Reviews of physiology, biochemistry and pharmacologyUndurti N Das
Parkinson's disease (PD) is due to degeneration of dopaminergic neurons in substantia nigra pars compacta. PD neuropathology is characterized by the presence of Lewy bodies that contain aggregated α-synuclein, which has been implicated in a range of interactions with phospholipid membranes and free fatty acids. I propose that α-synuclein interacts with arachidonic acid (AA) to regulate the function of dopaminergic neurons. α-Synuclein sequesters AA, whereas AA induces the formation of oligomers that are alpha-helical; resistant to fibril formation; more prone to disaggregation, enzymatic digestion, and degradation; and hence less likely to cause neuronal damage and induce PD. In addition, AA interacts with syntaxin to regulate exocytosis of various neurotransmitters, including dopamine. AA has potent anti-inflammatory actions, serves as a mechanotransducer, influences cell membrane fluidity, enhances glucose uptake by neurons, possesses cytoprotective action, and is the precursor of anti-inflammatory lipoxin A4 (LXA4), actions that maintain the integrity of dopaminergic neurons in the substantia nigra pars compacta. The dynamic equilibrium among α-synuclein, syntaxin, AA, exocytosis of dopamine, formation of LXA4, and the inflammatory process is involved in the development of PD. This implies that deficiency of AA can render dopaminergic neurons susceptible to inflammatory neurodegeneration and development of PD. Hence, it is proposed that administration of AA and DHA (that are present in substantial amounts in the brain) can be used in the prevention and management of PD.
Reviews of physiology, biochemistry and pharmacologyUndurti N Das
The human brain is rich in AA and DHA, which are crucial for normal brain growth and development and memory. They form a major structural component of neurons of the cerebral cortex and photoreceptor cells in the retina. AA and DHA support synaptic plasticity and contribute to efficient neurotransmission. Adequate amounts of AA and DHA support neuronal growth and the formation of new synapses and thus are crucial for memory and cognitive function.Depression, anxiety, schizophrenia, and other neurological diseases occur more frequently in those with coronary heart disease (CHD) and vice versa. Transient depression and anxious mood can trigger acute cardiac events and fatal arrhythmias. Serotonin and catecholamines play a significant role in depression and anxiety and are known to activate platelets, which increases the risk of cardiovascular events. Both serotonin and catecholamines modulate inflammation, while levels of pro-inflammatory cytokines are elevated in anxiety and depression and other psychiatric conditions and CHD. Depression, anxiety, and CHD involve altered essential fatty acid metabolism, particularly of AA and DHA, whose metabolites can inhibit platelet activation, suppress inflammation, and enhance acetylcholine levels. Acetylcholine, in turn, regulates the concentrations of serotonin and catecholamines. Acetylcholine and catecholamines have a modulatory influence on inflammation. Exercise is anti-inflammatory in nature, by virtue of its ability to enhance the formation of anti-inflammatory lipoxin A4, resolvins, protectin, and maresins and suppress pro-inflammatory cytokines IL-6 and TNF-α. AA and DHA enhance acetylcholine release and augment the formation of endothelial nitric oxide (NO). These results imply that anxiety, depression, and CHD are low-grade systemic inflammatory conditions that could benefit from the administration of appropriate amounts of AA and DHA. Risk factors for CHD such as obesity, type 2 diabetes mellitus, dyslipidemia, and atherosclerosis are all considered pro-inflammatory conditions.Since both neuropsychiatric conditions and recovery from CHD need the generation of new neurons and myocardial cells respectively that need to get integrated to the existing cells/tissues, it is proposed that a combination of brain-derived neurotrophic factor (BDNF) (that is needed for neuronal cells to survive), growth hormone (GH) (needed for growth of the newly generated neurons and myocardial cells), resolvins/lipoxins/protectins/maresins (needed to suppress inflammation and enhance wound healing), retinoic acid (needed for vertebrate development), and 1,4-DPCA that inhibits the excessive deposition of collagen and an inducer of formation of new blood vessels (angiogenesis) may be of significant benefit both in the prevention and management of neuropsychiatric conditions and CHD and their associated conditions such as obesity, diabetes mellitus, dyslipidemia, and atherosclerosis.
Methods in molecular biology (Clifton, N.J.)Jinglong Zhang, Kristen J Brennand, Bin Zhang, Minghui Wang, Aiqun Li
CRISPR screens, such as expanded CRISPR-compatible cellular indexing of transcriptomes and epitopes by sequencing (ECCITE-seq), enable the simultaneous measurement of transcriptomes, gRNA identity, and cell-surface protein expression at single-cell resolution to systematically interrogate gene function. This platform provides a powerful and scalable experimental approach for validating disease-associated regulators identified by large-scale association studies and other computational methods, including network-based analyses of multi-omics data. Here, as an example application, we describe an ECCITE-seq framework to characterize the transcriptomic consequences of perturbing multiple neuronal key driver genes associated with Alzheimer's disease (AD) in human-induced pluripotent stem cell (hiPSC)-derived neurons. More broadly, by integrating customized pooled gRNA libraries with different CRISPR effectors across multiple cell types, this approach allows for the assessment of the regulatory impact of candidate genes implicated in development and disease processes.
Brain impairment : a multidisciplinary journal of the Australian Society for the Study of Brain ImpairmentCornelia Wellecke, Mark Brown, Di Winkler, Jacinta Douglas
BACKGROUND: Peer support for people with acquired neurological disability is gaining worldwide popularity, yet it is conceptually unclear what constitutes valuable peer interactions. To build a greater understanding from the lived experience perspective, this scoping review synthesised literature on how adults with acquired neurological disability experience and perceive peer support. METHODS: Peer-reviewed literature published between 2013 and 2024 was identified through systematic searches of five databases. Thirty-two studies were included, covering a range of disabilities (e.g. acquired brain injury, spinal cord injury, multiple sclerosis) and peer support forms (e.g. one-to-one, group, informal). RESULTS: Analysis revealed that peer support participants perceive value across three domains: (1) capacity-building, (2) social connection, and (3) psychological adjustment. However, they can also experience frustrations and challenges that directly oppose these benefits. Suitable characteristics of peers and structures of peer programs, including acknowledgement of individual differences in the peer support experience, were identified as key to successful peer interactions. CONCLUSIONS: Peer support holds multifaceted value for people with acquired neurological disability; however, it is also a complex intervention that carries risks and requires sensitivity to individual variation. Consideration of these dynamics should be embedded in the design of peer programs and pursuit of peer support research.
Problemy sotsial'noi gigieny, zdravookhraneniia i istorii meditsinyM S Cherepianskii, A V Baranov, G O Penina
The multiple sclerosis is chronic autoimmune disease with high risk of disability. The effective management of this disease directly depends on the timely prescription and escalation of treatment with medications altering course of multiple sclerosis. The key factor in optimizing medical care is organization of specialized structures. The specialized Multiple Sclerosis Clinic was opened in the Komi Republic in the beginning of 2021. The purpose of the study is to assess dynamics of key indicators of medication therapy of multiple sclerosis during 2018-2024 and to determine impact of opening of Multiple Sclerosis Clinic on these indicators using methods of statistical analysis.
GliaAnda Cimpean, Jana Mizerakova, Noelia Martinez-Varea, Dana Marekova, Lucia Machova Urdzikova, James W Fawcett, Pavla Jendelova, Jessica C F Kwok
Aging-associated cognitive decline is closely linked to dysregulated glial activity and chronic neuroinflammation, which together constrain neuronal plasticity. Astrocytes and microglia are key regulators of the brain extracellular matrix (ECM), including perineuronal nets (PNNs), whose accumulation during aging contributes to reduced synaptic flexibility. Targeting ECM-glia interactions therefore represents a promising strategy to modulate neuroinflammatory and plasticity-related processes. Here, we investigated the effects of long-term oral administration of 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan and chondroitin sulfate synthesis, on glial reactivity, ECM remodeling, and cognitive function in aged mice (20-22 months). Aging was associated with PNN remodeling alongside pronounced astrocytic and microglial activation and infiltration of peripheral immune cells. Chronic 4-MU treatment reduced PNN accumulation to levels observed in younger (10-month-old) mice, indicating effective ECM remodeling. Notably, this was accompanied by a marked attenuation of astrocyte and microglial activation and a reduction in immune cell infiltration, suggesting a broad normalization of the neuroinflammatory milieu. Functionally, these glia-associated changes were paralleled by improved recognition memory, with treated aged mice performing at or above the level of younger controls. Long-term 4-MU administration was well tolerated, with no evident adverse effects. Together, our findings identify ECM modulation as a mechanism to regulate glial reactivity and neuroimmune interactions in the aging brain. By targeting hyaluronan-dependent pathways, 4-MU links ECM remodeling to suppression of neuroinflammation and restoration of cognitive function, highlighting its therapeutic potential in age-related neurodegenerative processes.
