Enhanced interest in letters and numbers in autistic children.

BACKGROUND: An intense and precocious interest in written material, together with a discrepancy between decoding and reading comprehension skills are defining criteria for hyperlexia, which is found in up to 20% of autistic individuals. It may represent the extreme end of a broader interest in written material in autism. This study examines the magnitude and nature of the interest in written material in a large population of autistic and non-autistic children. METHODS: All 701 children (391 autistic, 310 non-autistic) under the age of 7 referred to an autism assessment clinic over a span of 4 years were included. Ordinal logistic regressions assessed the association between diagnosis and the level of interest in letters and numbers. A nested sample of parents of 138 autistic, 99 non-autistic clinical, and 76 typically developing (TD) children completed a detailed questionnaire. Cox proportional hazards models analyzed the age of emergence of these interests. Linear regressions evaluated the association between diagnosis and interest level. The frequency of each behaviour showing interest and competence with letters and numbers were compared. RESULTS: In the two studies, 22 to 37% of autistic children had an intense or exclusive interest in letters. The odds of having a greater interest in letters was 2.78 times higher for autistic children than for non-autistic clinical children of the same age, and 3.49 times higher for the interest in numbers, even if 76% of autistic children were minimally or non-verbal. The age of emergence of these interests did not differ between autistic and TD children and did not depend on their level of oral language. Non-autistic children showed more interest in letters within a social context. LIMITATIONS: The study holds limitations inherent to the use of a phone questionnaire with caregivers and missing sociodemographic information. CONCLUSIONS: The emergence of the interest of autistic children toward written language is contemporaneous to the moment in their development where they display a strong deficit in oral language. Together with recent demonstrations of non-social development of oral language in some autistic children, precocious and intense interest in written material suggests that language acquisition in autism may follow an alternative developmental pathway.

Plasmonic Properties of Self-Assembled Gold Nanocrescents: Implications for Chemical Sensing.

A bottom-up approach, the Langmuir-Blodgett technique, is used for the preparation of composite thin films of gold nanoparticles and polymers: poly(styrene-b-2-vinylpyridine), poly-2-vinylpyridine, and polystyrene. The self-assembly of poly(styrene-b-2-vinylpyridine) at the air-water interface leads to the formation of surface micelles, which serve as a template for the organization of gold nanoparticles into ring assemblies. By using poly-2-vinylpyridine in conjunction with low surface pressure, the distance between nanostructures can be increased, allowing for optical characterization of single nanostructures. Once deposited on a solid substrate, the preorganized gold nanoparticles are subjected to further growth by the reduction of additional gold, leading to a variety of nanostructures which can be divided into two categories: nanocrescents and circular arrays of nanoparticles. The optical properties of individual structures are investigated by optical dark-field spectroscopy and numerical calculations. The plasmonic behavior of the nanostructures is elucidated through the correlation of optical properties with structural features and the identification of dominant plasmon modes. Being based on a self-assembly approach, the reported method allows for the formation of interesting plasmonic materials under ambient conditions, at a relatively large scale, and at low cost. These attributes, in addition to the resonances located in the near-infrared region of the spectrum, make nanocrescents candidates for biological and chemical sensing.

Multi-session transcutaneous spinal cord stimulation prevents chloride homeostasis imbalance and the development of hyperreflexia after spinal cord injury in rat.

Spasticity is a complex and multidimensional disorder that impacts nearly 75% of individuals with spinal cord injury (SCI) and currently lacks adequate treatment options. This sensorimotor condition is burdensome as hyperexcitability of reflex pathways result in exacerbated reflex responses, co-contractions of antagonistic muscles, and involuntary movements. Transcutaneous spinal cord stimulation (tSCS) has become a popular tool in the human SCI research field. The likeliness for this intervention to be successful as a noninvasive anti-spastic therapy after SCI is suggested by a mild and transitory improvement in spastic symptoms following a single stimulation session, but it remains to be determined if repeated tSCS over the course of weeks can produce more profound effects. Despite its popularity, the neuroplasticity induced by tSCS also remains widely unexplored, particularly due to the lack of suitable animal models to investigate this intervention. Thus, the basis of this work was to use tSCS over multiple sessions (multi-session tSCS) in a rat model to target spasticity after SCI and identify the long-term physiological improvements and anatomical neuroplasticity occurring in the spinal cord. Here, we show that multi-session tSCS in rats with an incomplete (severe T9 contusion) SCI (1) decreases hyperreflexia, (2) increases the low frequency-dependent modulation of the H-reflex, (3) prevents potassium-chloride cotransporter isoform 2 (KCC2) membrane downregulation in lumbar motoneurons, and (4) generally augments motor output, i.e., EMG amplitude in response to single pulses of tSCS, particularly in extensor muscles. Together, this work displays that multi-session tSCS can target and diminish spasticity after SCI as an alternative to pharmacological interventions and begins to highlight the underlying neuroplasticity contributing to its success in improving functional recovery.

