Search Results (186)

Background and Objectives: Sleep complaints are particularly relevant in the development of children, affecting cognitive development, neuropsychological functioning, and learning abilities. The aims of this study were as follows: (i) to determine the incidence of sleep disorders in low-risk infants and toddlers with hypoxic ischemic encephalopathy (HIE) treated with therapeutic hypothermia (TH), using the Italian version of the Sleep Disturbance Scale for Children (SDSC); and (ii) to compare the data with those of a healthy control group. Materials and Methods: This is a cross-sectional case–control study involving a total of 167 infants and toddlers (aged 6–36 months) with HIE treated with TH and 160 typically developing infants assessed using the SDSC filled out by the mother. A neurocognitive assessment was also performed. Exclusion criteria were mild perinatal asphyxia, major brain lesions, congenital malformations, severe postnatal infectious diseases, metabolic complications, cerebral palsy, neurodevelopmental impairment, and epilepsy. Results: In the study group, an abnormal total SDSC score was found in 1.8% of infants; 10% of infants had an abnormal score on at least one of the SDSC factors. No specific differences in the SDSC total and the factor scores were observed between the study and control group, with the exception of difficulties in maintaining sleep and sleep hyperhidrosis, with higher scores in HIE infants. Conclusions: Low-risk infants and toddlers with HIE showed a low incidence of sleep disorders, similar to those observed in control group, with some exceptions. As these incidences may increase significantly with age, further clinical assessments will be needed to confirm these data at older ages. Full article

Hypoxic–ischaemic encephalopathy (HIE), a leading cause of perinatal mortality and neurological impairment, affects 1–8/1000 live births in developed countries. Therapeutic hypothermia (TH), the standard treatment for moderate to severe HIE, reduces brain injury by lowering metabolic demand and inhibiting apoptosis. This case study presents a full-term female newborn delivered via caesarean section due to intrauterine asphyxia, with meconium aspiration syndrome and severe HIE (Apgar 0/0/0/2). Notwithstanding the presence of multiorgan failure and grade II intraventricular haemorrhage, TH was initiated within six hours. The patient received circulatory and respiratory support, sedation, and nitric oxide. Early rehabilitation was initiated immediately. Neurofunctional assessment using the TIMP test revealed initial delays (16–25th percentile) at 11 weeks of age; however, the subsequent two evaluations, conducted approximately every two weeks, indicated that the patient was within normal developmental ranges. A similar outcome was observed in the AIMS assessment conducted at seven months of age, which also yielded normal results. Despite MRI findings post-TH showing hypoxic and haemorrhagic lesions, the patient achieved normal development. This case demonstrates the effectiveness of combining TH with early physiotherapy in mitigating severe consequences of HIE, such as cerebral palsy and epilepsy. Long-term follow-up remains crucial for detecting later deficits, particularly during school age. The outcome of this case underscores the significance of timely intervention and multidisciplinary care. While TH and rehabilitation have been shown to improve prognosis, ongoing monitoring is crucial to ensure optimal neurological development trajectories. Full article

