Functional Deficits Research Articles

INVESTIGATING DRUG-INDUCED DEMENTIA IN A CNS MPS ASSESSING DEFICITS IN LTP FROM ANTICHOLINERGIC COGNITIVE BURDEN

Abstract Microphysiological systems (MPS) provide an avenue for small-scale modelling of organ constructs. In conjunction with human induced-pluripotent stem cells (hiPSCs) cultured on microelectrode arrays (MEAs), MPS enable the exploration of functional deficits in concurrence with drug efficacy. Central nervous system (CNS) neural network MPS can evaluate compound-induced cognitive impairment via synapse-dependent, long-term potentiation (LTP). The present work employed a previously validated hiPSC-cortical neuron LTP model to investigate drug-induced dementia onset by Anticholinergic Cognitive Burden (ACB). Utilizing an established CNS model of LTP, we have successfully been able to evaluate a dose-response relationship between ACB drug concentration and cognitive deficits. After discovering that many ACB drugs cause clinical drowsiness, caffeine was employed to re-awaken neuronal activity, akin to increased vigilance. Donepezil, an acetylcholinesterase inhibitor commonly used in the treatment of Alzheimer’s disease (AD), confirmed that LTP deficits resulted from cholinergic neurotransmission, demonstrating the ability of our CNS MPS to assess mechanism-specific synaptic decline. Synergistic effects of ACB drugs and amyloid-beta42 oligomers, which agglomerate to produce neurotoxic plaques in AD, depicted an exacerbation of LTP deficits, suggesting a higher risk of cognitive decline in patients with early-onset AD using anticholinergics. This study illustrated the ability of our human, CNS-based MPS to recapitulate cognitive dysfunction preceded by neurotransmitter homeostatic imbalance, further validating our LTP model for investigating mechanism-dependent disease phenotypes. This model can be expanded to assess synergistic effects of drugs effecting neural network integrity on preexisting conditions causing cognitive impairment, which were observed to be translatable to clinical symptoms.

Long-Term 5-HT1A Receptor Agonist NLX-112 Treatment Improves Functional Recovery After Spinal Cord Injury.

Spinal cord injury (SCI) results in functional deficits below the injured spinal level. The descending serotonergic system in the spinal cord is critically involved in the control of motor and autonomic functions. Specifically, SCI damages the projections of serotonergic fibers, which leads to reduced serotonin inputs and increased amounts of spinal serotonergic receptors. Our previous pharmacological study demonstrated that brief administration of a highly selective 5-HT1A receptor agonist, NLX-112, improves lower urinary tract (LUT) function at the termination stage of thoracic 8 (T8) contusive SCI in rats. However, whether chronic activation of serotonin 5-HT1A receptors by NLX-112 after SCI is beneficial remains an unanswered question. Here, we evaluated the efficacy of long-term NLX-112 intervention starting from two weeks post-T8 contusive SCI for an additional six weeks. We evaluated locomotion, LUT function, bladder morphology, and the number of spinal 5-HT1A receptors in both L4 and L6/S1 spinal cord segments. Our results indicate that NLX-112 treatment significantly improves locomotion in a dose-dependent fashion, improves LUT function, reduces bladder weight and bladder wall thickness, and reduces the SCI-upregulated spinal 5-HT1A receptors compared to vehicle-treated SCI animals. These data suggest promising therapeutic potential for long-term NLX-112 activation of 5-HT1A receptors to treat SCI.

Dysphagia in Rare Diseases and Syndromes: Current Approaches to Management and Therapeutic Innovations-A Systematic Review.

Background: This study presents a comprehensive investigation into the correlation between Rare Diseases and Syndromes (RDS) and the dysphagic disorders manifested during childhood and adulthood in affected patients. Dysphagia is characterized by difficulty or an inability to swallow food of any consistency, as well as saliva or medications, from the oral cavity to the stomach. RDS often present with complex and heterogeneous clinical manifestations, making it challenging to develop standardized diagnostic and therapeutic approaches. Dysphagia can arise from various etiologies, including those related to the central nervous system, inflammatory and neoplastic processes, anatomical or structural disorders, and neuromuscular conditions. These diverse etiologies can result in both structural and functional deficits or neurological impairments that compromise swallowing function. While RDS frequently leads to uncommon conditions, dysphagia remains an underrecognized complication. Objectives: The primary objective of this review is to illuminate the latest knowledge concerning the management of dysphagia in both pediatric and adult populations within the context of RDS, with a particular focus on current therapeutic approaches. To achieve this, the study provides a comprehensive analysis of existing strategies for managing dysphagia in RDS, highlighting recent advancements in therapy while identifying critical gaps in clinical knowledge and practice. By synthesizing available evidence, the review aims to deepen understanding of the unique challenges associated with dysphagia in these conditions and explore innovative interventions to enhance patient care and outcomes. Results: The integration of innovative therapeutic techniques into the speech-language pathology treatment of dysphagia augments traditional strategies, offering updated knowledge that can be applied to prognosis and therapeutic interventions across various ages and racial groups. This review also provides an overview of symptomatology, assessment techniques, and the specific characteristics of dysphagia associated with various genetic and acquired RDS.