Integrating accompanying patients into clinical oncology teams: limiting and facilitating factors.

OBJECTIVES: Since 2018, four establishments in Quebec have been instrumental in implementing the PAROLE-Onco program, which introduced accompanying patients (APs) into healthcare teams to improve cancer patients' experience. APs are patient advisors who have acquired specific experiential knowledge related to living with cancer, using services, and interacting with healthcare professionals. They are therefore in a unique and reliable position to be able to provide emotional, informational, cognitive and navigational support to patients who are dealing with cancer. We aimed to explore APs' perspectives regarding the limiting and facilitating factors in terms of how they are integrated into the clinical oncology teams. METHODS: A qualitative study based on semi-structured interviews and focus groups was conducted with 20 APs at the beginning of their intervention (T1) and, two years later, during a second data collection (T2). Limiting and facilitating factors of APs' integration into clinical teams were analyzed in terms of governance, culture, resources and tools. RESULTS: The limited factors raised by APs to be integrated into clinical teams include the following: confusion about the specific roles played by APs, lifting the egos of certain professionals who feel they are already doing what APs typically do, lack of identification of patient needs, absence of APs in project governance organizational boundaries, and team members' availability. Various communication challenges were also raised, resulting in the program being inadequately promoted among patients. Also mentioned as limiting factors were the lack of time, space and compensation. Creating opportunities for team members to meet with APs, building trust and teaching team members how APs' activities complement theirs were enhancing factors. Other facilitators include APs being involved in decision-making committees, being leaders in promoting the PAROLE-Onco program to patients and clinical team members and creating opportunities to communicate with team members to help enhance their work and provide feedback to improve patient services. Awareness of APs' added value for the team and patients is also a key facilitator. Regarding tools, offering accompanying services by telephone allows both patients and APs to benefit from the flexibility they need. CONCLUSION: Over time, APs were able to identify optimal factors for successful implementation. Recommendations include APs and professionals working in co-construction on organization, leadership, resources and status factors. This could help catalyze a change in culture within health establishments and allow people dealing with cancer to benefit from the experiential knowledge of other patients within their clinical team.

An integrated strategy involving high-throughput sequencing to characterize an unknown GM wheat event in Canada.

Glyphosate-resistant wheat plants were discovered in southern Alberta in 2017, representing an unauthorized GM release in Canada. The Canadian Food Inspection Agency undertook a series of experiments to characterize and identify this unknown GM wheat, as well as to develop and validate construct-specific and event-specific qPCR assays. Results of PCR-based assays and Sanger sequencing indicated the presence of CaMV 35S promoter (p35S), Rice Actin 1 intron (RactInt1), CP4-EPSPS gene and nopaline synthase terminator (tNOS) elements in the unknown GM wheat. Genome walking and bead capture strategies, combined with high-throughput sequencing, were used to identify the 5' and 3' wheat junctions and the subsequent mapping of the insert to chromosome 3B of the wheat genome. A probable transformation vector, pMON25497, was recognized, and further testing identified the unknown GM wheat as MON71200 event, one of two events obtained with the pMON25497 vector. The two construct-specific assays targeted the junctions of the RactInt1 and the CP4-EPSPS elements and the CP4-EPSPS and tNOS elements, while the event-specific assay was located at the 3' junction into the wheat genome. Both construct-specific and event-specific assays had limits of detection of 0.10% of MON71200 in a seed pool. As expected, the two construct-specific assays cross-reacted with other wheat and corn events containing the same elements in the same order. No cross-reactivity was observed for the event-specific assay. The integrated strategy employed in this study can serve as a model for other cases when facing similar challenges involving unknown GM events.

