Hyperhomocysteinemia (HHcy) and Klotho deficiency are commonly investigated in separate metabolic, renal, vascular, and neurological contexts, yet together they may illuminate how peripheral dysfunction is translated into cerebral vulnerability. This review develops a kidney-to-brain stress resilience framework in which HHcy represents a renal dysfunction-associated component of systemic metabolic and vascular stress, whereas α-Klotho represents a candidate indicator of biological resilience, supported mainly by experimental evidence and observational human studies. Declining renal function favors Hcy accumulation, reduces renal Klotho expression, and generates uremic, inflammatory, mineral, and hemodynamic disturbances that converge on the cerebral microvasculature. Experimental HHcy can additionally repress renal KL through HDAC9-dependent epigenetic regulation. At the brain-facing interface, circulating Hcy directly disrupts cerebral endothelial bioenergetics, redox homeostasis, inflammatory signaling, and tight-junction integrity, providing a plausible route from systemic metabolic disturbance to blood–brain barrier (BBB) and neurovascular-unit (NVU) dysfunction. Klotho-related mechanisms, in contrast, are associated with endothelial, antioxidant, mitochondrial, anti-inflammatory, and anti-senescent resilience, although circulating, renal, and CNS Klotho represent non-equivalent compartments and the causal contribution of circulating Klotho to human neurological disease remains uncertain. Clinical and imaging evidence from chronic kidney disease, cerebral small-vessel disease (CSVD), cognitive impairment, and ischemic stroke supports individual components of the proposed kidney circulation BBB/NVU brain continuum, but not a validated linear HHcy-Klotho molecular axis. We therefore define HHcy-high/Klotho-low status as a candidate metabolic stress-resilience phenotype and propose that the critical test is whether Klotho modifies the neurovascular consequences of a given Hcy burden. Establishing this framework will require cell-specific perturbation, compartment-resolved Klotho measurement, longitudinal neuroimaging, and prospective analyses linking renal dysfunction, BBB/NVU injury, CSVD progression, and cognitive decline.
BackgroundAutonomic dysfunction is a complex condition that affects every organ system in the body. The underlying mechanisms of autonomic dysfunction remain incompletely understood. There appears to be an association between patients with hypermobile Ehlers Danlos syndrome (hEDS), craniocervical instability (CCI), atlantoaxial instability (AAI), and autonomic dysfunction. There is biological plausibility for CCI and AAI being causes for autonomic dysfunction in these populations.ObjectiveThe objective of this review is to explore the literature on the potential association between CCI, AAI and autonomic dysfunction and to explore the biological plausibility of this association.MethodsA narrative review of PubMed was conducted through August 2026 to evaluate associations among hEDS, CCI/AAI, and autonomic dysfunction. Studies addressing autonomic dysfunction in hypermobility disorders, CCI/AAI, autonomic outcomes following cervical stabilization surgeries, and proposed neurovascular or autonomic mechanisms were included. Findings were synthesized narratively due to the heterogeneity of the study designs analyzed and outcome measures assessed.Results43 studies were included in the final review. Evidence consistently supported an association between hEDS and autonomic dysfunction and between hEDS and CCI/AAI. More limited evidence demonstrated a direct overlap between CCI/AAI and dysautonomia, while multiple series reports showed improvements in autonomic-associated symptoms following surgical stabilization procedures. Proposed mechanisms for autonomic dysfunction in CCI/AAI patients include vagal nerve involvement, internal jugular vein compression, altered cerebral venous outflow, and cervicomedullary effects. The evidence was predominantly retrospective and heterogeneous, with limited standardized autonomic testing, warranting further investigation and more robust future analysis.ConclusionCurrent evidence suggests that CCI and AAI represent under-recognized contributors to dysautonomia. While causality has not been established, anatomical, physiological, and clinical observations warrant further investigation into this relationship. Standardized diagnostic criteria for CCI/AAI, as well as autonomic dysfunction, must be established to further study these relationships. Prospective studies incorporating these diagnostic criteria and objective autonomic measurements will assist in clarifying these relationships and determine what interventions will help improve patient outcomes.