Executive functioning impairment in depressive and obsessive compulsive disorder: A comparative study

Background: Both Obsessive-Compulsive Disorder (OCD) and Depressive Disorder are debilitating and disabling in nature. Numerous studies have highlighted substantial deficits in executive functioning associated with these conditions. . Aim: To compare impairment in executive functioning in both depressive and obsessive-compulsive disorder. Methods: A total of sixty patients, thirty each for Obsessive compulsive Disorder and Depressive disorder fulfilling the inclusion and exclusion criteria have been selected using purposive sampling method. Modified Wisconsin card sorting Test was administered to assess the Executive functioning. Mann Whitney U test was used for statistical analysis. Results: The mean difference between impairment in executive functioning in both Obsessive compulsive disorder and Depressive disorder is statistically significant. Conclusion: The main findings of this research reveal that patients with obsessive compulsive disorder show greater impairment in executive functioning compared to those with depressive disorder.

Vitamin therapy in the treatment of mild traumatic brain injury: new horizons of clinical practice

Objective: To investigate the main aspects of the impact of vitamin therapy on the treatment effectiveness of patients with mild traumatic brain injury and to illustrate it on the example of individual clinical cases. Materials and Methods. The analysis of scientific sources of information in various electronic databases (PUBMED, ScienceDirect, Reserch4life, MEDLINE) on the ability of vitamins to reduce oxidative stress, stimulate neuroprotection, and improve cognitive function in people with mild traumatic brain injury over the past 10 years. The search included the following keywords and terms: vitamins (with separate letters B, C, D, E) and omega-3 fatty acids, mTBI, TBI, oxidative stress, micronutrients, physiological process, cognitive function, and biochemical and neurological consequences. To describe clinical cases, in addition to the well-known methods of examination of patients with mild traumatic brain injury, scales for assessing the psychoemotional state were used, namely the Hospital Anxiety and Depression Scale (HADS) for patients in somatic inpatient departments. Results. According to scientific sources of information, a positive effect of vitamins C, E and D on reducing oxidative stress was demonstrated, while B vitamins contributed more to the normalization of neuronal energy metabolism. Patients with mild traumatic brain injury treated with complex vitamin therapy demonstrated a reduction in the duration of mild traumatic brain injury symptoms, in particular headache, and improvement of psychoemotional state, mainly during the first 10 days of treatment. Conclusions. Since traumatic brain injury (TBI) is a complex clinical condition accompanied by both primary brain damage and a secondary biochemical cascade that contributes to prolonged neuroinflammation, oxidative stress, and cellular dysfunction, its treatment and rehabilitation require the development of new approaches, in particular with the use of vitamin therapy, which aims to support the function of the nervous system by providing neuroprotection, antioxidant action, and support for cellular energy metabolism. Clinical examples demonstrate a phenomenological tendency to a more pronounced recovery of the psycho-emotional state in a patient who was prescribed thiamine hydrochloride 100 mg, pyridoxine hydrochloride 100 mg, cyanocobalamin 1 mg (Vitaxon) by mouth once daily. The data from preclinical and clinical studies in recent years confirm the prospects of using vitamin supplements as part of the complex therapy of mild traumatic brain injury to reduce secondary brain damage, improve cognitive function, and accelerate patient recovery. Further research of the mechanisms of action of vitamins, optimal dosages, time windows of use, and impact on long-term outcomes is needed to improve the treatment of patients with mild traumatic brain injury, which may become an important component of personalized TBI therapy aimed at reducing functional deficits and improving patients' quality of life.