Journal of the peripheral nervous system : JPNSKryštof Prášil, Veronika Potočková, Tomáš Nedělka, Alžběta Prášilová, Radim Mazanec
BACKGROUND AND AIMS: Data on cardiovascular autonomic neuropathy (CAN) are sparse in Charcot-Marie-Tooth disease. We aimed to determine the prevalence of CAN in CMT1A and CMTX1 and its associations with neuropathy severity and heart rate variability (HRV), compared with age- and sex-matched controls. METHODS: Thirty-six CMT1A, 24 CMTX1 patients, and 62 controls underwent cardiovascular autonomic testing including the modified Ewing battery (Expiration: Inspiration ratio, 30:15 ratio, Valsalva ratio; complete in 41/62 controls), orthostatic blood pressure measurement, and HRV analysis from 10-min supine-standing recordings. Abnormality was defined using age-stratified 2.3rd-percentile cutoffs. CMT Neuropathy Score version 2 (CMTNSv2) and Survey of Autonomic Symptoms were recorded. Comparisons used Fisher's exact test and the Kruskal-Wallis test with Holm correction; HRV was age- and sex-adjusted. RESULTS: CAN was present in 30.6% of CMT1A and 33.3% of CMTX1, versus 10.0% of controls (p = 0.011). Definite CAN occurred only in CMT1A (11.1%), although the CMT1A-CMTX1 contrast was not significant (p = 0.14). The Valsalva ratio was lower in CMT1A than in CMTX1 (median 1.54 vs. 1.89, p = 0.001), with abnormal values confined to CMT1A (14.7%). After age and sex adjustment, vagal HRV was reduced in CMT1A but not CMTX1. INTERPRETATION: CAN affects approximately one-third of patients with CMT1A and CMTX1, roughly three times the control prevalence. Overall prevalence was similar in the two genotypes, but Valsalva impairment was confined to CMT1A, indicating that similar prevalence does not imply an identical pattern of involvement. Cardiovascular autonomic assessment warrants consideration in these patients, particularly perioperatively.
Australasian journal on ageingYared Belete Belay, Anita Goh, Briony Dow, Christa Dang, Steven Savvas, Frances Batchelor, Lidia Engel
OBJECTIVES: This paper reports the health economic component of the broader Promoting Independence Through Quality Dementia Care at Home (PITCH). The broader PITCH trial primarily evaluated the effect of dementia training on home care workers' competence in providing dementia care; this analysis evaluated intervention costs and selected secondary client and caregiver outcomes. METHODS: The PITCH intervention was tested via a multi-site national pragmatic stepped-wedge cluster randomised clinical trial, conducted across three Australian states. A micro-costing approach was used to estimate intervention and resource use costs. Secondary outcomes for clients and caregivers, including quality of life (QoL), caregiver burden and dyadic interaction, were assessed. Means (SDs) described costs and outcomes, with linear and multilevel mixed-effects regression used to estimate crude and adjusted mean differences, respectively. RESULTS: There were no significant improvements in most client and caregiver health, QoL, caregiver burden or dyadic interaction outcomes during the intervention phase, with decreases in proxy-reported Dementia QoL Utility (DEMQOL-U) and client self-reported visual analogue scale (EQ VAS). Improvements in caregiver burden and dyadic interaction were observed but were not statistically significant. Total costs increased from AU$68,925 in the control to AU$133,660 in the intervention phase, with an adjusted mean difference of AU$67,146 (95% CI: AU$16,957 to AU$117,334). CONCLUSIONS: This health economic analysis should be interpreted separately from and alongside, the main PITCH trial findings on the primary outcome of home care workers' competence. Within this secondary analysis, PITCH was associated with higher total costs during the intervention phase and no clear evidence of improvement in the selected secondary client and caregiver outcomes.
Journal of the peripheral nervous system : JPNSPeter Nørregaard Hansen, Lars Markvardsen, Hatice Tankisi, Henning Andersen, Thomas Krøigård, Søren Sindrup
BACKGROUND AND AIMS: Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an immune-mediated neuropathy that may cause persistent disability despite immunoglobulin treatment. Ion channel dysfunction has been demonstrated in CIDP, but no therapies specifically target this mechanism. We investigated whether fampridine improves clinical function and electrophysiological measures in CIDP patients with residual symptoms. METHODS: In this two-center, randomized, double-blind, placebo-controlled crossover trial, patients with CIDP receiving stable subcutaneous or intravenous immunoglobulin were assigned to 4 weeks of fampridine (10 mg twice daily) or placebo, separated by a washout period. Co-primary outcomes were changes in Six-Spot-Step Test (SSST) and Nine-Hole Peg Test (9-HPT). Secondary outcomes included clinical scores, patient-reported outcomes, nerve conduction studies, and nerve excitability testing. RESULTS: Twenty-eight patients were included in the study. No significant differences were observed between fampridine and placebo for SSST (p = 0.154) or 9-HPT (p = 0.857). Grip strength and R-ODS worsened during fampridine compared with placebo (Bonferroni-adjusted p = 0.007 for both), while other clinical outcomes showed no differences. Median nerve CMAP amplitude with proximal stimulation increased significantly during fampridine treatment (adjusted p = 0.040). No significant changes were observed in other electrophysiological variables, including nerve excitability testing. No serious adverse events occurred and adverse effects were predominantly mild. INTERPRETATION: Our study did not provide evidence that fampridine improves clinical function in CIDP patients with residual disability during stable immunoglobulin therapy. Targeting ion channel dysfunction in CIDP remains of interest, but alternative strategies may be required.
Vascular dementia (VaD), caused by reduced cerebral blood flow, is a common form of dementia lacking effective treatments. This study used genome-wide association study (GWAS) summary data, Mendelian randomization (MR), and colocalization analyzes to prioritize blood metabolites and candidate therapeutic targets associated with VaD. Key analyzes included metabolic pathway enrichment, a descriptive Phenome-Wide Association Study (PheWAS) of the broader curated association profiles of prioritized genes, mediation analysis, and in-silico compound prioritization with molecular docking. Twenty-four metabolites were associated with VaD, with taurocholate and glutaroyl carnitine prioritized as tier 1 metabolite-gene pairs. Pathway analysis implicated aminoacyl-tRNA and branched-chain amino acid biosynthesis pathways. Apolipoprotein E (APOE) and glutaryl-CoA dehydrogenase (GCDH) were prioritized candidate genes. The PheWAS recapitulated APOE's curated associations with Alzheimer's disease and lipid traits, whereas GCDH had a more restricted curated association profile dominated by glutaric acidemia type I; these patterns provide pleiotropic context but do not establish safety. Single-cell RNA-sequencing analysis localized APOE predominantly to microglia and astrocytes and GCDH predominantly to oligodendrocytes, providing cell-type-specific context. Mediation analysis identified a statistically supported indirect pathway involving alpha-2-macroglobulin receptor-associated protein for taurocholate. Aflatoxin B1 was highly ranked in an in-silico query but, because of its established toxicity, is not a therapeutic candidate. This study prioritizes metabolic and genetic candidates for experimental and clinical follow-up rather than establishing therapeutic targets.
Australasian journal on ageingIsabella Tan, Aletta E Schutte, Catherine Morgan, Henry Brodaty, Sonali R Gnanenthiran, Katya Numbers, Hueiming Liu, Menglu Ouyang, Paola Incerti, Padraig Kitt…
OBJECTIVE: To determine the potential feasibility and acceptability of combined screening for raised blood pressure (BP), atrial fibrillation (AF) and cognitive impairment (CI) in older adults within a setting of hearing health assessment for detection of hearing loss. METHODS: We recruited participants aged 65 years or older (n = 35; mean age 73 ± 6 years, 51% females) from the community to attend a single visit lasting approximately 60-90 min. Prior to a comprehensive hearing assessment, BP was measured with an automatic BP monitor with AF detection, and CI screening was conducted using the patient section of the General Practitioner Assessment of Cognition instrument. A subset of participants (n = 16, 50% females) was interviewed post study to evaluate acceptability. RESULTS: A total of 21 positive screens (six raised BP; two possible AF; 13 hearing loss) and 12 potential positive screens for possible CI were detected in 25 (71%) participants. Eight participants (23%) had more than one newly detected condition. Interviews revealed that combined screening was feasible and acceptable as participants felt it was 'convenient,' 'saves time' and 'more efficient.' CONCLUSIONS: Combined screening for raised BP, AF and CI in older adults within a hearing health assessment setting appears feasible and was generally perceived positively by participants in this pilot study. Further implementation studies should be conducted with process and outcome evaluation embedded to confirm feasibility and acceptability as well as to evaluate cost-effectiveness and health outcomes for combined screening in older adults.
