Age-related changes in sensory and motor components of the Hoffmann-reflex pathway of the flexor carpi radialis.

Ageing is accompanied by numerous changes within the sensory and motor components of the muscle spindle pathway. To further document these age-related changes, this study compared the characteristics of the Hoffmann (H) reflex and M wave, evoked with several pulse durations, between young and old adults. The H-reflex and M-wave recruitment curves were recorded at rest in the flexor carpi radialis of 12 young (21-36 years) and 12 older adults (62-80 years). For each pulse duration (0.05, 0.2 and 1 ms), the maximal M-wave (MMAX ) and H-reflex (HMAX ) amplitude, the M-wave amplitude associated with HMAX (MHmax ) and the H-reflex amplitude for a stimulus intensity evoking an M-wave of 5% MMAX (HM5% ) were measured. The strength-duration time constant and response threshold were estimated from the charge/stimulus-duration relation for the H reflex and M wave. Results indicate that varying pulse duration mainly induces a similar effect on H-reflex and M-wave recruitment curves between young and older adults. Regardless of pulse duration, old adults had lesser HMAX (p = 0.029) and HM5% (p < 0.001) but greater MHmax (p < 0.001). The H-reflex and M-wave response thresholds were greater in old than young adults (p = 0.003), but the strength-duration time constant was lesser in old than young adults for the H reflex (p = 0.048) but not the M wave (p = 0.21). These results suggest greater age-related changes in the sensory than the motor component of the H-reflex pathway, which may be indicative of a greater loss of sensory than motor axons or alterations of synapses between Ia afferents and motor neurones.

Revisiting the use of Hoffmann reflex in motor control research on humans.

Research in movement science aims at unravelling mechanisms and designing methods for restoring and maximizing human functional capacity, and many techniques provide access to neural adjustments (acute changes) or long-term adaptations (chronic changes) underlying changes in movement capabilities. First described by Paul Hoffmann over a century ago, when an electrical stimulus is applied to a peripheral nerve, this causes action potentials in afferent axons, primarily the Ia afferents of the muscle spindles, which recruit homonymous motor neurons, thereby causing an electromyographic response known as the Hoffmann (H) reflex. This technique is a valuable tool in the study of the neuromuscular function in humans and has provided relevant information in the neural control of movement. The large use of the H reflex in motor control research on humans relies in part to its relative simplicity. However, such simplicity masks subtleties that require rigorous experimental protocols and careful data interpretation. After highlighting basic properties and methodological aspects that should be considered for the correct use of the H-reflex technique, this brief narrative review discusses the purpose of the H reflex and emphasizes its use as a tool to assess the effectiveness of Ia afferents in discharging motor neurones. The review also aims to reconsider the link between H-reflex modulation and Ia presynaptic inhibition, the use of the H-reflex technique in motor control studies, and the effects of ageing. These aspects are summarized as recommendations for the use of the H reflex in motor control research on humans.

Trauma, protest, and therapeutic culture in Algeria since the 1980s.

This article focuses on the shift in sensitivities that took place between the 1980s and 2019 toward psychological suffering in Algeria. Promoters of psychotherapy showed an increase in receptivity-via the media, public authorities, and the general population-to their practices and discourses during this period. Based on professional literature, interviews with psychologists, psychiatrists, and psychoanalysts, and newspaper articles and essays, this article considers the following aspects: the use of psychotherapy, the authority of psychoanalytic/psychopathological analyses, and the ethics of relation in politics. Taking a social and cultural history of politics approach, it traces the discontinuous politicization of psychotherapy over the course of events (namely the uprising of 1988, the civil war of the 1990s, and the 2019 popular movement) and examines the interactions between the state, popular mobilizations, and the psychotherapists. The civil war of the 1990s coincided with the normalization of "trauma" on a global scale, and procedures for the prevention of posttraumatic stress disorder were put in place in Algeria from 1997 onwards. In this process of legitimizing psychological suffering and its treatment, the promoters of psychotherapy who belonged to the less visible margins gained authority. The year-long protest movement (2019) against the regime performed the ethics of relation, focusing on human relations, reflexivity, and living together. Promoters of psychotherapy identified consistently with the political subjectivities produced within the 2019 popular movement characterized by massive pacifist marches against the regime.