Using Heuristics and ‘TEACCH’ Material in Problem-Solving with Students with Autism-Asperger Syndrome

This study reports on the use of heuristics and TEACCH materials by students with Asperger syndrome for problem-solving tasks in a workshop. Taking visual representation as an organising principle, the use of heuristics such as trial and error, seeking regularities, and going backwards helped students overcome the difficulties associated with literal thinking and cognitive inflexibility, and poor shared and sustained attention related to deficits in central coherence and executive functioning. The interaction between, on the one hand, these heuristics, the visual material and manipulatives, and on the other, the characteristics of Asperger syndrome which they aim to mitigate is also considered.

Role of PCBP2 in regulating nanovesicles loaded with curcumin to mitigate neuroferroptosis in neural damage caused by heat stroke

ObjectiveThis study aims to elucidate the mechanisms by which nanovesicles (NVs) transport curcumin(CUR) across the blood–brain barrier to treat hypothalamic neural damage induced by heat stroke by regulating the expression of poly(c)-binding protein 2 (PCBP2).MethodsInitially, NVs were prepared from macrophages using a continuous extrusion method. Subsequently, CUR was loaded into NVs using sonication, yielding engineered cell membrane Nanovesicles loaded with curcumin (NVs-CUR), which were characterized and subjected to in vitro and in vivo tracking analysis. Evaluations included assessing the toxicity of NVs-CUR using the MTT assay, evaluating neuroprotection of NVs-CUR against H2O2-induced oxidative stress damage in PC12 cells, examining effects on cell morphology and quantity, and detecting ferroptosis-related markers through Western blot and transmission electron microscopy (TEM). Proteomic analysis was conducted on PC12 cells treated with NVs (n = 3) and NVs-CUR (n = 3) to identify downstream key factors. Subsequently, the expression of key factors was modulated, and rescue experiments were performed to validate the impact of NVs-CUR through the regulation of key factor expression. Furthermore, a mouse model of hypothalamic neural damage induced by heat stroke was established, where CUR, NVs-CUR, and ferroptosis inducer Erastin were administered to observe mouse survival rates, conduct nerve function deficit scoring, perform histological staining, and measure levels of inflammation and oxidative stress factors in hypothalamic tissue.ResultsNVs-CUR was successfully prepared with excellent stability, serving as an advantageous drug delivery system that effectively targets brain injury sites or neurons both in vitro and in vivo. Subsequent in vitro cell experiments demonstrated the biocompatibility of NVs-CUR, showing superior protective effects against H2O2-induced PC12 cell damage and reduced ferroptosis compared to CUR. Moreover, in the mouse model of hypothalamic neural damage induced by heat stroke, NVs-CUR exhibited enhanced therapeutic effects. Proteomic analysis revealed that NVs-CUR exerted its effects through the regulation of key protein PCBP2; silencing PCBP2 reversed the protective effect of NVs-CUR on neural damage and its inhibition of ferroptosis. Additionally, NVs-CUR regulated solute carrier family 7 member 11 (SLC7A11) expression by PCBP2; overexpression of SLC7A11 reversed the promotion of neural damage and ferroptosis by silencing PCBP2. Animal experiments indicated that ferroptosis inducers reversed the improved survival and nerve function observed with NVs-CUR, silencing PCBP2 reversed the ameliorative effects of NVs-CUR on hypothalamic neural injury induced by heat stroke, and overexpression of SLC7A11 further reversed the adverse effects of silencing PCBP2 on hypothalamic neural injury induced by heat stroke. This suggests that NVs-CUR alleviates hypothalamic neural damage induced by heat stroke by targeting the PCBP2/SLC7A11 axis to reduce neuronal ferroptosis.ConclusionThis study successfully developed engineered cell membrane NVs-CUR with neuron-targeting properties. NVs-CUR increased the expression of PCBP2, maintained the stability of SLC7A11 mRNA, reduced ferroptosis, and ultimately alleviated hypothalamic neuroinflammation induced by heatstroke.Graphical

Amelioration of signaling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia.

