Lifespan extension with preservation of hippocampal function in aged system xc--deficient male mice.

The cystine/glutamate antiporter system xc- has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT-/-) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT-/- mice led to the hypothesis that system xc- deletion would negatively affect life- and healthspan. Still, till now the role of system xc- in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT-/- mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT+/+ mice, was attenuated in xCT-/- mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT-/- mice. Targeting system xc- is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.

Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity.

Extensive research has uncovered diverse forms of synaptic plasticity and an array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cyclic 3',5'-cyclic adenosine monophosphate (cAMP)-dependent signaling pathways are crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of Popeye domain-containing protein 1 (POPDC1) (or blood vessel epicardial substance (BVES)), a cAMP effector protein, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as protein kinase A (PKA) and exchange factor directly activated by cAMP, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains, suggesting that POPDC1 may have an unique role in cAMP-mediated signaling. Our results show that Popdc1 is widely expressed in various brain regions including the hippocampus. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit PKA-dependent enhancement in CA1 long-term potentiation (LTP) in response to weaker stimulation paradigms, which in slices from wild-type mice induce only transient LTP. Loss of POPDC1, while not affecting basal transmission or input-specificity of LTP, results in altered response during high-frequency stimulation. Popdc1 KO mice also show enhanced forskolin-induced potentiation. Overall, these findings reveal POPDC1 as a novel negative regulator of hippocampal synaptic plasticity and, together with recent evidence for its interaction with phosphodiesterases (PDEs), suggest that POPDC1 is involved in modulating activity-dependent local cAMP-PKA-PDE signaling.

Electrophysiological alterations of the Purkinje cells and deep cerebellar neurons in a mouse model of Alzheimer disease (electrophysiology on cerebellum of AD mice).

Alzheimer's disease is histopathologically well defined by the presence of amyloid deposits and tau-related neurofibrillary tangles in crucial regions of the brain. Interest is growing in revealing and determining possible pathological markers also in the cerebellum as its involvement in cognitive functions is now well supported. Despite the central position of the Purkinje cell in the cerebellum, its electrophysiological behaviour in mouse models of Alzheimer's disease is scarce in the literature. Our first aim was here to focus on the electrophysiological behaviour of the cerebellum in awake mouse model of Alzheimer's disease (APPswe/PSEN1dE9) and the related performance on the water-maze test classically used in behavioural studies. We found prevalent signs of electrophysiological alterations in both Purkinje cells and deep cerebellar nuclei neurons which might explain the behavioural deficits reported during the water-maze test. The alterations of neurons firing were accompanied by a dual (~16 and ~228 Hz) local field potential's oscillation in the Purkinje cell layer of Alzheimer's disease mice which was concomitant to an important increase of both the simple and the complex spikes. In addition, ß-amyloid deposits were present in the molecular layer of the cerebellum. These results highlight the importance of the output firing modification of the AD cerebellum that may indirectly impact the activity of its subcortical and cortical targets.

Corticostriatal dysfunction and social interaction deficits in mice lacking the cystine/glutamate antiporter.

The astrocytic cystine/glutamate antiporter system xc- represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system xc-, xCT (xCT-/- mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT-/- mice. A proteomic and kinomic screen of the striatum of xCT-/- mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT-/- mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system xc- plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior.

Trace Amine Associate Receptor 1 (TAAR1) as a New Target for the Treatment of Cognitive Dysfunction in Alzheimer's Disease.

Worldwide, approximately 27 million people are affected by Alzheimer's disease (AD). AD pathophysiology is believed to be caused by the deposition of the ß-amyloid peptide (Aß). Aß can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory and involves postsynaptic glutamate receptor phosphorylation and trafficking. Moreover, Aß seems to be able to reduce glutamatergic transmission by increasing the endocytosis of NMDA receptors. Trace amines (TAs) are biogenic amines that are structurally similar to monoamine neurotransmitters. TAs bind to G protein-coupled receptors, called TAARs (trace amine-associated receptors); the best-studied member of this family, TAAR1, is distributed in the cortical and limbic structures of the CNS. It has been shown that the activation of TAAR1 can rescue glutamatergic hypofunction and that TAAR1 can modulate glutamate NMDA receptor-related functions in the frontal cortex. Several lines of evidence also suggest the pro-cognitive action of TAAR1 agonists in various behavioural experimental protocols. Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aß-induced dysfunction. Furthermore, we investigated, in vivo, the role of TAAR1 in cognitive dysfunction induced by Aß infusion in Aß-treated mice. In vitro data showed that Aß 1-42 significantly decreased NMDA cell surface expression while the TAAR1 agonist RO5256390 promoted their membrane insertion in cortical cells. In vivo, RO5256390 showed a mild pro-cognitive effect, as demonstrated by the better performance in the Y maze test in mice treated with Aß. Further studies are needed to better understand the interplay between TAAR1/Aß and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aß-induced cognitive impairments, such as AD.