Effects of tendon vibration and age on force reproduction task performed with wrist flexors.

The sense of force is suggested to rely in part on proprioceptive inputs when assessed with a force reproduction task. The age-related alterations in proprioceptive system could, therefore, alter the sense of force. This study investigated the effects of tendon vibration on a force reproduction task performed with the wrist flexors in 18 young (20-40 year) and 18 older adults (60-90 year). Participants matched a target force (5% or 20% of their maximal force) with visual feedback of the force produced (target phase), and reproduced the target force without visual feedback (reproduction phase) after a 5-s rest period with or without vibration. The force reproduction error was expressed as the ratio between the force produced during the reproduction and the target phases. For the trials with vibration, the error was expressed as the ratio between the force produced during the reproduction phase performed with and without vibration. Tactile acuity was assessed with a two-point discrimination test. The error was greater at 5% than at 20% contraction intensity (p < 0.001), and in older [56.5 (32.2)%; mean (SD)] than in young adults [33.5 (13.6)%] at 5% (p = 0.002) but not 20% target (p = 0.46). Tendon vibration had a greater effect at 5% than 20% contraction intensity, and in older [41.7 (32.4)%, p < 0.001] than young adults [20.0 (16.1)%]. Tactile acuity was lesser in older than young adults (p < 0.001). The results support the contribution of proprioception in the sense of force, and highlight a decrease in performance with ageing restricted to low-force contractions.

Motor learning induces time-dependent plasticity that is observable at the spinal cord level.

KEY POINTS: The spinal cord is an important contributor to motor learning It remains unclear whether short-term spinal cord adaptations are general or task-specific Immediately after task acquisition, neural adaptations were not specific to the trained task (i.e. were general) Twenty-four hours after acquisition, neural adaptations appeared to be task-specific The neural reorganization and generalization of spinal adaptations appears to be time-dependent. ABSTRACT: Spinal cord plasticity is an important contributor of motor learning in humans, although its mechanisms are still poorly documented. In particular, it remains unclear whether short-term spinal adaptations are general or task-specific. As a marker of neural changes that are observable at spinal level, we measured the Hoffmann reflex (H-reflex) amplitude in the soleus muscle of 18 young healthy human adults before, immediately after (acquisition), and 24 h after (retention) the learning of a skilled task (i.e. one-legged stance on a tilt board). H-reflexes were elicited 46 ± 30 ms before touching the tilt board. Additionally, and at the same time points, we measured the H-reflex with the subject sitting at rest and when performing an unskilled and untrained task (i.e. one-legged stance on the floor). After task acquisition, there was a decrease of the H-reflex amplitude measured at rest but not during the skilled or the unskilled task. At retention, there was a decrease of the H-reflex when measured during the skilled task but not during the unskilled task or at rest. Performance increase was not associated with changes in the H-reflex amplitude. After the acquisition of a new skilled task, spinal changes appeared to be general (i.e. observable at rest). However, 24 h after, these changes were task-specific (i.e. observable only during performance of the trained task). These results imply that skill training induces a time-dependent reorganization of the modulation of spinal networks, which possibly reflects a time-dependent optimization of the feedforward motor command.

HEXIM1 Diffusion in the Nucleus Is Regulated by Its Interactions with Both 7SK and P-TEFb.