The microglial triggering receptor expressed on myeloid cells 2 (TREM2) is required for diverse microglia responses in neurodegeneration, including immunometabolic plasticity, phagocytosis, and survival. We previously identified that patient iPSC-derived microglia (iPS-Mg) harboring the Alzheimer's disease (AD) TREM2R47H hypomorph display several functional deficits linked to metabolism. To investigate whether these deficits are associated with disruptions in metabolite signaling, we generated common variant, TREM2R47H and TREM2-/- variant human iPS-Mg. We assessed the ability of supplementation with citrate or succinate, key metabolites and cell cycle breaking points upon microglia activation, to overcome these functional deficits with potential impact on neurons. Succinate supplementation was more effective than citrate at overcoming mitochondrial deficits in OXPHOS and did not promote a glycolytic switch. Citrate enhanced the lipid content of TREM2R47H iPS-Mg and was more effective at overcoming Αβ phagocytic deficits, whereas succinate increased lipid content and phagocytic capacity in TREM2-/- iPS-Mg. Microglia cytokine secretion upon pro-inflammatory activation was moderately affected by citrate or succinate showing a condition-dependent increasing trend. Neither metabolite altered basal levels of soluble TREM2 shedding. In addition, neither citrate nor succinate enhanced glycolysis; instead, drove their effects through oxidative phosphorylation. IPS-neurons exposed to conditioned medium from TREM2 variant iPS-Mg showed changes in oxidative phosphorylation, which could be ameliorated when iPS-Mg were first treated with citrate or succinate. Our data point to discrete pathway linkage between microglial metabolism and functional outcomes with implications for AD pathogenesis and treatments.

Etiology of Antisocial Personality Disorder: A Review of Brain Function and Childhood Experiences

Antisocial Personality Disorder (ASPD) is a psychological disorder in which an individual engages exclusively or significantly in the deliberate violating of, scamming, as well as violence against other people for their gain. This review aims to provide a comprehensive account of the recent developments regarding biological, neurocognitive, and neuropsychological factors and environmental risks related to ASPD. Neuroimaging studies have been conducted to assess brain function using voxel-based morphometry (VBM) and imaging of functional magnetic resonance (fMRI) to determine structural and functional changes that occur. Previous studies have recognized marked grey matter volume (GMV) disruptions in the prefrontal cortex, temporal lobes, parietal regions, and aberrant functional connectivity profiles — particularly between attention and default mode networks. Of the environmental factor, childhood trauma is crucial for leading to necessary support of ASPD phenotype with emotional or physical abuse during infancy, significantly contributing to risk-prediction capacity—the systematic review methodology involved six critical evaluations of the study on neurobiology and childhood ASPD risk factors. Consistent neuroimaging data on brain structure (grey matter volume reductions) and functional connectivity and the critical role of early life experiences in susceptibility to this disorder are shown throughout. In conclusion, ASPD's etiology is multifactorial, involving a complex interaction of biological and environmental factors. Understanding the neurological underpinnings and developmental experiences leading to ASPD can inform more targeted interventions and treatment strategies for at-risk individuals, highlighting the need for early detection and therapeutic approaches to address brain function deficits and childhood adversities.

Evaluation of the Timed Up and Go Test in Patients with Knee Osteoarthritis Using Inertial Sensors

Background: There has been a growing interest in using inertial sensors to explore the temporal aspects of the Timed Up and Go (TUG) test. The current study aimed to analyze the spatiotemporal parameters and phases of the TUG test in patients with knee osteoarthritis (KOA) and compare the results with those of non-arthritic individuals. Methods: This study included 20 patients with KOA and 60 non-arthritic individuals aged 65 to 84 years. All participants performed the TUG test, and 17 spatiotemporal parameters and phase data were collected wirelessly using the BTS G-Walk inertial sensor. Results: Significant mobility impairments were observed in KOA patients, including slower gait speed, impaired sit-to-stand transitions, and reduced turning efficiency. These findings highlight functional deficits in individuals with KOA compared to their non-arthritic counterparts. Conclusions: The results emphasize the need for targeted physiotherapy interventions, such as quadriceps strengthening, balance training, and gait retraining, to address these deficits. However, the study is limited by its small sample size, gender imbalance, and limited validation of the BTS G-Walk device. Future research should include larger, more balanced cohorts, validate sensor reliability, and conduct longitudinal studies. Despite these limitations, the findings align with previous research and underscore the potential of inertial sensors in tailoring rehabilitation strategies and monitoring progress in KOA patients.

