmonologists' opinion was that it should no longer be used. Conclusions: Most specialists are up to date and understand the relevance of the changes in GINA reports from 2019. Nevertheless, dissemination and implementation of GINA novel management strategy is still needed

Exploring Quality of Life and Satisfaction with Treatment in Asthmatic Patients Receiving Dry Powder Inhalers: A Multinational Survey

Introduction: The quality of life (QoL) and device needs have not been characterized in asthmatic patients treated via dry powder inhalers (DPIs). The aim of this study was to assess the impact of asthma on health-related QoL, device satisfaction and preference in adult asthmatic patients using DPI devices, and to identify any DPI-associated unmet needs.Methods: An online survey was conducted between November and December 2019 on eligible patients from the Cint consumer panel across Europe. Newly designed, as well as validated questionnaires were used to collect data on QoL and inhaler satisfaction.Results: A total of 1063 asthmatic patient took part in the survey; 66% of the patients reported medium or high impact of asthma on the overall QoL. The majority of patients (61%) reported high level of satisfaction with their current device. The patients with medium-to-high impact of asthma on QoL were significantly less likely to be satisfied with their current device (55%) than those who reported low-to-medium impact of asthma on QoL (67%; p-value &lt;0.001). "Higher number of available doses', 'usability', 'clear dose counter" and 'feedback on correct inhalation' were the attributes mostly requested from a new device. The demand for user-friendly devices that provide feedback on correct drug administration was identified as an unmet need.Conclusions &amp; Clinical Relevance: In asthmatic patients with medium to high impact of asthma on the overall QoL, the satisfaction with the device is highly affected

Environmental impact of inhalers for respiratory diseases: decreasing the carbon footprint while preserving patient-tailored treatment

Patients with asthma and Chronic Obstructive Respiratory Disease (COPD) rely on three main device classes for inhalation therapy: metered-dose inhalers (MDIs), dry powder inhalers (DPIs) and soft-mist inhalers (SMIs). The carbon footprint (CF) of these inhalers differs with MDIs having a higher impact than DPIs and SMIs due to the propellant in MDIs. However, the certified CF of specific MDI products may differ significantly. MDIs still represent an essential option for many patients. Consequently, novel approaches shall be considered to balance environmental goals with patient health and well-being while maintaining a diverse range of choices for patients and physicians

Effects of Postinfarct Myelin-Associated Glycoprotein Antibody Treatment on Motor Recovery and Motor Map Plasticity in Squirrel Monkeys

Background and purposeNew insights into the brain's ability to reorganize after injury are beginning to suggest novel restorative therapy targets. Potential therapies include pharmacological agents designed to promote axonal growth. The purpose of this study was to test the efficacy of one such drug, GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule, myelin-associated glycoprotein, to facilitate recovery of motor skills in a nonhuman primate model of ischemic cortical damage.MethodsUsing a between-groups repeated-measures design, squirrel monkeys were randomized to 1 of 2 groups: an experimental group received intravenous GSK249320 beginning 24 hours after an ischemic infarct in motor cortex with repeated dosages given at 1-week intervals for 6 weeks and a control group received only the vehicle at matched time periods. The primary end point was a motor performance index based on a distal forelimb reach-and-retrieval task. Neurophysiological mapping techniques were used to determine changes in spared motor representations.ResultsAll monkeys recovered to baseline motor performance levels by postinfarct day 16. Functional recovery in the experimental group was significantly facilitated on the primary end point, albeit using slower movements. At 7 weeks post infarct, motor maps in the spared ventral premotor cortex in the experimental group decreased in area compared with the control group.ConclusionsGSK249320, initiated 24 hours after a focal cortical ischemic infarct, facilitated functional recovery. Together with the neurophysiological data, these results suggest that GSK249320 has a substantial biological effect on spared cortical tissue. However, its mechanisms of action may be widespread and not strictly limited to peri-infarct cortex and nearby premotor areas

Effects of postinfarct myelin-associated glycoprotein antibody treatment on motor recovery and motor map plasticity in squirrel monkeys.

Background and purposeNew insights into the brain's ability to reorganize after injury are beginning to suggest novel restorative therapy targets. Potential therapies include pharmacological agents designed to promote axonal growth. The purpose of this study was to test the efficacy of one such drug, GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule, myelin-associated glycoprotein, to facilitate recovery of motor skills in a nonhuman primate model of ischemic cortical damage.MethodsUsing a between-groups repeated-measures design, squirrel monkeys were randomized to 1 of 2 groups: an experimental group received intravenous GSK249320 beginning 24 hours after an ischemic infarct in motor cortex with repeated dosages given at 1-week intervals for 6 weeks and a control group received only the vehicle at matched time periods. The primary end point was a motor performance index based on a distal forelimb reach-and-retrieval task. Neurophysiological mapping techniques were used to determine changes in spared motor representations.ResultsAll monkeys recovered to baseline motor performance levels by postinfarct day 16. Functional recovery in the experimental group was significantly facilitated on the primary end point, albeit using slower movements. At 7 weeks post infarct, motor maps in the spared ventral premotor cortex in the experimental group decreased in area compared with the control group.ConclusionsGSK249320, initiated 24 hours after a focal cortical ischemic infarct, facilitated functional recovery. Together with the neurophysiological data, these results suggest that GSK249320 has a substantial biological effect on spared cortical tissue. However, its mechanisms of action may be widespread and not strictly limited to peri-infarct cortex and nearby premotor areas