GliaWei Kong, Hui Li, Zhou Wu, Yoshinori Hayashi, Hiroshi Nakanishi, Juan Zhao, Yutong Zhang, Hong Qing, Zhenzhen Quan, Junjun Ni
Neuroimmune responses critically shape the progression and outcome of ischemic stroke, yet the cell type-specific roles of myeloid populations remain incompletely defined. Cathepsin B (CatB), a lysosomal cysteine protease, has been implicated in neuroinflammation, but its contribution from distinct myeloid subsets is unclear. Transient middle cerebral artery occlusion (tMCAO) was induced in wild-type and CatB-deficient mice. Bone marrow chimeras were generated to selectively delete CatB in peripheral myeloid cells or resident microglia. Infarct severity, mortality, myeloid phenotypes, and transcriptional programs were assessed using flow cytometry, immunofluorescence, and bulk and cell type-resolved RNA sequencing. CatB expression was markedly upregulated in ischemic brain myeloid cells, with higher levels in infiltrating macrophages than in microglia. Selective deletion of CatB in peripheral myeloid cells, but not in microglia, significantly reduced infarct size, mortality, and pro-inflammatory gene expression after tMCAO. Transcriptomic analyses showed suppression of inflammatory pathways and preservation of neuronal signaling in mice lacking macrophage-derived CatB. Cell type-resolved RNA sequencing revealed that CatB deficiency shifted infiltrating macrophages toward a pro-resolving, tissue-repair phenotype characterized by increased expression of M2-associated genes, including Chil3. Consistently, CatB-deficient macrophages displayed enhanced pro-resolving polarization in response to ischemic neuron-derived signals in vitro. CatB was also elevated in circulating Ly6C+ monocytes after stroke. These findings identify peripheral myeloid-derived CatB as a key driver of ischemic brain injury and a potential therapeutic target.
Pakistan journal of pharmaceutical sciencesYan Dai, Anlang Dai, Yuhuan Liu
BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune demyelinating diseases of the central nervous system. The role of microRNA-34b (miR-34b) in NMOSD pathogenesis remains unclear. This study investigates the expression and functional mechanism of miR-34b in NMOSD, specifically its regulation of the TIA-1-stress granule pathway. OBJECTIVES: To determine the expression level of miR-34b in NMOSD tissues and cell lines and to elucidate whether miR-34b suppresses cell proliferation and promotes apoptosis by directly targeting the TIA-1-stress granule pathway. METHODS: Real-time PCR was used to detect miR-34b expression in 25 NMOSD tissue specimens obtained from a hospital laboratory (13 early-stage, 12 chronic-stage) and 10 normal control tissues, as well as in RGC-5 cells. RGC-5 cells were transfected with miR-34b mimics, inhibitors or negative controls. Cell proliferation was assessed by MTT assay and cell cycle distribution and apoptosis was analyzed by flow cytometry (PI staining and Annexin V-FITC/PI double staining, respectively). The direct binding between miR-34b and the 3'-UTR of TIA-1 mRNA was validated using a dual-luciferase reporter assay. Protein expression levels of TIA-1, SG, HuR, CDK2 and BCL-2 were measured by Western blot. A rescue experiment was performed by co-transfecting miR-34b mimics with a TIA-1 overexpression plasmid. RESULTS: miR-34b was lower in NMOSD vs controls (0.32 ± 0.08 vs. 1.00 ± 0.12, P<0.01), especially in the chronic stage. miR-34b mimics inhibited proliferation, induced G0/G1 arrest (68.5% vs. 52.1%, P<0.01) and increased apoptosis (22.6% vs. 8.3%, P<0.001). miR-34b inhibitor had opposite effects. miR-34b directly bound TIA-1 3'-UTR and downregulated TIA-1, SG, HuR. TIA-1 overexpression partially reversed miR-34b effects. CONCLUSIONS: miR-34b is downregulated in NMOSD. Overexpression of miR-34b suppresses proliferation and promotes apoptosis by targeting the TIA-1-stress granule pathway. Restoring miR-34b may be a therapeutic strategy for NMOSD.
Neuropsychopharmacology reportsNaoki Obata, Kenshi Terajima, Gen Miura, Yuta Muratake, Shun Irie, Yuichiro Watanabe
BACKGROUND: Neurosyphilis may present with a variety of clinical symptoms and neuroimaging findings and is thus likely to be overlooked. We report a case of neurosyphilis presenting with dementia, limbic encephalitis, and normal pressure hydrocephalus. CASE PRESENTATION: A 47-year-old man had gradually experienced cognitive decline for over a year. He was admitted to a psychiatric hospital. Brain computed tomography imaging showed ventricular enlargement. Serological tests for syphilis were positive. He was transferred to our hospital, where he exhibited gait disturbance, cognitive impairment, and urinary incontinence. Brain magnetic resonance imaging showed high signal intensity in both medial temporal lobes. Treponemal cerebrospinal fluid testing was positive. He was treated with intravenous benzylpenicillin for 36 days and two courses of intravenous methylprednisolone pulse therapy. His psychomotor agitation required physical restraint for 37 days and treatment with risperidone. Although his gait disturbance and urinary incontinence improved, no clinically meaningful change in cognitive impairment was observed. The high signal intensity on repeat imaging was attenuated. He was transferred back to the psychiatric hospital 3 months after admission. CONCLUSION: This case of neurosyphilis was characterized by early-onset dementia with limbic encephalitis and normal pressure hydrocephalus. Psychiatrists should be aware of the possibility of neurosyphilis in such cases.
Journal of the peripheral nervous system : JPNSRuby F Ross, Jennifer A Langsdorf, Norman Latov
BACKGROUND AND AIMS: Chronic inflammatory demyelinating neuropathy (CIDP) is a rare, immune-mediated neuropathy that is distinct from other immune-mediated, paraneoplastic, and paraproteinemic neuropathies that may have overlapping clinical features. Identification of the specific diagnosis in each patient is important as each of these disorders has distinct pathophysiology and treatment response. CASE REPORT: Here, we present an atypical case of CIDP in which the patient developed an IgM monoclonal gammopathy with positive anti-ganglioside antibodies over 20 years into his disease course. INTERPRETATION: Patients with CIDP may be predisposed to develop IgM autoantibodies or monoclonal gammopathies. If a patient with CIDP experiences clinical worsening while on maintenance therapy, it may be helpful to test for anti-ganglioside antibodies and monoclonal gammopathies and reassess if alternative treatment would be useful.
GliaNianzhuang Qiu, Jie Zhang, Huan Yi, Sihan Dong, Lei Han, Zhendong Feng, Shumin Gao, Jie Shi, Jia Jia Liu, Ye Wu, Xunbin Wei, Ya Bin Wei
Alexander disease (AxD) is a rare neurodegenerative disorder characterized by the pathological accumulation of Rosenthal fibers (RFs) and astrocytic inflammation. Despite advances in elucidating its genetic basis, effective therapeutic strategies remain limited. Recent studies indicate that astrocytes in AxD exhibit excessive mitochondrial fragmentation, which may cause mitochondrial dysfunction and inflammatory response. Photobiomodulation (PBM) has been shown to improve mitochondrial function and exert anti-inflammatory effects, suggesting it may be a promising candidate for the treatment of AxD. Here, we report that exposure to 1070-nm infrared light exerts therapeutic efficacy in AxD. Specifically, using the astrocytes derived from AxD patients and a mouse model of AxD, we demonstrate that PBM regulates AMPK/mTOR signaling and promotes mitophagy, thereby attenuating reactive oxygen species production from fragmented mitochondria and subsequent inflammatory status. This study suggests PBM may serve as a novel, non-invasive therapeutic approach for the treatment of AxD.