Impact of Overall and Specific Dimensions of Schizotypy on Theory of Mind

Background: Impairments in theory of mind (ToM) are highly prevalent among individuals with schizophrenia, resulting in substantial functional deficits. However, research on impairments in individuals with schizotypy has yielded inconsistent findings, with some studies finding ToM deficits in overall schizotypy, other studies finding ToM deficits in only specific schizotypy dimensions, and yet other studies finding no ToM deficits at all. One potential key factor that may account for this discrepancy is the use of schizotypy measures that do not adequately measure specific schizotypy dimensions. Additional limitations are employment of ToM measures that rely heavily on explicit cultural knowledge, verbal/reading comprehension, and/or other cognitive abilities. Method: To address these discrepant findings, we used the Schizotypal Personality Questionnaire-Brief Revised (Updated; SPQ-BRU) and the Multidimensional Schizotypy Scale (MSS) to tap overall schizotypy and specific schizotypy dimensions. To measure ToM, we used the Frith-Happé animations (FHA) and Strange Stories Film Task (SSFT). We examined the hypothesized negative relationship between schizotypy and ToM in a sample of 233 nonclinical individuals. Results: Regression analysis indicated no significant relationship between overall schizotypy and ToM on both the FHA (b = 0.01, t(196) = −0.75, p = 0.46) and SSFT (b = −0.20, t(195) = −1.69, p = 0.09). However, it did find that the negative schizotypy dimension was associated with poorer ToM performance on both the FHA (b = −0.11, t(194) = −2.7, p = 0.008) and SSFT (b = −0.12, t(193) = −3.22, p = 0.001). Also, exploratory analyses employing an extreme-group design approach indicated high schizotypy and high negative schizotypy groups displayed weaker ToM performance within all specific schizotypy dimensions. Conclusion: These results indicate that ToM impairments are present in schizotypy, especially within the negative schizotypy dimension. The results suggest important methodological implication for studying ToM in schizotypy and conceptualizing the latent structure of schizotypy.

Therapeutic Effects of Superinductive Magnetic Filed on Low Back Pain

Low back pain is one of the major public health problems, with approximately 1 in 3 adults experiencing an episode of low back pain during their lifetime. The aim of this study was to evaluate the effect on pain and physical function of a therapeutic protocol including analgesic electrotherapy, lumbar deconstrictor manual therapy and kinetic therapy and the superinductive magnetic field therapy. Patients were divided into two groups of 20 and 20 respectively. Group 1 was treated with the conventional protocol, while the second group received in adition the superinductive magnetic field therapy. Pain was assessed by VAS scale at admission and every 2 days, and functional deficit was assessed by the Fingertips to floor (FTF) test at admission, at 6 days and at discharge at 12 days. The Activities of Daily Living (ADL) scale was also used to assess physical function at admission and discharge. 40 patients (24 female, 16 male), average age 61 years ( ± 5.7), average BMI of 32.11± 7.38 SD, kg participated and their data were analyzed. An average percentage decrease in VAS was noticed after the 12 days of treatment of 67% for group1 and of 88% for group 2. The deficit in FTF was also better in group 2 (FTF= 16+5cm ) compared to FTF=22+3 in the control group. On ADL assessment, no significant differences were noted. Superinductive magnetic field therapy is effective in the treatment of low back pain relieving pain syndrome and improving physical function.

From diagnosis to rehabilitation of trigger finger: a narrative review.

Trigger finger (TF), also known as stenosing flexor tenosynovitis, is a common pathology of the fingers causing functional deficit of the hand. In recent years, new therapeutic approaches such as extracorporeal shock wave therapy (ESWT) and ultrasound-guided (USG) procedures have joined the most traditional conservative treatments as the adaptation of daily activities involving the affected hand and the orthosis. Likewise, the ultrasound (US) examination of the affected finger using modern high-frequency probes has progressively become part of the comprehensive assessment of patients with TF coupled with the medical history, the physical examination, and the functional scales. In this sense, considering the technological advances in both diagnostic and therapeutic fields, the non-surgical strategies have progressively grown defining a rehabilitation panel more complex than in the past. The present manuscript aims to provide an updated practical guide for clinicians and surgeons reviewing the state-of-art of both the assessment and the treatments of patients with TF to plan tailored rehabilitation management taking advantage of the matching of traditional and novel techniques.