Prevalence and incidence of narcolepsy symptoms in the US general population.

Objective: The objectives of this study are to evaluate the prevalence and incidence of Narcolepsy type 1 and type 2 and to determine the prevalence of narcolepsy diagnosis criteria in the US general population. Methods: This longitudinal study was conducted in the adult US general population in two occasions. The initial interviews included 15 states (Arizona, California, Colorado, Florida, Idaho, Missouri, New York, North Carolina, North Dakota, Oregon, Pennsylvania, South Dakota, Texas, Washington, and Wyoming). The follow-up interviews, was done three years later in eight of these states. Of the 19,136 contacted individuals, 15,929 completed the initial interview and 10,931 completed the follow-up. Participants were interviewed using the Sleep-EVAL system, an artificial intelligence tool. Narcolepsy Type 1 (with cataplexy) and Narcolepsy Type 2 (without cataplexy) were defined according to the ICSD-3 classification. Symptoms of narcolepsy were assessed by frequency per week and duration. Medical visits and diagnoses were also collected. Results: Participants were aged between 18 and 102 years of age (mean 45.8 ± 17.9 years), 51.3 % were women. The prevalence of narcolepsy with cataplexy was 12.6 per 100,000 individuals (95 % C.I., 0 to 30) and narcolepsy without cataplexy was 25.1 per 100,000. The incidence per year was 2.6 per 100,000 individuals (95 % C.I., 0 to 11). Conclusions: Narcolepsy is a rare condition affecting 37.7/100,000 individuals (126,191 individuals in the current US population). Our US general population prevalence is in line with rates found in community-based studies but lower than what is reported in claim database studies.

Multi-session transcutaneous spinal cord stimulation prevents chloridehomeostasis imbalance and the development of spasticity after spinal cordinjury in rat.

Spasticity is a complex and multidimensional disorder that impacts nearly 75% of individuals with spinal cord injury (SCI) and currently lacks adequate treatment options. This sensorimotor condition is burdensome as hyperexcitability of reflex pathways result in exacerbated reflex responses, co-contractions of antagonistic muscles, and involuntary movements. Transcutaneous spinal cord stimulation (tSCS) has become a popular tool in the human SCI research field. The likeliness for this intervention to be successful as a noninvasive anti-spastic therapy after SCI is suggested by a mild and transitory improvement in spastic symptoms following a single stimulation session, but it remains to be determined if repeated tSCS over the course of weeks can produce more profound effects. Despite its popularity, the neuroplasticity induced by tSCS also remains widely unexplored, particularly due to the lack of suitable animal models to investigate this intervention. Thus, the basis of this work was to use tSCS over multiple sessions (multi-session tSCS) in a rat model to target spasticity after SCI and identify the long-term physiological improvements and anatomical neuroplasticity occurring in the spinal cord. Here, we show that multi-session tSCS in rats with an incomplete (severe T9 contusion) SCI (1) decreases hyperreflexia, (2) increases the low frequency-dependent modulation of the H-reflex, (3) prevents potassium-chloride cotransporter isoform 2 (KCC2) membrane downregulation in lumbar motoneurons, and (4) generally augments motor output, i.e., EMG amplitude in response to single pulses of tSCS, particularly in extensor muscles. Together, this work displays that multi-session tSCS can target and diminish spasticity after SCI as an alternative to pharmacological interventions and begins to highlight the underlying neuroplasticity contributing to its success in improving functional recovery.

An exploratory cross-sectional study of the effects of ongoing relationships with accompanying patients on cancer care experience, self-efficacy, and psychological distress.