Pakistan journal of pharmaceutical sciencesKaihua Yang, Leyuan Zhou
BACKGROUND: Bergenin (BN), a C-glucoside of 4-O-methyl gallic acid, exhibits a broad spectrum of pharmacological activities, including notable antioxidant, anti-inflammatory and anticancer effects. OBJECTIVES: This study aimed to explore the impact of polydopamine nanoparticles loaded with bergenin (PDANPs-BN) on glioma and their mechanisms of action. METHODS: PDANPs-BN nanocomposites were prepared and U251 cells were cultured and divided into the BN group and the PDANPs-BN group. The biological processes of U251 cells were observed by using CASC11 mimic, si-CASC11 and agonists and inhibitors of AKT3. RESULTS: Compared to free BN, PDANPs-BN significantly inhibited the malignant biological behavior of U251 cells, reducing the cell proliferation rate by approximately 45% and suppressing migration capacity by about 60% (P<0.05). Mechanistic studies revealed that PDANPs-BN downregulated CASC11 expression levels by 2.1-fold, thereby inhibiting AKT3 signaling pathway activity. The strongest antitumor effect was observed when combined with si-CASC11 and an AKT3 inhibitor. While the addition of an AKT3 agonist partially reversed this effect, cell proliferation remained suppressedand colony-forming ability was altered. CONCLUSION: PDANPs-BN acts by targeting the CASC11/AKT3 axis, resulting in downregulation of CASC11 and consequent inhibition of AKT3 signaling, which ultimately curbs the malignant progression of glioma.
Journal of the peripheral nervous system : JPNSDelmont Emilien, Cintas Pascal, Tard Céline, Boucraut José, Magy Laurent, Frachet Simon, Labeyrie Céline, Echaniz-Laguna Andoni, Noel Nicolas, Svahn Juliette, …
BACKGROUND AND AIMS: In anti-myelin-associated glycoprotein (MAG) neuropathy, the efficacy of rituximab (RTX) is not demonstrated in randomized controlled trials. Combinations of RTX with conventional chemotherapy (immunochemotherapy, ICT) may provide potential benefit, but systematic evaluations are lacking. We aimed to compare the efficacy and safety of RTX and ICT in a multicenter retrospective real-world cohort. METHODS: Patients with anti-MAG antibody titers > 10 000 Buhlmann titer units (BTUs) were included. Treatment response was defined as an improvement of ≥ 1 point in the Overall Neuropathy Limitation Scale (ONLS) compared to baseline. Propensity score matching was used to account for differences in baseline characteristics between treatment groups. RESULTS: A total of 230 patients were included: 150 received RTX and 80 received ICT. Mean follow-up was 4 years (range, 1-20 years). One year after treatment, clinical improvement occurred in 61/147 (41%) patients treated with RTX and 39/78 (50%) treated with ICT (OR = 1.4 [0.8-2.5] p = 0.3). At last follow-up, clinical improvement occurred in 55/150 (37%) patients treated with RTX and 31/80 (39%) treated with ICT (OR = 1.1 [0.6-1.9] p = 0.8). Propensity score matching yielded similar results. Among ICT regimens, dexamethasone-RTX-cyclophosphamide was associated with the highest response rate. RTX induction, 1 g days 1 and 15, seemed superior to four-weekly infusions. Adverse events were more frequent with ICT than with RTX (28% vs. 15%; OR = 2.20 [1.07-4.54], p = 0.02). INTERPRETATION: In this cohort, adding chemotherapy to RTX was not associated with greater long-term improvement, despite a higher rate of adverse events. Prospective controlled studies are needed.
BACKGROUND: Elderly patients with cervical radiculopathy present therapeutic challenges owing to comorbidities and medication-related risks. Long-term pharmacotherapy and surgical interventions are often suboptimal, necessitating evaluation of optimized pulsed radiofrequency strategies under image guidance. OBJECTIVES: This superiority trial compared the efficacy and safety of ultrasound-guided cervical nerve root high-voltage pulsed radiofrequency (HVP-PRF) versus conventional pulsed radiofrequency (C-PRF) for pain management in elderly patients with cervical radiculopathy. METHODS: This single-center, parallel-group, assessor-blinded randomized controlled trial enrolled patients aged 60-85 years with cervical radiculopathy, randomly assigned (1:1) to HVP-PRF (70 V) or C-PRF (45 V). Procedures were performed under ultrasound guidance with sensory/motor stimulation confirmation and temperature ≤42°C. The primary outcome was change in upper-limb radiating pain on the Numeric Rating Scale (ΔNRS) from baseline to 3 months. Secondary outcomes included Neck Disability Index (NDI), neck pain NRS, Patient Global Impression of Change, responder rates, rescue analgesia use, and adverse events. Follow-up occurred at 1 week, 1, and 3 months. RESULTS: A total of 104 patients were randomized and 101 received treatment. At 3 months, HVP-PRF demonstrated significantly greater radiating pain improvement versus C-PRF (adjusted mean difference 1.24, 95% CI 0.46-2.02, P=0.002). Functional improvement (NDI) was superior in the HVP-PRF group at 3 months (AMD 6.47, 95% CI 2.11-10.83, P=0.004). Responder rates (≥50% pain reduction) were higher with HVP-PRF at 3 months (68.75% vs. 42.22%, OR 3.01, P=0.011) and 6 months (65.22% vs. 43.18%, OR 2.52, P=0.035). Rescue analgesic use was lower in the HVP-PRF group during 1-3 months intervals (both P<0.05). Adverse event rates were comparable (27.45% vs. 32.00%). CONCLUSION: Under ultrasound visualization and electrical stimulation-based target confirmation with temperature control ≤42°C, HVP-PRF provided greater and more durable relief of upper limb radiating pain compared with C-PRF in elderly patients with cervical radiculopathy, with a comparable safety profile.
Pakistan journal of pharmaceutical sciencesRoberto Lozano, Aragn Health Service, Zaragoza Zaragoza, Spain Spain
BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder treated with disease-modifying therapies such as risdiplam. In Spain, its use is regulated by a national pharmacoclinical protocol that requires structured monitoring. OBJECTIVES: To evaluate real-world use, protocol adherence and registry completeness of risdiplam in routine clinical practice. METHODS: A retrospective registry-based case series was conducted including patients with spinal muscular atrophy treated with risdiplam.Variables included age, SMA subtype, SMN2 copy number, diagnostic confirmation, treatment sequence and persistence. Protocol adherence was assessed according to national criteria. RESULTS: Ten patients were included in the study. SMA types II and III predominated, with one presymptomatic case. SMN2 copy number ranged from three to four in documented cases. Protocol adherence was confirmed in 70% of patients, while 30% lacked key eligibility variables. No off-protocol prescribing was identified. Treatment persistence was 100% and 60% of patients had previously received nusinersen. CONCLUSION: Risdiplam was used appropriately in accordance with protocol criteria. Registry incompleteness, rather than clinical deviation, was the main limitation and standardized data capture is essential for real-world evaluation.
RATIONALE: Jingtong Granules is a clinically approved seven-herb formula for CSR, a condition in which radicular pain is sustained partly by inflammatory and immune processes, yet the immune-cellular state of CSR and the immune-level mechanism of the formula remain poorly defined. METHODS: Using peripheral-blood transcriptomes from GSE223227 (7 controls, 9 CSR, and 30 degenerative cervical myelopathy), we profiled nine immune lineages by signature scoring, prioritized CSR-associated features with six machine-learning methods under permutation-based specificity testing, localized signature genes on the Human Protein Atlas sorted immune-cell reference, and linked the immune program to mass-spectrometry-confirmed constituents of Jingtong Granules by network pharmacology, molecular docking, molecular dynamics, and MM-GBSA. Two-level Mendelian randomization against cervical-specific FinnGen endpoints tested genetic causal directionality. RESULTS: CSR blood showed a bidirectional immune-rebalancing pattern: reduced NK-cell activity (p = 0.0164), increased M1-macrophage activity (p = 0.0311), and directionally higher neutrophil and lower CD8-cytotoxic scores. The neutrophil/myeloid effector program discriminated CSR from controls (AUROC 0.79), exceeding a size-matched random-panel null, whereas a generic NF-κB/TNF panel performed near chance; a composite rebalancing score reached a preliminary AUROC of 0.90 (95% CI 0.71-1.00). Network pharmacology nominated MPO as a formula-associated immune target, whereas patient-upregulated, neutrophil-localized ELANE and CTSG were prioritized as structurally tractable granule enzymes. The validated quality markers nodakenin and paeoniflorin docked favorably to ELANE and CTSG and remained in their catalytic pockets during molecular dynamics, with MM-GBSA binding free energies of -16.0 to -33.5 kcal/mol. Both markers also showed favorable drug-like physicochemical profiles. Mendelian randomization gave no support for an upstream genetic-causal role of the myeloid-skewed immune state in cervical disk disorders or radiculopathy. CONCLUSIONS: These exploratory, single-cohort findings characterize CSR peripheral blood as myeloid-skewed and cytotoxic-attenuated and nominate a traceable constituent-to-enzyme hypothesis in which mass-spectrometry-confirmed Jingtong Granules markers may engage patient-upregulated neutrophil granule enzymes, warranting replication and experimental validation.