Adequate post-ischemic reperfusion of the mouse brain requires endothelial NFAT5

Severity and outcome of strokes following cerebral hypoperfusion are significantly influenced by stress responses of the blood vessels. In this context, brain endothelial cells (BEC) regulate inflammation, angiogenesis and the vascular resistance to rapidly restore perfusion. Despite the relevance of these responses for infarct volume and tissue recovery, their transcriptional control in BEC is not well characterized. We revealed that oxygen and nutrient-deprived BEC activate nuclear factor of activated T-cells 5 (NFAT5)—a transcription factor that adjusts the cellular transcriptome to cope with environmental stressors. We hypothesized that NFAT5 controls the expression of genes regulating the response of BEC in the ischemic brain. The functional relevance of NFAT5 was assessed in mice, allowing the conditional EC-specific knock-out of Nfat5 (Nfat5(EC)−/−). Cerebral ischemia was induced by transient middle cerebral artery occlusion (MCAO) followed reperfusion up to 28 days. While loss of endothelial Nfat5 did not evoke any phenotypic abnormalities in mice under control conditions, infarct volumes, neurological deficits and the degree of brain atrophy were significantly pronounced following MCAO as compared to control animals (Nfat5fl/fl). In contrast, MCAO-induced edema formation, inflammatory processes and angiogenesis were not altered in Nfat5(EC)−/− mice. RNAseq analyses of cultured BEC suggested that loss of NFAT5 impairs the expression of Kcnj2 encoding a potassium channel that may affect reperfusion. In fact, lower levels of KCNJ2 were detected in arterial endothelial cells of Nfat5(EC)−/− versus Nfat5fl/fl mice. Laser speckle contrast imaging of the brain revealed an impaired perfusion recovery in Nfat5(EC)−/− versus Nfat5fl/fl mice after MCAO.Collectively, NFAT5 in arterial BEC is required for an adequate reperfusion response after brain ischemia that is presumably dependent on the maintenance of Kcnj2 expression. Consequently, impairment of the protective role of endothelial NFAT5 results in enlarged infarct sizes and more severe functional deficits of brain functions.

CSF1-R inhibition attenuates posttraumatic osteoarthritis and quadriceps atrophy following ligament injury.

Knee osteoarthritis contributes substantially to worldwide disability. Post-traumatic osteoarthritis (PTOA) develops secondary to joint injury, such as ligament rupture, and there is increasing evidence suggesting a key role for inflammation in the aetiology of PTOA and associated functional deficits. Colony stimulating factor 1 receptor (CSF1-R) has been implicated in the pathogenesis of musculoskeletal degeneration following anterior cruciate ligament (ACL) injury. We sought to assess the efficacy of CSF1-R inhibition to mitigate muscle and joint pathology in a mouse model of PTOA. Four-month-old mice were randomized to receive a CSF1-R inhibitor and studied for 7 or 28days after joint injury. Additionally, we profiled synovial fluid samples for CSF1-R from patients with injury to their ACL. Transcriptomic analysis of quadriceps muscle and articular cartilage in CSF1-R inhibitor-treated animals at 7days after injury revealed elevated chondrocyte differentiation within articular cartilage and enhanced metabolic and contractile gene expression within skeletal muscle. At 28days post-injury, CSF1-R inhibition attenuated PTOA severity and mitigated skeletal muscle atrophy. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA. Our findings support an opportunity for CSF1-R targeting to mitigate the severity of PTOA and muscle atrophy after joint injury. KEY POINTS: Posttraumatic osteoarthritis (PTOA) of the knee commonly results from direct injury to the joint, which is characterized by pain, weakness, and disability. Induction of colony stimulating factor one receptor (CSF1-R) is positively associated with knee trauma severity, and the initial acute inflammatory state suppresses muscle recovery and degrades articular cartilage. Skeletal muscle and articular cartilage transcriptomic response following direct joint injury in a murine model of PTOA is rescued by pharmacological inhibition of CSF1-R. CSF1-R inhibition mitigated skeletal muscle atrophy and attenuated PTOA severity and synovitis. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA, offering further evidence for CSF1-R as a therapeutic target across musculoskeletal tissues after injury.

Neurodevelopmental Abnormalities in Down Syndrome: Assessing Structural and Functional Deficits.

Down syndrome (DS) is a genetic intellectual disorder caused by trisomy of chromosome 21 (Hsa21) and presents with a variety of phenotypes. The correlation between the chromosomal abnormality and the resulting symptoms is unclear, partly due to the spectrum of impairments observed. However, it has been determined that trisomy 21 contributes to neurodegeneration and impaired neurodevelopment resulting from decreased neurotransmission, neurogenesis, and synaptic plasticity. DS is linked to synaptic abnormalities and hindered hippocampal neuron development as well. Altered synaptic plasticity in the hippocampus decreases long-term potentiation, leading to short- and long-term learning and memory deficits. Individuals with DS show reduced gray matter, which affects cerebral cortex structure and impairs coordination and thought. Neurotransmitter excess, such as increased gamma-aminobutyric acid (GABA) release, causes over-inhibition and contributes to cognitive deficits. This inhibition also affects hippocampal synaptic plasticity. Additionally, DS often involves neurodegeneration of cholinergic neurons in the basal forebrain, further impairing learning and memory. Reduced glutamate transmission and decreased amyloid precursor protein metabolism contribute to synaptic plasticity deficits and behavioral changes in DS. Decreased neurotransmission, diminished motor neurons, and impaired cerebellar and cerebral development are the main causes of motor deficits in DS. This review discusses the stark structural changes in DS and their functional consequences.