PurposeThis study aimed to evaluate the effect of ultrasound-guided stellate ganglion block (SGB) on intraoperative hemodynamic parameters in patients undergoing laparoscopic partial adrenalectomy.Patients and methodsA total of 72 patients with adrenal tumors scheduled for laparoscopic partial adrenalectomy were enrolled and randomly assigned in a 1:1 ratio to either the stellate ganglion block (SGB) group or the control group. The primary outcome was the incidence of intraoperative hypertension, defined as a systolic blood pressure (SBP) ≥180 mmHg or an increase of ≥30% in mean arterial pressure (MAP) from baseline. Secondary outcomes included MAP and heart rate (HR) measured at nine predefined perioperative time points, intraoperative vasoactive drug consumption, and the incidence of perioperative adverse events.ResultsThe incidence of intraoperative hypertension was significantly lower in the SGB group than in the control group (14.3% vs. 37.1%, p = 0.029). Compared with the control group, patients in the SGB group exhibited significantly lower MAP and HR at eight time points ranging from immediately after tracheal intubation until the end of surgery (p < 0.05). The intraoperative consumption of phentolamine was significantly lower in the SGB group than in the control group [0 (0–4) mg vs. 0 (0–0) mg; p = 0.008]. In contrast, the consumption of norepinephrine was significantly higher in the SGB group [0 (0–0) mg vs. 0 (0–8) mg; p = 0.004]. No statistically significant differences were observed between the two groups in the consumption of esmolol and atropine, or in the incidence of perioperative adverse events.ConclusionUltrasound-guided SGB lowers intraoperative hypertension incidence and phentolamine demand in laparoscopic partial adrenalectomy. Although the SGB group observed a slight increase in the intraoperative dose of norepinephrine, no perioperative adverse events occurred. There was also no significant difference in the incidence of adverse reactions between the two groups.
IntroductionSleep-disordered breathing (SDB) is highly prevalent after stroke and is associated with poor functional outcomes and increased mortality, yet systematic screening remains challenging because of limited polysomnography accessibility. We evaluated three electrocardiogram (ECG)-based indices for SDB screening in a large consecutive post-stroke cohort.MethodsThis retrospective single-centre cohort study included 1,929 consecutive patients hospitalised for stroke or transient ischaemic attack at Saint-Étienne University Hospital (2010–2021) who were in sinus rhythm with ECG signal quality adequate for ECG-derived respiration (EDR) analysis; patients with atrial fibrillation, pacemaker rhythm, or severe ectopy (>10% of beats) were excluded a priori. EDR, the Thoracic Impedance Disturbance Index (TIDI) and the Very Low Frequency Increment (VLFI) were compared with the simultaneous oxygen desaturation index (ODI) as reference standard. Sensitivity, specificity, accuracy and predictive values were calculated at ODI thresholds of 15/h and 30/h; a combined TIDI+EDR concordant rule was assessed as a post-hoc exploratory analysis.ResultsThe cohort comprised 61% males (mean age 65.9 years). Suspected SDB (ODI ≥ 5/h) was present in 74.6% of patients, moderate-to-severe SDB (ODI ≥ 15/h) in 38.9% and severe SDB (ODI ≥ 30/h) in 17.1%. For ODI ≥ 15/h (n = 750), TIDI had the highest sensitivity (93.3%) and negative predictive value (90.8%), whereas EDR had higher specificity (80.2%) and accuracy (74.2%); the combined rule reached 85.2% specificity and 72.9% positive predictive value. For ODI ≥ 30/h (n = 330), EDR showed specificity of 92.4% and accuracy of 85.2%, and the combined rule 95.4% and 86.9%, respectively. VLFI performed poorly across all metrics.DiscussionECG-based tools can identify post-stroke patients at high risk of SDB using routine cardiac monitoring. The complementary profiles of TIDI (rule-out) and EDR (rule-in) support a sequential screening approach, which requires prospective validation against polysomnography. VLFI is unsuitable for elderly stroke populations because of age-related autonomic dysfunction. Because patients with atrial fibrillation, pacemaker rhythm or severe arrhythmia were excluded, the findings may not generalise to this higher-arrhythmia-burden subgroup, who may also be at higher risk of SDB.
BackgroundFragile X syndrome is a monogenic cause of autism spectrum disorder. Fmr1-KO mice are a well-known model for the disease, and the model’s behavioral phenotype has been well-characterized. Unfortunately, translational molecular tissue biomarkers for this model remain sparse.MethodsTo identify new molecular biomarkers, we performed a gene sequencing analysis of caudate putamen tissue of Fmr1-KO mice at the age of 7 weeks. RNA sequencing analysis revealed 13 genes to be upregulated and 37 genes to be downregulated in the caudate putamen of Fmr1-KO mice. The two most upregulated genes were necdin (Ndn) and insulin degrading enzyme (Ide). Upregulation of Ndn and Ide genes was confirmed by real-time PCR. NDN protein expression was analyzed in the caudate putamen, hippocampus, and brainstem using immunofluorescent labeling. A co-labeling experiment assessed NDN expression in cholinergic neurons. Ide gene upregulation and its effect on insulin levels were evaluated, and protein expression analysis focused on NDN, parvalbumin, and myelin basic protein in the caudate putamen, cortex, and hippocampus.ResultsmRNA levels of Ndn and Ide and protein levels of NDN and IDE were strongly upregulated in the caudate putamen of Fmr1-KO mice. NDN protein expression was also increased in the hippocampus and brainstem, with partial expression observed in cholinergic neurons. Upregulated Ide gene expression was associated with reduced insulin levels in Fmr1-KO mice.ConclusionNDN and IDE emerge as promising candidates for preclinical disease-relevant biomarkers in Fmr1-KO mice. Future research needs to demonstrate whether disease-modulating drugs can alter the expression profile of these proteins and ultimately alleviate disease symptoms.