Endogenous Synthesis of Tetrahydroisoquinoline Derivatives from Dietary Factors: Neurotoxicity Assessment on a 3D Neurosphere Culture.

Tetrahydroisoquinoline (THIQ) alkaloids and their derivatives have a structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-known neurotoxin. THIQs seem to present a broad range of actions in the brain, critically dependent on their catechol moieties and metabolism. These properties make it reasonable to assume that an acute or chronic exposure to some THIQs might lead to neurodegenerative diseases including essential tremor (ET). We developed a method to search for precursor carbonyl compounds produced during the Maillard reaction in overcooked meats to study their reactivity with endogenous amines and identify the reaction products. Then, we predicted in silico their pharmacokinetic and toxicological properties toward the central nervous system. Finally, their possible neurological effects on a novel in vitro 3D neurosphere model were assessed. The obtained data indicate that meat is an alkaloid precursor, and we identified the alkaloid 1-benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol (1-benz-6,7-diol THIQ) as the condensation product of phenylacetaldehyde with dopamine; in silico study of 1-benz-6,7-diol-THIQ reveals modulation of dopamine receptor D1 and D2; and in vitro study of 1-benz-6,7-diol-THIQ for cytotoxicity and oxidative stress induction does not show any difference after 24 h contact for all tested concentrations. To conclude, our in vitro data do not support an eventual neurotoxic effect for 1-benz-6,7-diol-THIQ.

Olfactory and gustatory dysfunctions as a clinical presentation of mild-to-moderate forms of the coronavirus disease (COVID-19): a multicenter European study.

OBJECTIVE: To investigate the occurrence of olfactory and gustatory dysfunctions in patients with laboratory-confirmed COVID-19 infection. METHODS: Patients with laboratory-confirmed COVID-19 infection were recruited from 12 European hospitals. The following epidemiological and clinical outcomes have been studied: age, sex, ethnicity, comorbidities, and general and otolaryngological symptoms. Patients completed olfactory and gustatory questionnaires based on the smell and taste component of the National Health and Nutrition Examination Survey, and the short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS). RESULTS: A total of 417 mild-to-moderate COVID-19 patients completed the study (263 females). The most prevalent general symptoms consisted of cough, myalgia, and loss of appetite. Face pain and nasal obstruction were the most disease-related otolaryngological symptoms. 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders (p < 0.001). Olfactory dysfunction (OD) appeared before the other symptoms in 11.8% of cases. The sQO-NS scores were significantly lower in patients with anosmia compared with normosmic or hyposmic individuals (p = 0.001). Among the 18.2% of patients without nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0%. Females were significantly more affected by olfactory and gustatory dysfunctions than males (p = 0.001). CONCLUSION: Olfactory and gustatory disorders are prevalent symptoms in European COVID-19 patients, who may not have nasal symptoms. The sudden anosmia or ageusia need to be recognized by the international scientific community as important symptoms of the COVID-19 infection.

A proteomic analysis of contextual fear conditioned rats reveals dynamic modifications in neuron and oligodendrocyte protein expression in the dentate gyrus.