BACKGROUND: Centre hospitalier de l'Université de Montréal in Canada introduced accompanying patients (APs) into the breast cancer care trajectory. APs are patients who have been treated for breast cancer and have been integrated into the clinical team to expand the services offered to people affected by cancer. This study describes the profiles of the people who received the support and explores whether one-offs vs ongoing encounters with APs influence their experience of care, on self-efficacy in coping with cancer, and on their level of psychological distress. METHODS: An exploratory cross-sectional study was carried out among patients to compare patients who had one encounter with an AP (G1) with those who had had several encounters (G2). Five questionnaires were administered on socio-demographic characteristics, care pathway, evaluation of the support experience, self-efficacy in coping with cancer, and level of psychological distress. Logbooks, completed by the APs, determined the number of encounters. Linear regression models were used to evaluate the associations between the number of encounters, patient characteristics, care pathway, number of topics discussed, self-efficacy measures in coping with cancer, and level of psychological distress. RESULTS: Between April 2020 and December 2021, 60% of 535 patients who were offered support from an AP accepted. Of these, one hundred and twenty-four patients participated in the study. The study aimed to recruit a minimum of 70 patients with the expectation of obtaining at least 50 participants, assuming a response rate of 70%. There were no differences between G1 and G2 in terms of sociodemographic data and care pathways. Statistical differences were found between G1 and G2 for impacts on and the return to daily life (p = 0.000), the return to the work and impacts on professional life (p = 0.044), announcement of a diagnosis to family and friends (p = 0.033), and strategies for living with treatment under the best conditions (p = 0.000). Significant differences were found on the topics of cancer (p = 0.000), genetic testing (p = 0.023), therapeutic options (p = 0.000), fatigue following treatment (p = 0.005), pain and discomfort after treatment or surgery (p = 0.000), potential emotions and their management (p = 0.000) and the decision-making processes (p = 0.011). A significant relationship was found between the two groups for patients' ability to cope with cancer (p = 0.038), and their level of psychological distress at different stages of the care pathway (p = 0.024). CONCLUSIONS: This study shows differences between one-time and ongoing support for cancer patients. It highlights the potential for APs to help patients develop self-efficacy and cope with the challenges of cancer treatment.

Bumetanide increases postsynaptic inhibition after chronic SCI and decreases presynaptic inhibition with step-training.

Current anti-spastic medication significantly compromises motor recovery after spinal cord injury (SCI), indicating a critical need for alternative interventions. Because a shift in chloride homeostasis decreases spinal inhibition and contributes to hyperreflexia after SCI, we investigated the effect of bumetanide, an FDA-approved sodium-potassium-chloride intruder (NKCC1) antagonist, on presynaptic and postsynaptic inhibition. We compared its effect with step-training as it is known to improve spinal inhibition by restoring chloride homeostasis. In SCI rats, a prolonged bumetanide treatment increased postynaptic inhibition but not presynaptic inhibition of the plantar H-reflex evoked by posterior biceps and semitendinosus (PBSt) group I afferents. By using in vivo intracellular recordings of motoneurons, we further show that a prolonged bumetanide increased postsynaptic inhibition by hyperpolarizing the reversal potential for inhibitory postsynaptic potentials (IPSPs) after SCI. However, in step-trained SCI rats an acute delivery of bumetanide decreased presynaptic inhibition of the H-reflex, but not postsynaptic inhibition. These results suggest that bumetanide might be a viable option to improve postsynaptic inhibition after SCI, but it also decreases the recovery of presynaptic inhibition with step-training. We discuss whether the effects of bumetanide are mediated by NKCC1 or by off-target effects. KEY POINTS: After spinal cord injury (SCI), chloride homeostasis is dysregulated over time in parallel with the decrease in presynaptic inhibition of Ia afferents and postsynaptic inhibition of motoneurons, and the development of spasticity. While step-training counteracts these effects, it cannot always be implemented in the clinic because of comorbidities. An alternative intervention is to use pharmacological strategies to decrease spasticity without hindering the recovery of motor function with step-training. Here we found that, after SCI, a prolonged bumetanide (an FDA-approved antagonist of the sodium-potassium-chloride intruder, NKCC1) treatment increases postsynaptic inhibition of the H-reflex, and it hyperpolarizes the reversal potential for inhibitory postsynaptic potentials in motoneurons. However, in step-trained SCI, an acute delivery of bumetanide decreases presynaptic inhibition of the H-reflex, but not postsynaptic inhibition. Our results suggest that bumetanide has the potential to decrease spastic symptoms related to a decrease in postsynaptic but not presynaptic inhibition after SCI.

Homologation of the Alkyl Side Chain of Antimitotic Phenyl 4-(2-Oxo-3-alkylimidazolidin-1-yl)benzenesulfonate Prodrugs Selectively Targeting CYP1A1-Expressing Breast Cancers Improves Their Stability in Rodent Liver Microsomes.

Phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs) are a new family of antimitotic prodrugs bioactivated in breast cancer cells expressing CYP1A1. In this study, we report that the 14C-labeled prototypical PAIB-SO [14C]CEU-818 and its antimitotic counterpart [14C]CEU-602 are distributed in whole mouse body and they show a short half-life in mice. To circumvent this limitation, we evaluated the effect of the homologation of the alkyl side chain of the imidazolidin-2-one moiety of PAIB-SOs. Our studies evidence that PAIB-SOs bearing an n-pentyl side chain exhibit antiproliferative activity in the nanomolar-to-low-micromolar range and a high selectivity toward CYP1A1-positive breast cancer cells. Moreover, the most potent n-pentyl PAIB-SOs were significantly more stable toward rodent liver microsomes. In addition, PAIB-SOs 10 and 14 show significant antitumor activity and low toxicity in chorioallantoic membrane (CAM) assay. Our study confirms that homologation is a suitable approach to improve the rodent hepatic stability of PAIB-SOs.

Accompanying patients in clinical oncology teams: Reported activities and perceived effects.

INTRODUCTION: Since 2018, four establishments in Quebec, Canada, have decided to implement the PAROLE-Onco programme, which introduced accompanying patients (APs) in healthcare teams to improve the experience of cancer patients. APs are patient advisors who have had a cancer treatment experience and who conduct consultations to complement the service offered by providing emotional, informational and educational support to patients undergoing treatments (e.g., radiotherapy, chemotherapy, surgery), mostly for breast cancer. We aimed to explore the evolution of APs' perspectives regarding their activities within the clinical oncology teams as well as the perceived effects of their intervention with patients, the clinical team and themselves. METHODS: A qualitative study based on semistructured interviews and focus groups was conducted with APs at the beginning of their intervention (T1) and 2 years afterwards (T2). The themes discussed were APs' activities and the perceived effects of their interventions on themselves, on the patients and on the clinical team. RESULTS: In total, 20 APs were interviewed. In T2, APs' activities shifted from listening and sharing experiences to empowering patients by helping them become partners in their care and felt generally more integrated into the clinical team. APs help patients feel understood and supported, alleviate stress and become partners in the care they receive. They also alleviate the clinical team's workload by offering a complementary service through emotional support, which, according to them, helps patients feel calmer and more prepared for their appointments with healthcare professionals. They communicate additional information about their patients' health journey, which makes the appointment more efficient for healthcare professionals. When APs accompany patients, they feel as if they can make a difference in patients' lives. Their activities are perceived by some as an opportunity to give back but also as a way of giving meaning to their own experience, in turn serving as a learning experience. CONCLUSION: By mobilizing their experiential knowledge, APs provide emotional, informational, cognitive and navigational support, which allows patients to be more empowered in their care and which complements professionals' scientific knowledge, thereby helping to refine their sensitivity to the patients' experiences. PATIENT OR PUBLIC CONTRIBUTION: Two patient-researchers have contributed to the study design, the conduct of the study, the data analysis and interpretation, as well as in the preparation and writing of this manuscript.

Longitudinal study to assess antidepressant treatment patterns and outcomes in individuals with depression in the general population.

BACKGROUND: Major depressive disorder (MDD) is largely managed in primary care, but physicians vary widely in their understanding of symptoms and treatments. This study aims to better understand the evolution of depression from initial diagnosis over a 3-year period. METHODS: This was a noninterventional, retrospective, longitudinal study, with 2 waves of participant interviews approximately 3 years apart. Phone interviews were conducted using the hybrid artificial intelligence (AI) Sleep-EVAL system, an AI-driven diagnostic deep learning tool. Participants were noninstitutionalized adults representative of the general population in 8 US states. Diagnosis was confirmed according to the DSM-5 using the Sleep-EVAL System. RESULTS: 10,931 participants completed Wave 1 and 2 (W1, W2) interviews. The prevalence of MDD, including partial and complete remission, was 13.4 % and 19.6 % in W1 and W2, respectively. About 42 % of MDD participants at W1 continued to report depressive symptoms at W2. Approximately half of antidepressant (AD) users in W1 were moderately to completely dissatisfied with their treatment; 29.6 % changed their AD for a different one, with 16.4 % switching from one SSRI to another between W1 and W2. Primary care physicians were the top AD prescribers, both in W1 (45.7 %) and W2 (59%), respectively. LIMITATIONS: Data collected relied on self-reporting by participants. As such, the interpretation of the data may be limited. CONCLUSIONS: Depression affects a sizeable portion of the US population. Dissatisfaction with treatment, frequent switching of ADs, and changing care providers are associated with low rates of remission. Residual symptoms remain a challenge that future research must address.