BACKGROUND: In aspirin-treated unstable angina (UA), heterogeneity in on-treatment arachidonic acid (AA)-induced platelet aggregation and cholesterol reduction contributes to residual ischemic risk. Insomnia is prevalent in coronary disease, yet its association with specific aspirin-sensitive platelet aggregation kinetics and lipid parameters remains undefined. METHODS: In a cross-sectional cohort of 198 aspirin-treated UA patients, 38 routine hematologic or biochemical variables including AA-induced platelet aggregation indices were analyzed using principal component analysis (PCA) and unsupervised phenotyping (k-means and hierarchical clustering). Elastic-net logistic regression and machine learning classifiers were used for multivariable modeling, and performance was estimated by cross-validation. Correlation-network analysis and Shapley additive explanations (SHAP) supported interpretability. RESULTS: Unsupervised analyses consistently identified two phenotypes. Insomnia was enriched in a platelet-lipid phenotype characterized by lower platelet aggregation indices and a lower lipid marker profile. The K-nearest neighbors (KNN) model demonstrated strong cross-validated discrimination (AUC = 0.934; average precision = 0.923), while all four classifiers converged with AUC > 0.925. After age matching, elastic-net logistic regression retained only AA-induced maximal platelet aggregation (PmaxAggR) and total cholesterol (CHOL) as independent predictors, with odds ratios of 0.927 and 0.340, respectively (both p < .001). Inflammatory markers, including neutrophil count and monocyte count, were no longer selected. Network analysis placed insomnia within the platelet-lipid module linked to PMaxAggR, CHOL, and some other platelet or lipid indices. CONCLUSIONS: In age-matched, aspirin-treated UA patients, insomnia is independently associated with reduced PMaxAggR and lower CHOL, with inflammatory markers no longer significant after age-balancing. These findings delineate an age-independent platelet-cholesterol axis linked to insomnia, potentially reflecting shared autonomic and neurobiological dysregulation, and motivate sleep evaluation as part of platelet-reactivity phenotyping in this population.
OBJECTIVES: Burnout can impair clinical judgment and is prevalent across all medical subspecialties. Neurology, in particular, is associated with high rates of burnout and low satisfaction with work-life balance. METHODS: A standardized survey using the abbreviated Maslach Burnout Inventory was administered from December 2020 to March 2022. Faculty from 19 academic neurology departments in the United States participated. Demographic, career, compensation, equity, domestic circumstances, parental leave, and burnout data were collected as part of the Women in Neurology Collaborative Study. Statistical analysis was performed using IBM SPSS version 30.0 and R version 4.4.4. RESULTS: Among the 311 neurology faculty participants, 185 (59.5%) identified as women and 277 (89.1%) were clinical faculty members. The mean reported duration of practice was 14.4 years (SD 11.3 years). Approximately 98.4% (n = 306/311) of respondents reported experiencing moderate-to-high levels of burnout. Burnout and depersonalization were consistently high across all career stages (>96.6%), while the subscale of emotional exhaustion (EE) rose significantly by the late-career stage (p < 0.001). Moderate-to-high EE among neurology faculty was associated with sex, academic rank, and career stage. In unadjusted analyses, leadership titles and research involvement were associated with higher rates of EE but were not statistically significant after adjustment for career stage and respective career advancement indicator. Participants in leadership positions had significantly higher observed rates of EE compared with those without leadership roles (p = 0.002). Participants who reported a history of involvement in funded research had significantly higher rates of EE compared with those with no history of funded research (p = 0.001). Among individuals in the mid-career stage, full professors had significantly higher odds of EE compared with assistant professors (OR = 6.00, 95% CI 1.34-26.81; p = 0.019). No significant differences in the rate of overall burnout were detected by sex, academic rank, career stage, or career advancement indicators. DISCUSSION: High burnout and EE rates among academic neurology faculty were common across career stages, with EE rising significantly among late-career faculty members. Higher EE rates were also seen among faculty with leadership roles and funded research involvement, although these associations were not significant after adjustment. Neurology departments may consider measures aimed at reducing burnout in the future, with particular attention to faculty in late-career stages.
Annals of human biologySilvia Caino, Carolina Caminiti, Rocio Rabosto Moleón, Gabriela Krochik, Mariana Del Pino
BACKGROUND: Children with Prader-Willi syndrome (PWS) show distinctive patterns of growth and body composition. Although growth hormone (GH) therapy is widely used, many patients continue to be monitored without treatment, making anthropometric data from untreated populations valuable for clinical follow-up. We previously developed Argentine references for height and body segments in GH-untreated children with PWS. AIM: To extend that work by characterising patterns of adiposity using weight, body mass index (BMI), and skinfold thickness measurements in children with PWS who had not received GH therapy or individualised very low energy diets. SUBJECTS AND METHODS: Anthropometric data were obtained from clinically and genetically confirmed patients followed at a tertiary paediatric hospital. Measurements included weight, BMI, and triceps, bicipital, suprailiac, and subscapular skinfolds. Age and sex specific curves were generated using the LMS method. A total of 167 children were included (82 males, 85 females) with a total of 1,119 weight, 1,009 BMI, 815 triceps skinfold, 643 biceps skinfold and 615 suprailiac skinfold measurements. RESULTS: Weight and BMI centiles showed an early upward shift after the second year of life, with the greatest divergence occurring in early childhood. Skinfold thicknesses were consistently elevated across ages, including in infants and young children, indicating early alterations in body composition. CONCLUSION: Together with previously published Argentine linear growth references, these findings provide a more comprehensive framework for evaluating growth and body composition, particularly adiposity trajectories in children with PWS.
NAR genomics and bioinformaticsAndrea Álvarez-Pérez, Alejandro Rodríguez-González, Jan Baumbach, Lucía Prieto-Santamaría, Mhaned Oubounyt
Alzheimer's disease is a complex neurodegenerative disorder characterized by progressive cognitive decline and neuroinflammation. Although its molecular hallmarks are well documented, cell-type-specific mechanisms driving gene dysregulation remain elusive. While single-cell RNA sequencing resolves cellular states, most studies focus on individual genes rather than coordinated programs. Moreover, a gap persists between interpretable network-based models and artificial intelligence foundation models, which capture complex interactions but lack mechanistic transparency. Whether these approaches converge or provide complementary views remains unclear. We present an integrated study combining SCANet, for reconstructing co-expression and gene regulatory networks, with scGPT foundation model. Applied to over 1.3 million cells across 18 cell types, this approach revealed that Alzheimer-associated transcriptional changes concentrate within coherent co-expression modules, for extracellular matrix organization, immune signaling, and neuronal communication. Genes prioritized by scGPT were largely embedded within SCANet modules, indicating convergence at the gene level; however, higher-order architecture agreement was limited and cell-type-specific. Thus, scGPT highlights influential genes, whereas SCANet resolves their modular organization, providing complementary information. By integrating both methods, we recovered known Alzheimer-related pathways and identified novel regulatory candidates, including the CEBPB-CENPQ axis in vulnerable SST-GABA interneurons. This demonstrates that combining network biology with foundation models enables gene prioritization and mechanistic interpretation.
NAR genomics and bioinformaticsLuca Morandi, Francesco Casadei, Sara De Fanti, Luigi Bonan, Francesco Ravaioli, Flavia Palombo, Alessia Fiorentino, Silvia de Pasqua, Veria Vacchiano, Patrizi…
Expansion repeat disorders are caused by abnormal expansions of short tandem repeats (STRs). We evaluated targeted long-read nanopore sequencing for comprehensive characterization of STR expansions in 132 participants, including patients with myotonic dystrophy type 1 (DM1, n = 51) and DM2 (n = 3) already characterized by Southern blot, C9orf72-associated amyotrophic lateral sclerosis (ALS n = 11) evaluated by repeat primed polymerase chain reaction (RP-PCR; validation group), suspected spinocerebellar ataxia (SCA, n = 46), cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS; n = 13), Huntington's disease (1), Kennedy disease (1), Friedreich ataxia (FRDA, 2), and 4 healthy controls (test group). Native DNA was sequenced using adaptive sampling (AS) on Oxford Nanopore GridION or PromethION-2Solo platforms. Long-PCR sequencing was performed for comparison. We also developed NanoExpansion, a Python-based tool for sizing expanded alleles and detecting sequence interruptions. We correctly characterized all DM1, DM2, ALS, FRDA, Huntington's disease, and Kennedy disease cases, and identified eight SCA27B, two SCA37, three SCA31, one SCA3, and nine CANVAS cases. Compared with the AS approach, long-PCR underestimated alleles exceeding 800 repeats. Repeat interruptions were detected in 27/51 (52.9%) DM1 cases and 1/10 (10%) ALS, but not in CANVAS, FRDA, Huntington's disease, Kennedy disease, or SCA cases. This integrated sequencing analysis pipeline provides accurate, comprehensive characterization of repeat expansion disorders and has the potential to improve routine genetic diagnosis.