Background: Hypoxic–ischemic encephalopathy (HIE) is a leading cause of severe neurological impairments in childhood. Therapeutic hypothermia (TH) is both safe and effective in neonates born at ≥36 weeks gestation with moderate to severe HIE. We aimed to evaluate short-term outcomes—including brain injury detected on magnetic resonance imaging (MRI)—in infants born at 34–35 weeks of gestation drawing on our clinical experience with neonates under 36 weeks of gestational age (GA). Methods: In this retrospective cohort study, 20 preterm infants with a GA of 34 to 35 weeks and a matched cohort of 80 infants with a GA of ≥36 weeks who were diagnosed with moderate to severe HIE and underwent TH were included. Infants were matched in a 1:4 ratio based on the worst base deficit in blood gas and sex. Maternal and neonatal characteristics, brain MRI findings and short term outcomes were compared. Results: Infants with a GA of 34–35 weeks had a lower birth weight and a higher rate of caesarean delivery (both p < 0.001). Apgar scores, sex, intubation rate in delivery room, blood gas pH, base deficit and lactate were comparable between the groups. Compared to infants born at ≥36 weeks of GA, preterm neonates were more likely to receive inotropes, had a longer time to achieve full enteral feeding, and experienced a longer hospital stay. The mortality rate was 10% in the 34–35 weeks GA group. Neuroimaging revealed injury in 66.7% of infants born at 34–35 weeks of gestation and in 58.8% of those born at ≥36 weeks (p = 0.56). Injury was observed across multiple brain regions, with white matter being the most frequently affected in the 34–35 weeks GA group. Thalamic and cerebellar abnormal signal intensity or diffusion restriction, punctate white matter lesions, and diffusion restriction in the corpus callosum and optic radiations were more frequently detected in infants born at 34–35 weeks of gestation. Conclusions: Our study contributes to the growing body of literature suggesting that TH may be feasible and tolerated in late preterm infants. Larger randomized controlled trials focused on this vulnerable population are necessary to establish clear guidelines regarding the safety and efficacy of TH in late preterm infants. Full article

Liver, the center of substance metabolism, plays a vital role in the hibernation of mammals, a topic arousing increasing interest from researchers around the world. However, it remains unclear how the liver regulates energy metabolism during the hibernation of mammals. Metabolic disorders in the liver are closely associated with numerous diseases. In this research on chipmunks (Tamias sibiricus), we compared histological changes in the liver and energy source between the conditions for hibernation and room temperature, and subsequently conducted transcriptome sequencing analysis. The results demonstrate that lipid metabolism becomes a significant energy source during hibernation via the retinol signaling pathway and PPAR signaling pathway, thereby suggesting the importance of the liver in maintaining homeostasis when facing hypothermia. Furthermore, the result provides us with a novel perspective to obtain an insight into liver metabolic reprogramming and potential therapeutic strategies for metabolic disease in the liver. Full article

Background/Objectives: Although there is a critical need for timely, accurate recognition of infants with hypoxic ischemic encephalopathy (HIE) eligible for therapeutic hypothermia (TH), there is little published literature that comprehensively validates strategies to achieve this. For the Mater Mothers’ Hospital, a screening protocol combining use of umbilical cord gases according to obstetric criteria and other evidence of depression at birth with a decision aid (the HIE Trigger Tool (TT)) for at-risk infants was developed. We audited whether the protocol supported appropriate clinical decisions. Methods: Obstetric records were searched from 1 January 2016 to 31 July 2022 for eligible infants. Neonatal records were examined to assess usage, determine outcomes (diagnosis of HIE or other neurological conditions, use of TH, mortality and neurodevelopmental outcomes) and detect any additional HIE cases. Results: Of 64,055 live births ≥35 weeks, 35.4% had cord gases taken. Of 580 eligible infants, the TT was applied to 498 (86.3%), 155 of whom screened positive for HIE (any severity). Of 76 infants with moderate or severe encephalopathy, 69 received TH. The other seven had contraindications to TH (n = 2), late presentations without any depression at birth (>6 h, n = 3) or other causes of their encephalopathy (n = 2). The TT (which per instructions was commenced by one hour of age) was used to identify 61 of the infants with moderate/severe encephalopathy, while 15 were diagnosed before it was applied. No infants who screened negative using the TT presented later with seizures or any other signs of moderate or severe HIE. Conclusions: The protocol including cord gases and the HIE TT is an effective method of screening for acute HIE needing TH. Full article