How nuclear proteins diffuse and find their targets remains a key question in the transcription field. Dynamic proteins in the nucleus are classically subdiffusive and undergo anomalous diffusion, yet the underlying physical mechanisms are still debated. In this study, we explore the contribution of interactions to the generation of anomalous diffusion by the means of fluorescence spectroscopy and simulation. Using interaction-deficient mutants, our study indicates that HEXIM1 interactions with both 7SK RNA and positive transcription elongation factor b are critical for HEXIM1 subdiffusion and thus provides evidence of the effects of protein-RNA interaction on molecular diffusion. Numerical simulations allowed us to establish that the proportions of distinct oligomeric HEXIM1 subpopulations define the apparent anomaly parameter of the whole population. Slight changes in the proportions of these oligomers can lead to significant shifts in the diffusive features and recapitulate the modifications observed in cells with the various interaction-deficient mutants. By combining simulations and experiments, our work opens new prospects in which the anomaly α coefficient in diffusion becomes a helpful tool to infer alterations in molecular interactions.

Age-related changes in leg proprioception: implications for postural control.

In addition to being a prerequisite for many activities of daily living, the ability to maintain steady upright standing is a relevant model to study sensorimotor integrative function. Upright standing requires managing multimodal sensory inputs to produce finely tuned motor output that can be adjusted to accommodate changes in standing conditions and environment. The sensory information used for postural control mainly arises from the vestibular system of the inner ear, vision, and proprioception. Proprioception (sense of body position and movement) encompasses signals from mechanoreceptors (proprioceptors) located in muscles, tendons, and joint capsules. There is general agreement that proprioception signals from leg muscles provide the primary source of information for postural control. This is because of their exquisite sensitivity to detect body sway during unperturbed upright standing that mainly results from variations in leg muscle length induced by rotations around the ankle joint. However, aging is associated with alterations of muscle spindles and their neural pathways, which induce a decrease in the sensitivity, acuity, and integration of the proprioceptive signal. These alterations promote changes in postural control that reduce its efficiency and thereby may have deleterious consequences for the functional independence of an individual. This narrative review provides an overview of how aging alters the proprioceptive signal from the legs and presents compelling evidence that these changes modify the neural control of upright standing.

FRET Image Correlation Spectroscopy Reveals RNAPII-Independent P-TEFb Recruitment on Chromatin.

Biochemical studies have revealed that the RNA Polymerase II (RNAPII) pause release is triggered by phosphorylation of the transcription machinery by the positive transcription elongation factor b (P-TEFb). However, there are no direct report that P-TEFb and RNA polymerase II interact in single living cells and the biophysical mechanisms mediating this association are still unclear. Förster resonance energy transfer (FRET) detects molecular interactions at the subcellular level. Time domain fluorescence lifetime imaging provides an accurate quantification of FRET efficiency, EFRET, because it is fluorochrome concentration-independent and insensitive to fluorescence bleed-through. However, the way FRET signal is usually analyzed does not provide information about the areas where protein-protein interactions take place. In this work, we developed a method, dubbed FRET image correlation spectroscopy (FICS), which relied on FRET fluorescence lifetime imaging image acquisition and image correlation spectroscopy of EFRET clusters to quantify the spatial distribution of interaction clusters in the nucleus. The combination of high content FRET microscopy with batch image analysis allowed a robust statistical analysis. By applying FICS, we characterized the area and density of interaction clusters between P-TEFb and RNAPII or histone H2A in single living cells. The FICS method applied to cells expressing genetically engineered mutated proteins confirmed that the histidine-rich domain of P-TEFb is required for its interaction with RNAPII. Furthermore, it demonstrated that P-TEFb was also located in close vicinity to histone H2A, independently of its interactions with RNAPII. These results support the hypothesis that P-TEFb dynamics on chromatin regulate its recruitment on RNAPII.

Influence of Proprioceptive Inputs and Force Feedback Modality on Force Reproduction Performance.