BACKGROUND: Evidence regarding repeated remimazolam administration remains limited. We hypothesized that remimazolam would be associated with fewer adverse events than propofol while maintaining stable sedative requirements across three repeated sedation sessions. METHODS: Patients with cervical cancer undergoing three fractions of interstitial brachytherapy were randomized to propofol or remimazolam. The primary outcome was the proportion of sedation episodes with at least one prespecified intraoperative adverse event across three sessions. Secondary outcomes included sedative dose, hemodynamics, and sleep quality assessed using the Pittsburgh Sleep Quality Index (PSQI) and Athens Insomnia Scale (AIS). RESULTS: A total of 100 participants were randomized, of whom 91 completed all three prespecified sedation sessions and were included in the primary per-protocol analysis (46 in the propofol group and 45 in the remimazolam group). Across 138 propofol and 135 remimazolam episodes, overall adverse events were less frequent with remimazolam (17.78% vs. 59.42%; RR, 0.30; 95% CI, 0.18-0.49; p < 0.001). Respiratory depression (3.70% vs. 26.09%; RR, 0.14; 95% CI, 0.04-0.53; p = 0.004) and hypotension (8.15% vs. 41.30%; RR, 0.20; 95% CI, 0.09-0.42; p < 0.001) were also lower with remimazolam. Remimazolam requirements remained stable across sessions (third vs. first: mean difference, 0.19 mg; 95% CI, -0.78 to 1.15; p = 0.846). No significant between-group differences were observed in PSQI or AIS scores. CONCLUSION: Across three consecutive sedation sessions for interstitial brachytherapy, remimazolam was associated with fewer respiratory and hemodynamic adverse events than propofol, while sedative requirements remained stable across the three sessions. TRIAL REGISTRATION: Chinese Clinical Trial Registry (identifier: ChiCTR2500108294).
Nursing inquiryPatricia Morris, Rose McCloskey, Janet Durkee-Lloyd, Karla O'Regan
Bathing Without a Battle is a widely circulated video training resource in residential dementia care, but the assumptions it advances about bathing, refusal, and appropriate nursing practice have received limited critical attention. This paper analyzes how the text constructs resistance to assisted bathing and how it frames legitimate nursing responses to that resistance. A three-part Faircloughian critical discourse analysis is used, attending to social structures, processes of production and dissemination, and the textual features through which meaning is enacted. The bulk of the analysis focuses on genre, discourse, and style to examine how the video governs practice and moral reasoning. Findings indicate that the program positioned itself as an early form of clinical practice guideline by linking instructional conventions with the authority of academic research. It also illuminates the lexical choices used to portray cleanliness as a non-negotiable objective, while clients' refusals are positioned as problems (of technique, discomfort, or pathology) to overcome rather than expressions of agency. Finally, the paper demonstrates how the video's emphasis on pleasure operates as a stylistic and moral device that shapes nurses as responsible for producing care that is both hygienic and affectively acceptable. The paper concludes by considering the ethical implications of this framing for autonomy in dementia care and the normalization of persuasion when care outcomes are predetermined. Trial Registration: Clinical trial registration is not applicable, as this study did not involve a clinical trial.
Artificial cells, nanomedicine, and biotechnologyHuiqian Yang, Hongjie Du, Chunyan Zang, Jian Liu, Zheng Wang, Fenglei Xu, Hui Li, Xiaoming Li
This study aimed to identify key biomarkers for obstructive sleep apnoea (OSA) by analysing RNA-seq (GSE75097: 6 control and 42 OSA) and single-cell RNA-seq (GSE214865: 11 control and 11 OSA) datasets. Differential expression analysis revealed 575 DEGs between OSA and control groups. Using weighted gene co-expression network analysis (WGCNA) combined with machine learning approaches (Random Forest, SVM-RFE and LASSO), we identified four hub genes (C17ORF91, HBEGF, PGBD2 and ZNF616) as candidate biomarkers, showing exploratory discriminatory performance (AUC > 0.7). Gene set enrichment analysis (GSEA) revealed that these genes are associated with pathways related to hypoxia response, atherosclerosis and metabolic reprogramming (NES as low as -2.049, adj. p < .05), as well as immune regulation (NES up to 1.932, adj. p < .05). Single-cell RNA sequencing analysis further demonstrated that cMonocytes play a central role in OSA progression, exhibiting the highest scores for hypoxia, metabolic dysfunction and atherosclerosis risk. An exploratory nomogram incorporating these hub genes showed favourable internal performance within the discovery cohort. These findings provide hypothesis-generating insights into the molecular features associated with OSA and identify these genes as candidate biomarkers that require independent external and functional validation. Further validation of these genes may provide a basis for evaluating their potential diagnostic and therapeutic relevance in OSA.
Neurology. Clinical practiceShervin Badihian, Margarita Fedorova, Bradley Ashley Ong, Nicolas R Thompson, Neil Nero, Ken Uchino, Shumei Man
PURPOSE OF REVIEW: Digital health interventions are increasingly used in medicine to manage chronic conditions. However, the effectiveness, feasibility, and consistency of these interventions in poststroke risk factor management and secondary prevention remain uncertain. We conducted a systematic review and meta-analysis to evaluate the effect of digital health-supported interventions on vascular risk factor control among stroke survivors. We systematically searched MEDLINE, Embase, and Cochrane CENTRAL from inception through September 2025 for randomized, single-arm, and observational studies evaluating digital health interventions, defined as mobile health applications, wearable devices, or combined platforms, among adults with ischemic stroke, hemorrhagic stroke, or transient ischemic attack. Outcomes of interest included systolic and diastolic blood pressure, lipid levels, weight, physical activity, medication adherence, quality of life, and clinical events. Random-effects meta-analyses were performed for outcomes reported by ≥ 3 studies. Feasibility outcomes, including recruitment, retention, adherence, and usability were synthesized qualitatively. RECENT FINDINGS: Twenty-nine studies encompassing 8,389 participants were included. Digital health interventions were associated with modest reductions in systolic blood pressure compared with control conditions, including usual care and minimal-intervention comparators (pooled between-group mean difference, -5.8 mm Hg; 95% CI -9.9 to -1.6). However, prediction intervals crossed the null value, and between-study heterogeneity was substantial. No consistent effects were observed for diastolic blood pressure, lipid levels, or weight. Reporting of physical activity, medication adherence, and quality-of-life outcomes was heterogeneous, precluding quantitative pooling, although most studies reported favorable trends. Overall feasibility was high, with an aggregate dropout rate of 3.6% (95% CI 3.2%-4.0%) and high user acceptability across studies. Most trials enrolled participants with mild functional impairment and short follow-up durations (median ≈3 months). Few studies were powered to assess recurrent stroke or mortality. SUMMARY: Digital health-supported interventions for secondary stroke prevention seem feasible and acceptable, with evidence of modest short-term improvements in blood pressure. However, clinical effectiveness across other vascular risk factors remains inconsistent. In addition, substantial heterogeneity, short follow-up, and limited high-quality evidence constrain causal inference and preclude conclusions regarding sustained clinical benefit.
Global health actionHelena Hildenwall, Dorothy Akongo, Emmanuel Tenywa, Svante Norgren, Moses Kyangwa, Alfred Yayi, William Mugowa Waibi, Viveka Nordberg, Agnes Linnér, Eva Svenss…
Despite major global progress in child health, significant inequalities remain between low- and high-income countries. In Uganda's Busoga region, child mortality is still high, largely due to preventable conditions and limited healthcare resources. In response, a paediatric health partnership was established in 2021 between the Busoga region and Stockholm, Sweden. Following a quality-of-care assessment in two Ugandan hospitals, the collaboration identified four priority areas: paediatric emergency care, neonatology, child neurology with a focus on epilepsy, and child rights. Over 3 years, 63 staff exchanges have taken place, enabling joint reviews of clinical practices and identification of improvement needs. A key achievement is the implementation of the WHO Emergency Triage, Assessment and Treatment Plus (ETAT+), supported by training 14 national facilitators who now serve as focal persons in their facilities. Initiatives in neonatology have strengthened early interventions for premature and low birth weight infants such as improved nursing care, infection prevention, and nutrition practices. In neurology, the introduction of an epilepsy registry and education programmes has reduced stigma and improved management. The child rights initiative has trained more than 80 ambassadors and fostered child-friendly hospital environments that promote participation. The in-hospital mortality dropped over the project period (2020-2025) from 26.4% to 21.7% for neonates (p = 0.021) and from 3.8% to 2.8% (p = <0.01) for children less than five outside the neonatal period. Despite resource constraints, the partnership has benefited both regions. This twinning model highlights how equitable international collaborations can sustainably advance child health and reinforce healthcare systems in diverse settings.