Myocardial infarction (MI) remains a leading cause of morbidity and mortality worldwide. While timely reperfusion therapies such as percutaneous coronary intervention (PCI) and thrombolysis are essential for salvaging ischemic myocardium, they can paradoxically exacerbate tissue injury through a process known as myocardial infarction reperfusion injury (MIRI). MIRI can contribute to up to 50% of the final infarct size, significantly diminishing the benefits of revascularization and leading to worsened cardiac outcomes. The pathophysiology of MIRI involves complex, interrelated mechanisms including oxidative stress, calcium overload, mitochondrial dysfunction, inflammatory responses, apoptosis, and dysregulated autophagy. Post-reperfusion recovery is further complicated by structural and functional abnormalities such as microvascular obstruction, endothelial dysfunction, and myocardial stunning. Clinically, distinguishing reperfusion injury from ischemic damage is challenging and often requires the use of sensitive biomarkers, such as cardiac troponins, alongside advanced imaging modalities. Although a range of pharmacological (e.g., antioxidants, calcium channel blockers, mitochondrial stabilizers, anti-inflammatory agents) and non-pharmacological (e.g., hypothermia, gene therapy, stem cell-based therapies) interventions have shown promise in preclinical studies, their clinical translation remains limited. This is largely due to the multifactorial and dynamic nature of MIRI. In this context, network pharmacology offers a systems-level approach to understanding the complex biological interactions involved in MIRI, facilitating the identification of multi-target therapeutic strategies. Integrating network pharmacology with omics technologies and precision medicine holds potential for advancing cardioprotective therapies. This review provides a comprehensive analysis of the molecular mechanisms underlying MIRI, examines the current clinical challenges, and explores emerging therapeutic strategies. Emphasis is placed on bridging the translational gap through validated, multi-target approaches and large-scale, multicenter clinical trials. Ultimately, this work aims to support the development of innovative and effective interventions for improving outcomes in patients with myocardial infarction. Full article

Background/Objectives: Stratifying post-cardiac arrest survivors based on the likelihood of good neurologic outcomes can guide the decision for targeted temperature management (TTM). This study aimed to compare the impact of TTM on neurological improvement among comatose out-of-hospital cardiac arrest (OHCA) survivors stratified by the revised post-cardiac arrest syndrome for therapeutic hypothermia (rCAST) score. Methods: This retrospective observational cohort study was conducted from February 2018 to April 2023 at the emergency department. We calculated the rCAST score immediately after the return of spontaneous circulation in adult patients and compared neurological outcomes at discharge for TTM based on the severity classification of the rCAST score (low: ≤5.5; moderate: 6.0–14.0; high: ≥14.5). We utilized inverse probability of treatment weighting (IPTW) analysis to adjust for selection bias and potential confounding factors between the TTM and non-TTM groups. Results: Among 300 comatose OHCA survivors, the proportions of patients with good neurological outcomes at discharge were 60.7% (17/28), 38.9% (56/144), and 2.3% (3/128) in the low, moderate, and high-severity rCAST groups, respectively. With increasing severity of the rCAST, the absolute difference in the proportion of patients with good neurological outcomes decreased between those who underwent TTM and those who did not (68.0% vs. 0.0%; p = 0.023, 45.2% vs. 27.5%; p = 0.037, and 3.5% vs. 0.0%; p = 0.221, respectively). After adjusting using IPTW, TTM was associated with good neurologic outcomes in the moderate-severity group (odds ratio, 2.31; 95% confidence interval, 1.09–4.91; p = 0.029). Conclusions: This study suggests that TTM may offer specific benefits for certain groups of OHCA survivors. Further research is needed to refine risk stratification tools for improved patient selection. Full article

Survivors of severe hypothermia frequently exhibit cognitive impairments. However, the underlying mechanisms remain inadequately understood. In order to reveal the scientific problem of cognitive dysfunction caused by severe hypothermia, providing an experimental basis for clinical treatment, this study utilized animal models and combined cognitive behavioral, morphological, and molecular biological experiments. The results showed that severe hypothermia leads to an accumulation of iron ions in the cerebral cortex tissue exceeding 70%, while increased Acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression enhances sensitivity to ferroptosis. This process results in a nearly 50% decrease in glutathione (GSH) expression and over 50% degradation of glutathione peroxidase 4 (GPX4), leading to GPX4 deactivation and increased lipid peroxidation, which in turn nearly doubles the levels of oxidative products such as MDA and 4NHE. Notably, ferroptosis inhibition using Ferrostatin-1 (Fer-1) effectively mitigates the degenerative death of cerebral cortical neurons induced by severe hypothermia, significantly improving the associated cognitive deficits. These findings suggest that severe hypothermia may induce ferroptosis in cortical neurons through the Nrf2/SLC7A11/GSH/GPX4 signaling axis. Targeted inhibition of ferroptosis has the potential to be a promising therapeutic direction for the prevention and treatment of cognitive impairment caused by severe hypothermia. Full article