Adapting Human-Based Transcutaneous Spinal Cord Stimulation to Develop a Clinically Relevant Animal Model.

Transcutaneous spinal cord stimulation (tSCS) as a neuromodulatory strategy has received great attention as a method to promote functional recovery after spinal cord injury (SCI). However, due to the noninvasive nature of tSCS, investigations have primarily focused on human applications. This leaves a critical need for the development of a suitable animal model to further our understanding of this therapeutic intervention in terms of functional and neuroanatomical plasticity and to optimize stimulation protocols. The objective of this study is to establish a new animal model of thoracolumbar tSCS that (1) can accurately recapitulate studies in healthy humans and (2) can receive a repeated and stable tSCS treatment after SCI with minimal restraint, while the electrode remains consistently positioned. We show that our model displays bilateral evoked potentials in multisegmental leg muscles characteristically comparable to humans. Our data also suggest that tSCS mainly activates dorsal root structures like in humans, thereby accounting for the different electrode-to-body-size ratio between the two species. Finally, a repeated tSCS treatment protocol in the awake rat after a complete spinal cord transection is feasible, tolerable, and safe, even with minimal body restraint. Additionally, repeated tSCS was capable of modulating motor output after SCI, providing an avenue to further investigate stimulation-based neuroplasticity and optimize treatment.

Comparison of circulating fibrocytes from non-asthmatic patients with seasonal allergic rhinitis between in and out of pollen season samples.

BACKGROUND: Allergic rhinitis is a risk factor for asthma development. In asthma, fibroblast progenitors, fibrocytes, are increased in the blood and bronchial mucosa following allergen exposure. These cells may play a role in lower airways remodeling as observed in non-asthmatic subjects with allergic rhinitis. OBJECTIVE: To determine the influence of seasonal allergen exposure on blood circulating fibrocytes in allergic rhinitic subjects without asthma. METHODS: Non-asthmatic subjects with seasonal allergic rhinitis had blood sampling at baseline and at the peak of rhinitis symptoms. Cells were stained for fibrocyte markers (CD34, CD45, CXCR4, collagen I) and analyzed by flow cytometry. RESULTS: Data from 26 subjects (11M:15F) aged 29 ± 8 years were analysed. Compared to baseline, there was a significant decrease in blood fibrocytes during the pollen season in subjects sensitized to trees [median (25-75 percentile), 9.3 (6.4-20.7)% vs 7.0 (4.2-10.1)%, P = 0.007] and a significant increase in subjects sensitized to grass [12.7 (9.9-23.1)% vs 64.0 (57.6-73.6)%, P < 0.001] and ragweed [8.0 (7.4-10.8)% vs 48.2 (43.5-52.6)%, P < 0.001]. A significant decrease in CXCR4 mean fluorescence was also observed between the two visits [1814 (1261-2235) vs 1352 (814-1796) (arbitrary units), P = 0.02]. CONCLUSIONS AND CLINICAL RELEVANCE: These results contribute to document dynamic variations in blood fibrocytes' activation and migration into the airways following natural exposure to allergens. These findings may help identify one of the potential factors involved in the development of asthma in allergic rhinitic subjects.

Branched alkyl of phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates as unique cytochrome P450 1A1-activated antimitotic prodrugs: Biological evaluation and mechanism of bioactivation.