The sense of force can be assessed using a force reproduction task (FRT), which consists of matching a target force with visual feedback (TARGET phase) and reproducing it without visual feedback (REPRODUCTION phase). We investigated the relevance of muscle proprioception during the TARGET phase (EXP1) and the influence of the sensory source used for the force feedback (EXP2). Accordingly, EXP1 compared the force reproduction error (RE) between trials with (LV) and without (NoLV) local tendon vibration applied on the first dorsal interosseous during the TARGET phase, while EXP2 compared RE between trials performed with visual (VISIO) or auditory (AUDIO) feedback. The FRT was performed with the index finger at 5% and 20% of the maximal force (MVC). RE was greater with LV compared with NoLV at 5% (p = 0.004) but not 20% MVC (p = 0.65). The involvement of muscle proprioception in RFT was further supported by the increase in RE with LV frequency (supplementary experiment). RE was greater for VISIO than AUDIO at 5% (p < 0.001) but not 20% MVC (p = 0.054). This study evidences the relevance of proprioceptive inputs during the target PHASE and the influence of the force feedback modality on RE, and thereby on the assessment of the sense of force.

Epidural Spinal Electrogram Provides Direct Spinal Recordings in Awake Human Participants.

Little is known about the electrophysiological activity of the spinal cord during voluntary movement control in humans. We present a novel method for recording electrophysiological activity from the human spinal cord using implanted epidural electrodes during naturalistic movements including overground walking. Spinal electrograms (SEGs) were recorded from epidural electrodes implanted as part of a test trial for patients with chronic pain undergoing evaluation for spinal cord stimulation. Externalized ends of the epidural leads were connected to an external amplifier to capture SEGs. Electromyographic and accelerometry data from the upper and lower extremities were collected using wireless sensors and synchronized to the SEG data. Patients were instructed to perform various arm and leg movements while SEG and kinematic data were collected. This study proves the safety and feasibility of performing epidural spinal recordings from human subjects performing movement tasks.

[P-TEFb and Brd4: actors of the transcription pause release as therapeutical targets]. / P-TEFb et Brd4 - Acteurs de la levée de pause transcriptionnelle, possibles cibles thérapeutiques.

Most cell physiology events are dictated by the integration of perceived signals and the elaboration by cells of adapted answers via the execution of proper transcriptional programs. In order to ensure an optimal control of these answers, many regulation mechanisms have been selected throughout the evolution, thus allowing to fine-tune transcript expression. The transcriptional pause and its release by P-TEFb (Positive Transcription Elongation Factor) have been evidenced two decades ago. Since then, the importance of such mechanisms has been highlighted by the association between alterations of this machinery and the appearance of diseases. P-TEFb and Brd4 have thus recently emerged as potential therapeutical targets for cancers and AIDS notably. In this review, we present a brief case history and an up-to-date synthesis of models for transcriptional pause release. We later discuss on the pathophysiological processes associated with this mechanism and clinical trials targeting Brd4 and P-TEFb.

The extended cytoplasmic tail of the human B4GALNT2 is critical for its Golgi targeting and post-Golgi sorting.

The Sda /Cad antigen reported on glycoconjugates of human tissues has an increasingly recognized wide impact on the physio-pathology of different biological systems. The last step of its biosynthesis relies on the enzymatic activity of the ß1,4-N-acetylgalactosaminyltransferase-II (B4GALNT2), which shows the highest expression level in healthy colon. Previous studies reported the occurrence in human colonic cells of two B4GALNT2 protein isoforms that differ in the length of their cytoplasmic tail, the long isoform showing an extended 66-amino acid tail. We examined here, the subcellular distribution of the two B4GALNT2 protein isoforms in stably transfected colonic LS174T cells and in transiently transfected HeLa cells using fluorescence microscopy. While a similar subcellular distribution at the trans-Golgi cisternae level was observed for the two isoforms, our study pointed to an atypical subcellular localization of the long B4GALNT2 isoform into dynamic vesicles. We demonstrated a critical role of its extended cytoplasmic tail for its Golgi targeting and post-Golgi sorting and highlighted the existence of a newly described post-Golgi sorting signal as well as a previously undescribed fate of a Golgi glycosyltransferase. DATABASE: The proteins ß1,4GalNAcT II, ß1,4-GalT1, FucT I, FucT VI and ST3Gal IV are noted B4GALNT2, B4GALT1, FUT1, FUT6 and ST3GAL4, whereas the corresponding human genes are noted B4GALNT2, B4GALT1, FUT1, FUT6 and ST3GAL4 according to the HUGO nomenclature.