Assessing hand motor function in chronic immune-mediated neuropathies: a proof-of-concept study using a data glove

BackgroundChronic immune-mediated neuropathies are clinically heterogeneous and require regular, objective, and multidimensional monitoring to individualize treatment. However, established outcome measures are insufficient regarding measurement quality criteria (e.g., reliability, objectivity) or functional relevance. Wearables such as data gloves might be helpful, allowing repeated quantification of complex everyday life-relevant motor function of the hand.Methods25 patients with chronic inflammatory demyelinating polyneuropathy or multifocal motor neuropathy were followed-up at five time points during maintenance therapy with intravenous immunoglobulin. 14 of them showed clinically relevant hand motor impairment. We examined the patients’ hand function using a data glove which quantifies the active range of motion (ROM) of the hand based on three different movement patterns. In addition, clinical outcome parameters (grip strength measurement, MRC Sum Score, INCAT disability score), nerve conduction studies (NCS), and high-resolution ultrasound (HRUS) were performed, and patient-reported outcome measures (PROMs) like the Rasch-built Overall Disability Scale (R-ODS) were assessed. We calculated correlation coefficients, performed Receiver Operating Characteristic analysis, as well as correlation analyses for the glove data and clinical outcome parameters. Longitudinal analyses were based on a Linear Mixed Model, and we assessed construct validity of the data glove by analyzing correlations between the glove measurements and well-established clinical parameters.ResultsWe found good to excellent test–retest reliability for the ROM in all glove movement patterns (Intraclass correlation coefficients = 0.83–0.94), underlining the ability to capture clinical stability. Moreover, the glove demonstrated adequate, sensitivity and specificity in detecting hand motor impairment (area under the curve (AUC): 0.714–0.780), and it performed better than NCS and HRUS (AUC: 0.552/0.701). The AUC values for the metrically scaled parameters include: Vigorimeter (AUC: 0.929) and R-ODS (AUC: 0.698). Additionally, the data glove proved to be a valid tool, as we demonstrated moderate to strong, significant correlations between the glove and established clinical parameters (especially Vigorimeter), as well as PROMs (especially R-ODS).ConclusionsThis data glove allowed for a non-invasive assessment of the hand motor function and yielded investigator-independent results that reliably reflected individual functional deficits with relevance to everyday life. Future studies should explore the ability to predict clinically meaningful responses to immunomodulatory treatment and to support and monitor rehabilitation progress, with potential applications in other neurological diseases as well.Trial registration at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS: 00027345), retrospectively registered on 23rd March 2022: https://drks.de/search/de/trial/DRKS00027345

Prenatal Origins of Obstructive Airway Disease: Starting on the Wrong Trajectory?

From the results of well-performed population health studies, we now have excellent data demonstrating that deficits in adult lung function may be present early in life, possibly as a result of developmental disorders, incurring a lifelong risk of obstructive airway diseases such as asthma and chronic obstructive pulmonary disease. Suboptimal fetal development results in intrauterine growth restriction and low birth weight at term (an outcome distinct from preterm complications), which are associated with subsequent obstructive disease. Numerous prenatal exposures and disorders compromise fetal development and these are summarized herein. Various physiological, structural, and mechanical abnormalities may result from prenatal disruption, including changes to airway smooth muscle structure-function, goblet cell biology, airway stiffness, geometry of the bronchial tree, lung parenchymal structure and mechanics, respiratory skeletal muscle contraction, and pulmonary inflammation. The literature therefore supports the need for early life intervention to prevent or correct growth defects, which may include simple nutritional or antioxidant therapy. © 2024 American Physiological Society. Compr Physiol 14:5729-5762, 2024.

Lung Function Recovery from Pulmonary Exacerbations Treated with Oral Antibiotics in Primary Ciliary Dyskinesia.