Contextual memory is an intricate process involving synaptic plasticity and network rearrangement. Both are governed by many molecular processes including phosphorylation and modulation of protein expression. However, little is known about the molecules involved in it. Here, we exploited the advantages of a quantitative proteomic approach to identify a great number of molecules in the rat dentate gyrus after a contextual fear conditioning session. Our results allowed us to highlight protein expression patterns, not only related to neuroplasticity, but also to myelin structure, such as myelin basic protein and myelin proteolipid protein showing a decrease in expression. Validation of the modification in protein expression reveals a dynamic profile during the 48 h following the fear conditioning session. The expression of proteins involved in neurite outgrowth, such as BASP-1 and calcineurin B1, and in synaptic structure and function, VAMP2 and RAB3C, was increased in the dentate gyrus of rats submitted to fear conditioning compared to controls. We showed that the increase in BASP-1 protein was specific to fear conditioning learning as it was not present in immediate-shock rats, neither in rats exposed to a novel environment without being shocked. As myelin is known to stabilise synaptic network, the decrease in myelin proteins suggests a neuroglia interactive process taking place in the dentate gyrus in the 24 h following contextual fear learning, which has never been demonstrated before. These results therefore open the way to the study of new plasticity mechanisms underlying learning and memory.

Regional and time-dependent neuroprotective effect of hypothermia following oxygen-glucose deprivation.

The neuroprotective effect of hypothermia has been demonstrated in in vivo and in vitro models of cerebral ischemia. In regard to the hippocampus, previous studies have mainly focused on CA1 pyramidal neurons, which are very vulnerable to ischemia. But the dentate gyrus (DG), in which neuronal proliferation occurs, can also be damaged by ischemia. In this study, we explored the neuroprotective effect of postischemic hypothermia in different areas of the hippocampus after mild or severe ischemia. Organotypic hippocampal slice cultures were prepared from 6- to 8-day-old rats and maintained for 12 days. Cultures were exposed to 25 or 35 min of oxygen and glucose deprivation (OGD). Neuronal damage was quantified after 6, 24, 48, and 72 h by propidium iodide fluorescence. Mild hypothermia (33°C) was induced 1 h after the end of OGD and was maintained for a period of 24 h. Short OGD produced delayed neuronal damage in the CA1 area and in the DG and to a lesser extend in the CA3 area. Damage in CA1 pyramidal cells was totally prevented by hypothermia whereas neuroprotection was limited in the DG. Thirty-five-minute OGD induced more rapid and more severe cell death in the three regions. In this case, hypothermia induced 1 h after OGD was unable to protect CA1 pyramidal cells whereas hypothermia induced during OGD was able to prevent cell loss. This study provides evidence that neuroprotection by hypothermia is limited to specific areas and depends on the severity of the ischemia.

Templated misfolding of Tau by prion-like seeding along neuronal connections impairs neuronal network function and associated behavioral outcomes in Tau transgenic mice.

Prion-like seeding and propagation of Tau-pathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. However, the involvement of templated misfolding of Tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Here we analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice. Spontaneous and GABA(A)R-antagonist-induced neuronal network activity were affected following templated Tau-misfolding using synthetic preformed Tau fibrils in cultured primary neurons. Electrophysiological analysis in organotypic hippocampal slices of Tau transgenic mice demonstrated impaired synaptic transmission and impaired long-term potentiation following Tau-seed induced Tau-aggregation. Intracerebral injection of Tau-seeds in TauP301S mice, caused prion-like spreading of Tau-pathology through functionally connected neuroanatomical pathways. Electrophysiological analysis revealed impaired synaptic plasticity in hippocampal CA1 region 6 months after Tau-seeding in entorhinal cortex (EC). Furthermore, templated Tau aggregation impaired cognitive function, measured in the object recognition test 6 months post-seeding. In contrast, Tau-seeding in basal ganglia and subsequent spreading through functionally connected neuronal networks involved in motor control, resulted in motoric deficits reflected in clasping and impaired inverted grid hanging, not significantly affected following Tau-seeding in EC. Immunostaining, biochemical and electron microscopic analysis in the different models suggested early pathological forms of Tau, including Tau-oligomers, rather than fully mature neurofibrillary tangles (NFTs) as culprits of neuronal dysfunction. We here demonstrate for the first time using in vitro, ex vivo and in vivo models, that prion-like spreading of Tau-misfolding by Tau seeds, along unique neuronal connections, causes neuronal network dysfunction and associated behavioral dysfunction. Our data highlight the potential relevance of this mechanism in the symptomatic progression in Tauopathies. We furthermore demonstrate that the initial site of Tau-seeding thereby determines the behavioral outcome, potentially underlying the observed heterogeneity in (familial) Tauopathies, including in TauP301 mutants.