Strengthening Primary Care Through Family Medicine Around the World Collaborating Toward Promising Practices.

BACKGROUND AND OBJECTIVES: There is a limited evidentiary base on the development of family medicine in different contexts and countries. The lack of evidence impedes our ability to compare and characterize family medicine models and identify areas of success that have led to the effective provision of care. This paper offers a comparative compilation and analysis of the development of family medicine training programs in seven countries: Brazil, Canada, Ethiopia, Haiti, Indonesia, Kenya, and Mali. METHODS: Using qualitative case studies, this paper examines the process of developing family medicine programs, including enabling strategies and barriers, and shared lessons. An appreciative inquiry framework and complex adaptive systems thinking inform our qualitative study. RESULTS: Committed partnerships, the contribution of champions, health policy, and adaptability were identified as key enablers in all seven case studies. The case studies further reveal that some enablers were more salient in certain contexts as compared to others, and that it is the interaction of enablers that is crucial for understanding how and why initiatives succeeded. The barriers that emerged across the seven case studies include: (1) resistance from other medical specialties, (2) lack of resources and capabilities, (3) difficulty in sustaining support of champions, and (4) challenges in brokering effective partnerships. CONCLUSIONS: A key insight from this study is that the implementation of family medicine is nonlinear, dynamic, and complex. The findings of this comparative analysis offer insights and strategies that can inform the design and development of family medicine programs elsewhere.

Intrathecal catheter-associated inflammatory mass in a neurofibromatosis type-1 patient receiving fentanyl and bupivacaine.

BACKGROUND: Catheter-associated inflammatory masses (CIMs) are a rare but serious complication of intrathecal drug delivery devices. CIM formation is influenced by local medication concentration, which is determined in part by flow dynamics at the catheter tip. Underlying spinal pathologies, such as neoplasms, may alter flow at the catheter tip, thereby contributing to CIM formation. Moreover, they may also complicate the clinical and radiologic diagnosis of a CIM. CASE DESCRIPTION: A 36-year-old man with neurofibromatosis type 1 presented to our emergency department with complaints of increased back pain and leg weakness. To treat pain secondary to his multiple spinal masses, he had previously undergone placement of an implantable drug delivery system, which infused a compounded drug of fentanyl and bupivacaine. Imaging studies depicted numerous masses consistent with neurofibromatosis, including a compressive mass located circumferentially at the porous catheter terminus and proximal to the catheter tip. Surgical removal of this mass was performed; pathologic findings were consistent with a catheter tip granuloma. CONCLUSIONS: In the described case, CIM formation likely resulted from a combination of, 1) an unusually high fentanyl concentration, and, 2) altered infusate flow due to spinal neurofibromas. Consideration of underlying spinal pathologies, particularly mass lesions, is critical to the management of intrathecal drug delivery devices.

Genetic deletion and pharmacological inhibition of phosphodiesterase 10A protects mice from diet-induced obesity and insulin resistance.