Patients with Primary Ciliary Dyskinesia (PCD) experience acute pulmonary exacerbations (PEx). In Cystic Fibrosis (CF), PEx treated with oral antibiotics (oPEx) were found to be related to short and long-term lung function deficits, however the impact oPEx on lung function in patients with PCD has not yet been assessed. To assess the impact of oPEx on lung function recovery in PCD and determine the factors associated with poorer response. This was a retrospective study of pediatric patients with PCD followed between 2000 to 2022 at SickKids (Toronto, Canada). PEx were defined as an increase in baseline symptoms with a physician decision to treat with systemic (intravenous (IV) or oral antibiotics. Lung function recovery was defined as a forced expiratory volume in 1 second (FEV1) measurement ≥90% of a stable baseline within 12 months before the PEx. Univariate and multivariate analyses were completed to identify risk factors for nonresponse. 337 PEx events in 85 patients were included in this analysis, of which 297 (88%) were treated with oral antibiotics. The mean (SD) follow up time for patients was 6.7 years (3.5) and the mean age of oPEx was 12.5 years (3.2). Patients with oPEx had a significant drop from baseline in mean FEV1 values at time of PEx (85.1% to 69.5%) with absolute and relative changes of -10.4% and -12.9%, respectively. At follow up (3 months post PEx) and up to 12 months post PEx, the mean FEV1 was 79.6% and 84.1%, respectively. 73.2% of the patients had lung function recovery at follow up visit which increased to 84.2% within one year post event. We identified two risk factors for nonresponse: being a non responder on the last PEx and younger age at time of oPEx. Conclusions oPEx in PCD show a similar pattern previously seen in CF patients with a decrease in FEV1 during exacerbation and an improvement post therapy. Most oPEx events recover to baseline FEV1 within the year post-exacerbation, with younger age and being non responder in the last PEx identified as risk factors for nonresponse.

Apolipoprotein E dysfunction in Alzheimer's disease: a study on miRNA regulation, glial markers, and amyloid pathology.

Apolipoprotein E (ApoE) plays a crucial role in lipid homeostasis, predominantly expressed in astrocytes and to a lesser extent in microglia within the central nervous system (CNS). While the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), its precise role in AD pathogenesis remains elusive. Apoe-knockout (Apoe-ko) mice, mice expressing human APOE4, and human APOE4 carriers exhibit similar deficits in lipid metabolism, cognitive and behavioral functions, and neurodegeneration. The retina, as part of the CNS, has been studied to investigate the underlying mechanisms of AD, including neuroinflammation, amyloid aggregation, and neurodegeneration. This study explores ApoE's role in AD by analyzing brain and eye samples from Apoe-ko mice, focusing on identifying potential retinal biomarkers associated with ApoE dysfunction. We compared female Apoe-ko mice on a regular diet to age-matched C57BL/6J controls at 3 and 9 months. Our investigations included microRNAs (miRNAs), their target messenger RNAs (mRNAs), and selected protein markers, including astroglial (Gfap), microglial/macrophage (Iba1 and Trem2) markers, and amyloid precursor protein (APP)/amyloid-β (Aβ) peptides implicated in AD pathogenesis. We also examined female Apoe-ko mice on a high-fat diet versus a regular diet at 9 months for differential miRNA and mRNA expressions. Our findings demonstrated that miRNA levels were generally lower in 3-month-old Apoe-ko mice but increased in 9-month-old mice across five distinct brain regions, as well as in eye tissue and tear fluid. A high-fat diet further enhanced miRNA dysregulation in brain and eye tissues, but not in tear fluid. Target mRNAs were generally higher in the neocortex-hippocampus and eye tissue of 3-month-old Apoe-ko mice but decreased with age, except for glial cell mRNAs like Gfap and Aif1. Protein analysis revealed elevated Gfap expression, and increased APP/Aβ peptide accumulation in the neocortex-hippocampus, including brain endothelial cells at the meninges, as well as in the retina of 9-month-old Apoe-ko mice. These findings highlight ApoE's pivotal role in AD, demonstrating its impact on inflammatory and amyloidogenic/angiogenic miRNA expression, glial homeostasis, and APP/Aβ peptide clearance. The observed upregulation of proinflammatory miR-146a and anti-amyloidogenic/angiogenic miR-15a in 9-month-old Apoe-ko mice suggests their potential as tear-based biomarkers for ApoE dysfunction.