TWIK-related K+ (TREK-1) channels are involved in pain perception and their pharmacological activation has potential for pain relief. The development of new pharmacological tools to study these channels and enrich our knowledge of structure–activity relationships is therefore important. We optimized a high throughput screening method based on thallium flux monitoring for the detection of TREK-1 activators in chemical libraries. We screened 1040 compounds from the French National Essential Chemical Library and identified LPS2336 as a potent TREK-1 activator with an EC₅₀ of 11.76 µM. Thirty-three LPS2336 analogs were subsequently tested but none of them retained activity on TREK-1. In vivo, LPS2336 produces antinociceptive activity when administered systemically and, to a lesser extent, intracerebroventricularly, but not intrathecally, showing that targeting peripheral TREK-1 channels may be important to produce pain relief, with the interest of reducing potential central adverse effects. LPS2336 was shown to produce sedation and hypothermia with a narrow therapeutic window. As these adverse effects are also observed in TREK-1 knock-out mice, they are likely mediated by off-targets. Our work provides key optimization steps for thallium-based assays and a new pharmacological tool for the study of TREK-1 channels. It also raises the importance of investigating adverse effects in vivo at early stages of drug discovery. Full article

Background/Objectives: Hypoxic–ischemic encephalopathy (HIE), affecting 1.3–1.7/1000 live births, is treated with conventional therapeutic hypothermia (TH) but carries significant mortality and neurological impairment. Here, we compared intravascular cooling with extracorporeal membrane oxygenation (ECMO) and conventional TH in neonates with moderate to severe HIE. Methods: We retrospectively analyzed single-center neonates born in 2000–2022. Neonates with a 10 min Apgar score ≤ 3 or umbilical artery pH ≤ 6.7, along with persistent pulmonary hypertension of the newborn and an oxygenation index of ≥25 to <40, were divided into ECMO (n = 17) and conventional TH (n = 18) groups and administered the Kyoto Scale of Psychological Development at 18 months. Results: Neonatal and maternal characteristics were similar between the groups. A significantly higher proportion of the ECMO group (70.6% vs. 33.3%) achieved a developmental quotient ≥ 70. Conclusions: Intravascular cooling with ECMO may improve the neurodevelopmental outcomes of neonates with HIE, severe acidosis, and low Apgar scores. Full article