We recently discovered a new family of prodrugs deriving from phenyl 4-(2-oxo-3-imidazolidin-1-yl)benzenesulfonates (PIB-SOs) bioactivatable by cytochrome P450 1A1 (CYP1A1) into potent antimitotics referred to as phenyl 4-(2-oxo-3-alkylimidazolidin-1-yl)benzenesulfonates (PAIB-SOs). PAIB-SOs display significant selectivity toward human breast cancer cells based on the N-dealkylation of PAIB-SOs into their corresponding PIB-SOs by CYP1A1. In this study, we have evaluated the molecular mechanism of the bioactivation of PAIB-SOs into PIB-SOs by branching the linear alkyl chain on the imidazolidin-2-one (IMZ) moiety of PAIB-SOs by branched alkyl groups such as isopropyl, isobutyl and sec-butyl. Our results show that PAIB-SOs bearing an isobutyl group on the IMZ moiety and either a methoxy, a chloro or a bromo group at positions 3, 3,5 or 3,4,5 on the aromatic ring B exhibit antiproliferative activity ranging from 0.13 to 6.9 µM and selectivity toward MCF7 and MDA-MB-468 mammary cancer cells comparatively to other cell lines tested. Moreover, the most potent and selective PAIB-SOs bearing an isobutyl group and either a 3,5-Cl (44), 3,5-Br (45) or a 3,4,5-OMe (46) on the IMZ moiety exhibit antiproliferative activity in the sub-micromolar range and high selectivity ratios toward mammary cancer cells. They stop the cell cycle of MCF7 cells in the G2/M phase and disrupt their cytoskeleton. Furthermore, our studies evidenced that PAIB-SOs bearing either an isopropyl, a sec-butyl or an isobutyl group are hydroxylated on the carbon atom adjacent to the IMZ (Cα-OH) but only PAIB-SOs bearing an isobutyl group are bioactivated into PIB-SOs. Finally, PAIB-SOs 45 and 46 exhibit low toxicity toward normal cells and chick embryos and are thus promising antimitotic prodrugs highly selective toward CYP1A1-expressing breast cancer cells.

Ethical Foundations of the Accompanying Patient's Role for an Enhanced Patient Experience: A Scoping Review.

In recent years, recognizing patients' experiential knowledge to improve the quality of care has resulted in the participation of patient advisors at various levels of healthcare systems. Some who are working at the clinical level are called accompanying patients (AP). A PRISMA-ScR exploratory scoping review of the literature was conducted on articles published from 2005 to 2021. Articles not in English or French and grey literature were excluded. The databases searched included Medline, PubMed, Scopus, and Google Scholar. The data were organized according to the similarities in the ethical foundations of the included papers. Out of 2095 identified papers, 8 met inclusion criteria. Terms used to describe APs included peer support, resource parent, and peer health mediator. The clinical settings included psychiatry/mental health and neonatology. APs, patients, healthcare professionals, managers and policy makers were included in the studies. Three personal ethical foundations describing the foundations of the AP role were found: resilience, listening skills and altruism. The ethical foundations of this role also addressed interpersonal and interprofessional relationships with other actors in the healthcare system. The literature on the ethical foundations of APs is sparse, with heterogeneous methodologies. Further studies mobilizing well-defined methodologies would further validate the current results and deepen our understanding of the ethical foundations of the AP role.

Exercise-Induced Plasticity in Signaling Pathways Involved in Motor Recovery after Spinal Cord Injury.

Spinal cord injury (SCI) leads to numerous chronic and debilitating functional deficits that greatly affect quality of life. While many pharmacological interventions have been explored, the current unsurpassed therapy for most SCI sequalae is exercise. Exercise has an expansive influence on peripheral health and function, and by activating the relevant neural pathways, exercise also ameliorates numerous disorders of the central nervous system (CNS). While the exact mechanisms by which this occurs are still being delineated, major strides have been made in the past decade to understand the molecular underpinnings of this essential treatment. Exercise rapidly and prominently affects dendritic sprouting, synaptic connections, neurotransmitter production and regulation, and ionic homeostasis, with recent literature implicating an exercise-induced increase in neurotrophins as the cornerstone that binds many of these effects together. The field encompasses vast complexity, and as the data accumulate, disentangling these molecular pathways and how they interact will facilitate the optimization of intervention strategies and improve quality of life for individuals affected by SCI. This review describes the known molecular effects of exercise and how they alter the CNS to pacify the injury environment, increase neuronal survival and regeneration, restore normal neural excitability, create new functional circuits, and ultimately improve motor function following SCI.

Enhancing KCC2 activity decreases hyperreflexia and spasticity after chronic spinal cord injury.