Phosphodiesterase 10A (PDE10A) is a novel therapeutic target for the treatment of schizophrenia. Here we report a novel role of PDE10A in the regulation of caloric intake and energy homeostasis. PDE10A-deficient mice are resistant to diet-induced obesity (DIO) and associated metabolic disturbances. Inhibition of weight gain is due to hypophagia after mice are fed a highly palatable diet rich in fats and sugar but not a standard diet. PDE10A deficiency produces a decrease in caloric intake without affecting meal frequency, daytime versus nighttime feeding behavior, or locomotor activity. We tested THPP-6, a small molecule PDE10A inhibitor, in DIO mice. THPP-6 treatment resulted in decreased food intake, body weight loss, and reduced adiposity at doses that produced antipsychotic efficacy in behavioral models. We show that PDE10A inhibition increased whole-body energy expenditure in DIO mice fed a Western-style diet, achieving weight loss and reducing adiposity beyond the extent seen with food restriction alone. Therefore, chronic THPP-6 treatment conferred improved insulin sensitivity and reversed hyperinsulinemia. These data demonstrate that PDE10A inhibition represents a novel antipsychotic target that may have additional metabolic benefits over current medications for schizophrenia by suppressing food intake, alleviating weight gain, and reducing the risk for the development of diabetes.

Antidiabetic properties of the histamine H3 receptor protean agonist proxyfan.

Proxyfan is a histamine H3 receptor protean agonist that can produce a spectrum of pharmacological effects including agonist, inverse agonist, and antagonist. We have discovered that proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip glucose tolerance test in either lean or high-fat/cholesterol diet-induced obese mice. It also reduced plasma glucose levels comparable to that of metformin (300 mg/kg orally) in a nongenetic type 2 diabetes mouse model. The dose-dependent decrease in glucose excursion correlated with inhibition of ex vivo H3 receptor binding in the cerebral cortex. In addition, glucose levels were significantly reduced compared with vehicle-treated mice after intracerebroventricular administration of proxyfan, suggesting the involvement of central H3 receptors. Proxyfan-induced reduction of glucose excursion was not observed in the H3 receptor knockout mice, suggesting that proxyfan mediates this effect through H3 receptors. Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels in a glucose-independent manner. However, no difference in insulin sensitivity was observed in proxyfan-treated mice. The H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist zolantidine had modest effects on glucose excursion, and neither inhibited the glucose excursion reduced by proxyfan. The H3 receptor antagonist/inverse agonist, thioperamide, had weaker effects on glucose excursion compared with proxyfan, whereas the H3 receptor agonist imetit did not affect glucose excursion. In conclusion, these findings demonstrate, for the first time, that manipulation of central histamine H3 receptor by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose-independent mechanism.

Energy metabolic profile of mice after chronic activation of central NPY Y1, Y2, or Y5 receptors.

OBJECTIVE: Neuropeptide Y (NPY), a 36-amino acid peptide with orexigenic properties, is expressed abundantly in the central nervous system and binds to several NPY receptor subtypes. This study examines the roles of the NPY Y1, Y2, and Y5 receptor(s) in energy homeostasis. RESEARCH METHODS AND PROCEDURES: We administered intracerebroventricular NPY (3 microg/d) or selective peptide agonists for the Y1, Y2, and Y5 receptor subtypes to C57Bl/6 mice for 6 days by mini-osmotic pumps to assess the role of each receptor subtype in NPY-induced obesity. Energy expenditure (EE) and respiratory quotient (RQ) were studied using indirect calorimetry. Adiposity was measured by DXA scanning and fat pad dissection. Insulin sensitivity was tested by whole-blood glucose measurement after an insulin challenge. RESULTS: Central administration of the selective Y1 agonist, Y5 agonist, or NPY for 6 days in mice significantly increased body weight, adiposity, and RQ, with significant hyperphagia in the Y5 agonist- and NPY-treated groups but not in the Y1 agonist-treated group. The NPY, Y1, or Y5 agonist-treated mice had little change in total EE during ad libitum and pair-feeding conditions. Conversely, selective activation of the Y2 receptor reduced feeding and resulted in a significant, but transient, weight loss. DISCUSSION: Central activation of both Y1 and Y5 receptors increases RQ and adiposity, whereas only Y5 receptor activation reduces energy expended per energy ingested. Selective activation of Y2 autoreceptors leads to hypophagia and transient weight loss, with little effect on total EE. Our study indicates that all three NPY receptor subtypes may play a role in regulating energy homeostasis in mice.