Tauopathy contributes to synaptic and cognitive deficits in a murine model for Alzheimer's disease.

Tau alterations are now considered an executor of neuronal demise and cognitive dysfunction in Alzheimer's disease (AD). Mouse models combining amyloidosis and tauopathy and their parental counterparts are important tools to further investigate the interplay of abnormal amyloid-ß (Aß) and Tau species in pathogenesis, synaptic and neuronal dysfunction, and cognitive decline. Here, we crossed APP/PS1 mice with 5 early-onset familial AD mutations (5xFAD) and TauP301S (PS19) transgenic mice, denoted F(+)/T(+) mice, and phenotypically compared them to their respective parental strains, denoted F(+)/T(-) and F(-)/T(+) respectively, as controls. We found dramatically aggravated tauopathy (~10-fold) in F(+)/T(+) mice compared to the parental F(-)/T(+) mice. In contrast, amyloidosis was unaltered compared to the parental F(+)/T(-) mice. Tauopathy was invariably and very robustly aggravated in hippocampal and cortical brain regions. Most important, F(+)/T(+) displayed aggravated cognitive deficits in a hippocampus-dependent spatial navigation task, compared to the parental F(+)/T(-) strain, while parental F(-)/T(+) mice did not display cognitive impairment. Basal synaptic transmission was impaired in F(+)/T(+) mice compared to nontransgenic mice and the parental strains (≥40%). Finally, F(+)/T(+) mice displayed a significant hippocampal atrophy (~20%) compared to nontransgenic mice, in contrast to the parental strains. Our data indicate for the first time that pathological Aß species (or APP/PS1) induced changes in Tau contribute to cognitive deficits correlating with synaptic deficits and hippocampal atrophy in an AD model. Our data lend support to the amyloid cascade hypothesis with a role of pathological Aß species as initiator and pathological Tau species as executor.

Long-term potentiation can be induced in the CA1 region of hippocampus in the absence of αCaMKII T286-autophosphorylation.

α-calcium/calmodulin-dependent protein kinase (αCaMKII) T286-autophosphorylation provides a short-term molecular memory that was thought to be required for LTP and for learning and memory. However, it has been shown that learning can occur in αCaMKII-T286A mutant mice after a massed training protocol. This raises the question of whether there might be a form of LTP in these mice that can occur without T286 autophosphorylation. In this study, we confirmed that in CA1 pyramidal cells, LTP induced in acute hippocampal slices, after a recovery period in an interface chamber, is strictly dependent on postsynaptic αCaMKII autophosphorylation. However, we demonstrated that αCaMKII-autophosphorylation-independent plasticity can occur in the hippocampus but at the expense of synaptic specificity. This nonspecific LTP was observed in mutant and wild-type mice after a recovery period in a submersion chamber and was independent of NMDA receptors. Moreover, when slices prepared from mutant mice were preincubated during 2 h with rapamycin, high-frequency trains induced a synapse-specific LTP which was added to the nonspecific LTP. This specific LTP was related to an increase in the duration and the amplitude of NMDA receptor-mediated response induced by rapamycin.

Mechanism for long-term memory formation when synaptic strengthening is impaired.

Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with training-induced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.

Stretch-injury promotes microglia activation with enhanced phagocytic and synaptic stripping activities.

Microglial cells, as the primary defense line in the central nervous system, play a crucial role in responding to various mechanical signals that can trigger their activation. Despite extensive research on the impact of chemical signaling on brain cells, the understanding of mechanical signaling in microglia remains limited. To bridge this gap, we subjected microglial cells to a singular mechanical stretch and compared their responses with those induced by lipopolysaccharide treatment, a well-established chemical activator. Here we show that stretching microglial cells leads to their activation, highlighting their significant mechanosensitivity. Stretched microglial cells exhibited distinct features, including elevated levels of Iba1 protein, a denser actin cytoskeleton, and increased persistence in migration. Unlike LPS-treated microglial cells, the secretory profile of chemokines and cytokines remained largely unchanged in response to stretching, except for TNF-α. Intriguingly, a single stretch injury resulted in more compacted chromatin and DNA damage, suggesting potential long-term genomic instabilities in stretched microglia. Using compartmentalized microfluidic chambers with neuronal networks, we observed that stretched microglial cells exhibited enhanced phagocytic and synaptic stripping activities. These findings collectively suggest that stretching events can unlock the immune potential of microglial cells, contributing to the maintenance of brain tissue homeostasis following mechanical injury.