Physiotherapy research international : the journal for researchers and clinicians in physical therapyYuanyuan Zhu, Lu Xia, Liyan Cai, Xin Chen, Linjun Yu, Shinian Yang, Xiao Zhu
BACKGROUND AND PURPOSE: This study sought to develop and validate a predictive model integrating the Braden scale to forecast the recovery of activities of daily living (ADL) in patients with post-stroke hemiplegia. Additionally, it aimed to evaluate the effectiveness of a comprehensive rehabilitation program. METHODS: A retrospective analysis was conducted on 324 patients with hemiplegic stroke admitted to our hospital between August 2023 and August 2025. Candidate variables were selected from demographics, comorbidities, neuroimaging features, laboratory findings, early treatment, complications, Braden scale scores and ADL assessments. Patients were categorized into low and high ADL recovery groups based on the median post-treatment ADL score. A logistic regression model was developed and presented as a nomogram. Model performance was assessed using receiver operating characteristic (ROC) analysis, calibration curves, and decision curve (DCA) analysis, followed by internal validation. Additionally, in a subgroup of 82 patients who underwent comprehensive rehabilitation, detailed functional assessments including motor function, balance, walking ability, and activity of daily living (ADL) were conducted before and after intervention. RESULTS: A total of 324 patients with post-stroke hemiplegia were included in the analysis. Comparative analysis between the high and low ADL recovery groups revealed that the high recovery group was significantly younger (p < 0.001) and had a higher proportion of females. This group also exhibited lower CRP levels (p = 0.003), higher albumin (ALB, p < 0.001) and cholesterol (CHOL) levels (p = 0.039), a lower rate of multi-lesion involvement (p < 0.001), a higher rate of thrombolysis (p = 0.019), a lower incidence of infection (p < 0.001), a lower rate of specific medicine intake (p = 0.021), higher baseline ADL scores at admission (p < 0.001), and higher Braden scale scores both before and after treatment (p < 0.001). Multivariable logistic regression identified sex, thrombolysis, infection incidence, and post-treatment Braden scale as independent predictors of ADL recovery. The nomogram showed excellent discrimination, with an AUC of 0.888 (95% CI: 85.4%-92.2%). At the optimal cut off value of 0.55, the model achieved a sensitivity of 84.3% and a specificity of 76.6%. In the rehabilitation subgroup (N = 82), significant post-treatment improvements were observed in motor function (upper limb p < 0.001, hand p = 0.002, lower limb p < 0.001), balance (Berg Balance Scale and Fugl-Meyer assessment; both p < 0.001), walking capability (p < 0.001), and overall performance (p < 0.001). DISCUSSION: The findings indicate that sex, incidence of infection, thrombolysis, and the post-treatment Braden scale were independent predictors of ADL recovery. Moreover, the comprehensive rehabilitation program was associated with significant functional improvements in motor skills, balance, ADL, and walking proficiency.
GliaJanssen M Kotah, Marina Trombetta Lima, Esmée C Dragt, Asimenia Voulgaroglou, Nieske Brouwer, Inge R Holtman, Susanne M Kooistra, Bart J L Eggen
Microglia play a key role in the pathophysiology of Alzheimer's Disease (AD) and their increased heterogeneity likely affects disease progression. We previously identified distinct microglial signatures that were enriched in AD donors and associated with amyloid and tau, respectively. Here we generated a snRNAseq dataset from postmortem control and AD cases and analyzed alterations in cell-cell communication pathways that might be relevant to AD pathophysiology. One signaling pathway perturbed in AD cases involved SPP1, and while this pathway was also present in control samples, microglia-microglia SPP1 signaling was restricted to AD donors. Further analyses within microglia-microglia signaling predict AD-specific induction of GAS6-AXL signaling (from inflammatory and ribosomal microglia), and SPP1-ITGAV/ITGB5 signaling (from disease-associated and inflammatory microglia, among others). Together, these findings might in part explain the increased microglia phagocytic profile described in AD. RNAscope confirmed enrichment of SPP1 expressing microglia near amyloid plaques in AD brain tissue samples. These data indicate altered cellular communications between microglia in the AD brain.
Metabolic and bariatric surgery achieves durable weight loss and meaningful improvement in obesity-related comorbidities yet carries a risk of neurological complications that remains under-recognised in routine clinical practice. This systematic review, registered with PROSPERO (CRD42024591611) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, searched MEDLINE, Embase, Emcare, CINAHL and Cochrane databases through September 2023 to evaluate the incidence, spectrum, timing, pathophysiology and management of post-operative neurological complications. Twelve studies comprising over 5000 patients were included. Reported incidence ranged from 1.4% to 16%, with peripheral neuropathy the most frequent manifestation. Mononeuropathies, particularly carpal tunnel syndrome, were prominent in several cohorts, while central complications including Wernicke encephalopathy occurred less commonly but with considerably greater severity. Thiamine deficiency was the predominant aetiological factor. Onset varied from days to several years postoperatively, with early presentations typically compression-related and later ones nutritionally mediated. Outcomes were generally favourable with early intervention, though severe or delayed cases were associated with persistent neurological deficits and occasional mortality. Neurological complications after bariatric surgery are heterogeneous and largely preventable, and structured post-operative follow-up with consistent adherence to nutritional supplementation remains central to reducing long-term harm.
BACKGROUND AND OBJECTIVES: Dizziness is a common emergency department (ED) concern, yet posterior-circulation strokes can be difficult to detect with standard clinical tools and neuroimaging alone. Quantitative video head impulse test (vHIT) provides an objective bedside measure of vestibulo-ocular reflex function and can help differentiate central from peripheral causes of acute dizziness. METHODS: We conducted a prospective, single-center feasibility and diagnostic-accuracy study of adults (18-90 years) presenting on an ED stroke pathway for acute dizziness. vHIT was performed within 48 hours of presentation, after completion of standard stroke evaluation. Two vestibular-trained clinicians, blinded to clinical and imaging data, classified vHIT as peripheral, central, equivocal, or poor quality. The reference standard (stroke vs nonstroke) was the final diagnosis adjudicated by stroke neurologists using all clinical information, noncontrast CT, and MRI when available. Diagnostic metrics for stroke were calculated for interpretable vHIT studies and in an intention-to-diagnose analysis. RESULTS: Thirty patients underwent vHIT; 11 (36.7%) had acute ischemic stroke and 19 (63.3%) had nonstroke diagnoses. Interpretable vHIT results (central or peripheral pattern) were obtained in 23 of 30 patients (76.7%). Overall, vHIT patterns were central in 19 (63.3%), peripheral in 4 (13.3%), equivocal in 3 (10.0%), and poor quality in 4 (13.3%). Among strokes, 9 of 11 (81.8%) had a central pattern and none had a peripheral pattern. In the primary analysis of interpretable studies, vHIT sensitivity and negative predictive value for stroke were both 100%, while specificity was 28.6% and overall accuracy was 56.5%. In the intention-to-diagnose analysis including all patients, sensitivity and negative predictive value remained 100%, with specificity at 21.1% and accuracy at 50.0%. DISCUSSION: Our findings suggest that vHIT was feasible in most ED stroke-pathway patients with acute dizziness and demonstrated high sensitivity and negative predictive value when a clearly peripheral pattern was present, supporting its potential role as an adjunctive rule-out tool. However, specificity was low, and nearly one-quarter of studies were equivocal or poor quality, limiting its use as a standalone diagnostic test. With further validation and larger studies, vHIT may help support more targeted use of hospital admissions, diagnostic workups, and ED stroke resources in patients without evidence of central pathology.
NAR cancerEmily A Dangelmaier, Dorthy Fang, Isabel P Hardy, Kyal Sin Htet, Nicole S Harry, Renee Pascoe, Je Won Yang, Clara D Wang, Sigrid Nachtergaele
N 6-methyladenosine (m6A) regulates nearly every aspect of messenger RNA (mRNA) processing and function, impacting downstream gene expression programs. Changes in m6A have been implicated in many different types of cancer, and inhibition of m6A installation is emerging as a cancer therapeutic strategy. However, chemoresistance remains a significant clinical challenge in the treatment of glioblastoma (GBM). We established GBM cell culture models of acquired temozolomide (TMZ) resistance, analyzed the role of m6A in controlling resistance-associated pathways, and assessed the effects of METTL3 inhibition. We show that m6A stabilizes key genes and pathways promoting TMZ resistance, and that METTL3 inhibition can reverse this and restore TMZ sensitivity. These findings highlight that TMZ resistance can occur independent of a glioma stem cell population and that changes in m6A need not be driven by changes in METTL3 expression. Collectively, our results suggest that genes associated with TMZ resistance are stabilized by m6A methylation even as the majority of the transcriptome remains subject to m6A-mediated mRNA decay. Moreover, these data highlight METTL3 inhibition as a promising therapeutic approach to overcoming TMZ resistance in GBM.