After spinal cord injury (SCI), the majority of individuals develop spasticity, a debilitating condition involving involuntary movements, co-contraction of antagonistic muscles, and hyperreflexia. By acting on GABAergic and Ca2+-dependent signaling, current anti-spastic medications lead to serious side effects, including a drastic decrease in motoneuronal excitability which impairs motor function and rehabilitation efforts. Exercise, in contrast, decreases spastic symptoms without decreasing motoneuron excitability. These functional improvements coincide with an increase in expression of the chloride co-transporter KCC2 in lumbar motoneurons. Thus, we hypothesized that spastic symptoms can be alleviated directly through restoration of chloride homeostasis and endogenous inhibition by increasing KCC2 activity. Here, we used the recently developed KCC2 enhancer, CLP257, to evaluate the effects of acutely increasing KCC2 extrusion capability on spastic symptoms after chronic SCI. Sprague Dawley rats received a spinal cord transection at T12 and were either bike-trained or remained sedentary for 5 weeks. Increasing KCC2 activity in the lumbar enlargement improved the rate-dependent depression of the H-reflex and reduced both phasic and tonic EMG responses to muscle stretch in sedentary animals after chronic SCI. Furthermore, the improvements due to this pharmacological treatment mirror those of exercise. Together, our results suggest that pharmacologically increasing KCC2 activity is a promising approach to decrease spastic symptoms in individuals with SCI. By acting to directly restore endogenous inhibition, this strategy has potential to avoid severe side effects and improve the quality of life of affected individuals.

Locomotor deficits induced by lumbar muscle inflammation involve spinal microglia and are independent of KCC2 expression in a mouse model of complete spinal transection.

Spinal cord injury (SCI) is associated with damage to musculoskeletal tissues of the spine. Recent findings show that pain and inflammatory processes caused by musculoskeletal injury mediate plastic changes in the spinal cord. These changes could impede the adaptive plastic changes responsible for functional recovery. The underlying mechanism remains unclear, but may involve the microglia-BDNF-KCC2 pathway, which is implicated in sensitization of dorsal horn neurons in neuropathic pain and in the regulation of spinal excitability by step-training. In the present study, we examined the effects of step-training and lumbar muscle inflammation induced by complete Freund's adjuvant (CFA) on treadmill locomotion in a mouse model of complete spinal transection. The impact on locomotor recovery of each of these interventions alone or in combination were examined in addition to changes in microglia and KCC2 expression in the dorsal and ventral horns of the sublesional spinal cord. Results show that angular motion at the hip, knee and ankle joint during locomotion were decreased by CFA injection and improved by step-training. Moreover, CFA injection enhanced the expression of the microglial marker Iba1 in both ventral and dorsal horns, with or without step-training. However, this change was not associated with a modulation of KCC2 expression, suggesting that locomotor deficits induced by inflammation are independent of KCC2 expression in the sublesional spinal cord. These results indicate that musculoskeletal injury hinders locomotor recovery after SCI and that microglia is involved in this effect.

Deletion of S100a8 and S100a9 Enhances Skin Hyperplasia and Promotes the Th17 Response in Imiquimod-Induced Psoriasis.

High concentrations of the damage-associated molecular patterns S100A8 and S100A9 are found in skin and serum from patients suffering from psoriasis, an IL-17-related disease. Notably, although the expression of these proteins correlates with psoriatic disease severity, the exact function of S100A8 and S100A9 in psoriasis pathogenesis remains unclear. In this study, we investigated the role of S100A8 and S100A9 in psoriasis-associated skin hyperplasia and immune responses using S100a8-/- and S100a9-/- mice in an imiquimod-induced model of psoriasis. We found that S100a8-/- and S100a9-/- psoriatic mice exhibit worsened clinical symptoms relative to wild-type mice and increased expression of S100A9 and S100A8 proteins in keratinocytes, respectively. In addition, the loss of S100A8 enhances proliferation of keratinocytes and disrupts keratinocyte differentiation. We further detected elevated production of IL-17A and -F from CD4+ T cells in the absence of S100A8 and S100A9, as well as increased infiltration of neutrophils in the skin. In addition, treatment with anti-IL-17A and -F was found to reduce psoriasis symptoms and skin hyperplasia in S100a8-/- and S100a9-/- mice. These data suggest that S100A8 and S100A9 regulate psoriasis by inhibiting production of IL-17A and -F, thereby, to our knowledge, providing new insights into their biological functions.