Nucleus incertus provides eye velocity and position signals to the vestibulo-ocular cerebellum: a new perspective of the brainstem-cerebellum-hippocampus network.

The network formed by the brainstem, cerebellum, and hippocampus occupies a central position to achieve navigation. Multiple physiological functions are implicated in this complex behavior. Among these, control of the eye-head and body movements is crucial. The gaze-holding system realized by the brainstem oculomotor neural integrator (ONI) situated in the nucleus prepositus hypoglossi and fine-tuned by the contribution of different regions of the cerebellum assumes the stability of the image on the fovea. This function helps in the recognition of environmental targets and defining appropriate navigational pathways further elaborated by the entorhinal cortex and hippocampus. In this context, an enigmatic brainstem area situated in front of the ONI, the nucleus incertus (NIC), is implicated in the dynamics of brainstem-hippocampus theta oscillation and contains a group of neurons projecting to the cerebellum. These neurons are characterized by burst tonic behavior similar to the burst tonic neurons in the ONI that convey eye velocity-position signals to the cerebellar flocculus. Faced with these forgotten cerebellar projections of the NIC, the present perspective discusses the possibility that, in addition to the already described pathways linking the cerebellum and the hippocampus via the medial septum, these NIC signals related to the vestibulo-ocular reflex and gaze holding could participate in the hippocampal control of navigation.

Low-back related leg pain: is the nerve guilty? How to differentiate the underlying pain mechanism.

Low back pain (LBP) that radiates to the leg is not always related to a lesion or a disease of the nervous system (neuropathic pain): it might be nociceptive (referred) pain. Unfortunately, patients with low-back related leg pain are often given a variety of diagnoses (e.g. 'sciatica'; 'radicular pain'; pseudoradicular pain"). This terminology causes confusion and challenges clinical reasoning. It is essential for clinicians to understand and recognize predominant pain mechanisms. This paper describes pain mechanisms related to low back-related leg pain and helps differentiate these mechanisms in practice using clinical based scenarios. We illustrate this by using two clinical scenarios including patients with the same symptoms in terms of pain localization (i.e. low-back related leg pain) but with different underlying pain mechanisms (i.e. nociceptive versus neuropathic pain).

Enhancing OSA Assessment with Explainable AI.

Explainable Artificial Intelligence (xAI) is a rapidly growing field that focuses on making deep learning models interpretable and understandable to human decision-makers. In this study, we introduce xAAEnet, a novel xAI model applied to the assessment of Obstructive Sleep Apnea (OSA) severity. OSA is a prevalent sleep disorder that can lead to numerous medical conditions and is currently assessed using the Apnea-Hypopnea Index (AHI). However, AHI has been criticized for its inability to accurately estimate the effect of OSAs on related medical conditions. To address this issue, we propose a human-centric xAI approach that emphasizes similarity between apneic events as a whole and reduces subjectivity in diagnosis by examining how the model makes its decisions. Our model was trained and tested on a dataset of 60 patients' Polysomnographic (PSG) recordings. Our results demonstrate that the proposed model, xAAEnet, outperforms models with traditional architectures such as convolutional regressor, autoencoder (AE), and variational autoencoder (VAE). This study highlights the potential of xAI in providing an objective OSA severity scoring method.Clinical relevance- This study provides an objective OSA severity scoring technique which could improve the management of apneic patients in clinical practice.

Management of Low Back Pain: Do Physiotherapists Know the Evidence-Based Guidelines?