Neurology. Clinical practiceDavid O Acero-Garces, Eliza Gordon-Lipkin, Doris D M Lin, Lisa R Sun, Ryan J Felling, Philippe Gailloud, Matthew J Elrick, Carlos A Pardo, Haiwen Chen
BACKGROUND AND OBJECTIVES: Spinal cord stroke (SCS) is an underrecognized cause of severe acute myelopathy in children that can be misdiagnosed as an infectious or inflammatory process. Limited characterization of clinical and neuroimaging features of pediatric SCS impede timely and accurate diagnoses. Our objectives were to (1) identify clinical and radiologic features of SCS to prompt timely evaluation and accurate diagnosis and (2) gain insight into mechanisms of SCS. METHODS: We conducted a retrospective case analysis of children (<18 years old) diagnosed with SCS at a specialized referral institution between 2010 and 2025. Clinical records, imaging, and laboratory data were reviewed to identify key features of pediatric SCS. RESULTS: Among the 56 included patients, 28 were male (50%), and the age distribution was bimodal, with peaks at 1 and 14 years. Pediatric SCS presented with hyperacute onset of motor, sensory, bladder/bowel, and pain symptoms. The lesions were predominantly anterocentral, longitudinally extensive, with the cervical spinal cord being most often affected. Over time from the onset of symptoms, MRI diffusion restriction decreased, while gadolinium enhancement increased. CSF profile was noninflammatory in 95% of cases. Suspected mechanisms were identified in 63% of cases, with vascular compression being the most commonly identified mechanism in 17 participants (30%), while 38% were idiopathic. Chiari I malformations were identified as the main suspected cause of vascular compression, occurring in a subgroup of young patients with cervical SCS (n = 8, 14%). Serum studies identified hypercoagulability in 38% of the 40 participants evaluated. DISCUSSION: Recognition of specific clinical and neuroimaging profiles in pediatric patients with SCS may facilitate earlier identification and intervention. We propose a systematic evaluation of clinical history, with particular attention to the temporal course from symptom onset to nadir, early acquisition of spine MRIs with diffusion-weighted imaging sequences, serologic evaluations for hypercoagulability, and CSF studies to exclude inflammatory etiologies. This approach will provide a framework for continued efforts to better understand the mechanisms underlying pediatric SCS and develop prevention and treatment strategies.
Neurology. Clinical practiceMeagan M Watson, Mackenzi L Moore, Ashley Parker, Wesley T Kerr, Jared J Woodward, Laura A Strom
BACKGROUND AND OBJECTIVES: Functional neurologic disorders (FNDs) are highly prevalent across neurologic service lines, with functional/dissociative seizures (FDSs) being the most common FND symptom. Despite clear diagnostic criteria and evidence-based treatments, people with FDSs are frequently misdiagnosed, stigmatized, or routed through ineffective care. A key driver of these gaps is the referral process. This study evaluates referral patterns into an established ambulatory, multidisciplinary FDS program, identifies reasons for referral ineligibility, and proposes targeted interventions to promote sustainable development. METHODS: A retrospective analysis was conducted of patients referred to the University of Colorado (CU) FDS treatment program over 6 months. Demographics, referral characteristics, documentation availability, and program enrollment were abstracted from the electronic health record. Multivariable logistic regression identified factors associated with referral ineligibility, fulfillment of International League Against Epilepsy (ILAE) FDS criteria, and successful acquisition of diagnostic records. RESULTS: Of 318 individuals referred (mean age 38 years; 72% female; 67% White, 15% Hispanic/Latino), 47% were enrolled in the CU FDS program, while 53% were ineligible, primarily because of incomplete diagnostic documentation (30%). While 56% of referrals originated from neurology, only 42% met ILAE-concordant, probable diagnostic criteria. Multivariable logistic regression identified insurance status as the strongest predictor of ineligibility, with uninsured patients (odds ratio (OR) 12.40, p < 0.01) and Medicaid recipients (OR 2.39, p = 0.01) facing higher risk of ineligibility than those with private insurance. Conversely, inpatient status (OR 0.15, 0 < 0.01) and Hispanic ethnicity (OR 0.40, p = 0.04) were protective against ineligibility, and patients referred from inpatient settings were more likely to meet probable ILAE criteria (OR 10.08, p < 0.01). DISCUSSION: FDS care is a shared clinical responsibility. Health care professionals' referral practices are critical for the feasibility and sustainability of FDS programs, particularly when referring patients who use public insurance (i.e., Medicaid). Of equal importance is understanding the limitations of health care systems' operational processes (e.g., scheduling). Unless purposefully included, FDS is not a default diagnosis. Therefore, when operational processes change, FDS is easily forgotten. As such, active engagement through thoughtful referral practices, use of established diagnostic guidelines (e.g., ILAE recommendations), and maintaining accountability for the patient rather than relying on referral as a final step are essential.
Journal of experimental child psychologyBojana Vuković, Mirela Duranović
The present study investigated whether script type (Latin vs. Cyrillic) differentially influences the temporal characteristics of handwriting in children with dyslexia, chronological age-matched controls (CA), and spelling-level matched controls (SL). Four tasks varying in cognitive and linguistic demands were administered: name and surname writing, an alphabet task, a dictation task including real words, pseudowords, and nonwords, and a text composition task. Temporal handwriting measures were obtained using Eye and Pen software. Writing in Cyrillic generally required longer total task duration than writing in Latin. Across groups, total task duration was longer in Cyrillic during the name and surname, alphabet, real word, and composition tasks. Significant Group × Script interactions for total task duration were observed only in the pseudoword and nonword tasks, indicating that the CA and SL groups required more time to write in Cyrillic than in Latin, whereas no significant script-related difference was observed in the children with dyslexia. A significant Group × Script interaction for pen speed was observed only in the pseudoword task, where children with dyslexia wrote faster in Cyrillic than in Latin. In the composition task, Cyrillic was associated with longer writing duration, longer pause duration, and a greater percentage of pause time across groups, whereas a significant Group × Script interaction was observed only for between-word pauses. The findings suggest that script-specific visual-orthographic characteristics contribute to handwriting performance, while differences between children with dyslexia and typically developing peers emerge for selected handwriting measures under specific task demands.
Neurology. Clinical practiceAdele Ratti, Luca Bosco, Christian Laurini, Luca Angelini, Benedetta Sorrenti, Massimo Filippi, Stefano Carlo Previtali, Yuri Matteo Falzone
PURPOSE OF REVIEW: Cranial neuropathies are a frequent reason for neurologic consultation, yet they remain diagnostically challenging because of a broad etiologic spectrum and overlapping clinical presentations. This review aims to support clinicians in achieving an accurate and timely diagnosis by classifying cranial neuropathies according to the main pathogenic mechanisms, with particular attention to rare and underrecognized entities, and by proposing a clinician-oriented diagnostic algorithm to improve diagnostic precision and efficiency. RECENT FINDINGS: A comprehensive and structured synthesis of the causes of cranial neuropathies is currently lacking. Available literature is largely confined to single-cranial nerve reviews or disease-specific settings and further limited by inconsistent terminology that may blur the distinction between peripheral cranial nerve involvement and brainstem nuclear syndromes. As a result, an integrated framework to guide diagnostic reasoning in daily practice remains unavailable. Recent advances in antibody testing, neurogenetics, high-resolution neuroimaging, and targeted immunotherapies have expanded the diagnostic and therapeutic landscape, increasing the need for an updated, mechanism-based approach that can be readily applied in clinical practice. SUMMARY: We identify major etiologic categories associated with cranial neuropathies, including immune-mediated and rheumatologic diseases, paraproteinemic disorders, hereditary conditions, and infectious and compressive etiologies. For each category, we summarize representative disorders, underlying pathophysiologic mechanisms, and practical diagnostic clues, and we highlight relevant mimics that may complicate the differential diagnosis. We then propose a three-tier diagnostic algorithm integrating clinical pattern recognition with brain MRI, CSF analysis, and targeted neurophysiologic studies. By systematically combining clinical, imaging, and laboratory data, this framework is intended to increase diagnostic accuracy and support early recognition of uncommon but treatable causes of cranial neuropathy.