BACKGROUND: Clinical practice guidelines promote bio-psychosocial management of patients suffering from low back pain (LBP). The objective of this study was to examine the current knowledge, attitudes and beliefs of physiotherapists about a guideline-adherent approach to LBP and to assess the ability of physiotherapists to recognise signs of a specific LBP in a clinical vignette. METHODS: Physiotherapists were recruited to participate in an online study. They were asked to indicate whether they were familiar with evidence-based guidelines and then to fill in the Health Care Providers' Pain and Impairment Relationship Scale (HC-PAIRS), Back Pain Attitudes Questionnaire (Back-PAQ), Neurophysiology of Pain Questionnaire (NPQ), as well as questions related to two clinical vignettes. RESULTS: In total, 527 physiotherapists participated in this study. Only 38% reported being familiar with guidelines for the management of LBP. Sixty-three percent of the physiotherapists gave guideline-inconsistent recommendations regarding work. Only half of the physiotherapists recognised the signs of a specific LBP. CONCLUSIONS: The high proportion of physiotherapists unfamiliar with guidelines and demonstrating attitudes and beliefs not in line with evidence-based management of LBP is concerning. It is crucial to develop efficient strategies to enhance knowledge of guidelines among physiotherapists and increase their implementation in clinical practice.

Modulation of Cytosolic Phospholipase A2 as a Potential Therapeutic Strategy for Alzheimer's Disease.

Background: Alzheimer's disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA2-IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach. Objective: A cPLA2-IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy. Methods: We targeted the cPLA2-IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic acid dosage [AA], cPLA2-IVA cellular translocation) before being tested in vivo. We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA2-IVA itself, the NMDA receptor, AßPP and tau by IHC after i.v. injection in APP/PS1 mice. Results: Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA2-IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA2-IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation. Conclusions: cPLA2-IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD.

Erectile dysfunction in copper and cobalt miners: a cross-sectional study in the former Katanga province, Democratic Republic of the Congo.

Background: The African Copperbelt is a site of intense artisanal and industrial mining and refining of copper and cobalt. Aim: We aimed to investigate factors that are possibly associated with erectile dysfunction (ED) in metal miners in the former Katanga province of the Democratic Republic of the Congo. Methods: In a cross-sectional study of 138 miners and 139 controls (bakers), we administered questionnaires to obtain sociodemographic and occupational data and to assess male sexual function (International Index of Erectile Function [IIEF]) and marital relation quality (Revised Dyadic Adjustment Scale). Furthermore, we measured trace metals in blood and urine, as well as testosterone and thyroid hormones in serum. Outcomes: Outcomes included the prevalence of questionnaire-derived ED and the relation of ED with individual characteristics, serum testosterone, and environmental factors. Results: Miners were on average 4 years older than bakers (mean ± SD, 37.5 ± 6.9 vs 33.3 ± 5.7 years). Miners had significantly lower scores than bakers on the IIEF (median [IQR], 66 [49-73] vs 73 [66-74]) and the 3 domains of the Revised Dyadic Adjustment Scale (consensus, satisfaction, cohesion). Free testosterone was significantly lower in miners than bakers (ng/dL; 8.11 [6.90-10.10] vs 10.52 [8.83-12.58]; P ˂ .001). In miners, sex hormone-binding globulin correlated positively with blood Pb and urinary Cd. In a multivariable analysis, mild to moderate ED or moderate ED (IIEF-erectile function score ≤18) was significantly associated with having a mining-related job (adjusted odds ratio [aOR], 2.6; 95% CI, 1.3-5.3), work seniority ˃5 years (aOR, 2.3; 95% CI, 1.1-4.6), alcohol consumption (aOR, 2.8; 95% CI, 1.2-6.7), and aphrodisiacs use (aOR, 4.2; 95% CI, 2.2-8.0). Mediation analysis showed that marital relationship partially mediated the relation between work seniority >5 years in mining and ED. Clinical Implications: The high prevalence of ED found in artisanal mine workers indicates that work-related factors should be considered as possibly contributing, directly or indirectly, to sexual dysfunction in men. Strengths and Limitations: Strengths include being the first epidemiologic study documenting ED with validated questionnaires and its possible determinants, including exposure to toxic metals, among young artisanal miners vs a suitable control group. Limitations are the cross-sectional design with convenience sampling and absence of objective confirmation of ED. Conclusion: As compared with controls, miners reported poorer sexual function and lower quality of their marital relationship, and they had lower free testosterone levels, which may be due to their high exposure to trace metals.