Hypothermia (HT) is used clinically for neonatal hypoxic–ischemic encephalopathy (HIE); however, the brain protection is incomplete and selective regional vulnerability and lifelong consequences remain. Refractory damage and impairment with HT cooling/rewarming could result from unchecked or altered persisting cell death and proteinopathy. We tested two hypotheses: (1) HT modifies neurodegeneration type, and (2) intrinsically disordered proteins (IDPs) and encephalopathy cause toxic conformer protein (TCP) proteinopathy neonatally. We studied postmortem human neonatal HIE cases with or without therapeutic HT, neonatal piglets subjected to global hypoxia-ischemia (HI) with and without HT or combinations of HI and quinolinic acid (QA) excitotoxicity surviving for 29–96 h to 14 days, and human oligodendrocytes and neurons exposed to QA for cell models. In human and piglet encephalopathies with normothermia, the neuropathology by hematoxylin and eosin staining was similar; necrotic cell degeneration predominated. With HT, neurodegeneration morphology shifted to apoptosis-necrosis hybrid and apoptotic forms in human HIE, while neurons in HI piglets were unshifting and protected robustly. Oligomers and putative TCPs of α-synuclein (αSyn), nitrated-Syn and aggregated αSyn, misfolded/oxidized superoxide dismutase-1 (SOD1), and prion protein (PrP) were detected with highly specific antibodies by immunohistochemistry, immunofluorescence, and immunoblotting. αSyn and SOD1 TCPs were seen in human HIE brains regardless of HT treatment. αSyn and SOD1 TCPs were detected as early as 29 h after injury in piglets and QA-injured human oligodendrocytes and neurons in culture. Cell immunophenotyping by immunofluorescence showed αSyn detected with antibodies to aggregated/oligomerized protein; nitrated-Syn accumulated in neurons, sometimes appearing as focal dendritic aggregations. Co-localization also showed aberrant αSyn accumulating in presynaptic terminals. Proteinase K-resistant PrP accumulated in ischemic Purkinje cells, and their target regions had PrP-positive neuritic plaque-like pathology. Immunofluorescence revealed misfolded/oxidized SOD1 in neurons, axons, astrocytes, and oligodendrocytes. HT attenuated TCP formation in piglets. We conclude that HT differentially affects brain damage in humans and piglets. HT shifts neuronal cell death to other forms in human while blocking ischemic necrosis in piglet for sustained protection. HI and excitotoxicity also acutely induce formation of TCPs and prion-like proteins from IDPs globally throughout the brain in gray matter and white matter. HT attenuates proteinopathy in piglets but seemingly not in humans. Shifting of cell death type and aberrant toxic protein formation could explain the selective system vulnerability, connectome spreading, and persistent damage seen in neonatal HIE leading to lifelong consequences even after HT treatment. Full article

Neuroprotective strategies in coronary artery interventions are essential due to the rising number of high-risk patients undergoing procedures like coronary artery bypass grafting (CABG), totally endoscopic coronary artery bypass (TECAB), and hybrid revascularization. In this review article, we summarize the neurological complications associated with coronary artery disease intervention and the risk mitigation strategies. CABG carries significant risks, including ischemic stroke, encephalopathy, seizures, and peripheral nerve injuries. Risk factors include advanced age, hypertension, diabetes, and atherosclerosis. Off-pump CABG minimizes stroke risk by avoiding aortic manipulation and CPB. TECAB and hybrid revascularization have fewer reported neurological complications but still pose risks of stroke and cranial nerve injuries. Pharmacological neuroprotection includes agents such as barbiturates, volatile anesthetics, lidocaine, NMDA receptor antagonists, magnesium, nimodipine, corticosteroids, and aprotinin. Deep hypothermic circulatory arrest (DHCA) is reserved for complex aortic cases requiring a bloodless surgical field. Intraoperative strategies involve cerebral perfusion monitoring, embolic protection devices, and therapeutic hypothermia. Preoperative optimization targets risk factors, arrhythmia prevention, and antiplatelet therapy management. Postoperatively, timely antiplatelet administration, glucose control, hemodynamic stabilization, and cognitive monitoring are critical. Comprehensive neuroprotective approaches, spanning pre- to postoperative phases, aim to reduce neurological complications and enhance outcomes in coronary interventions. Full article

Background: Newborns, including preterm infants, are capable of responding to pain. Recurrent pain exposure is associated with suboptimal motor development, cognitive impairments, abnormal brain growth, and maladapted nociceptive reactions. Problem: Current agents, primarily opioids and benzodiazepines, raise major concerns due to their adverse effects, including insufficient sedation or analgesia, withdrawal, depressed respiratory effort, tolerance, and occasional paradoxical agitation. Commonly used drugs such as midazolam and morphine have been shown to induce neuroapoptosis and neurodevelopmental abnormalities in animal studies. Evaluation—Dexmedetomidine: As a specific alpha-2 adrenergic agonist, dexmedetomidine causes a significantly lower reduction in breathing effort. It has over 800 times greater affinity for alpha-2 receptors compared to alpha-1 receptors. Common side effects include bradycardia and hypotension. Prolonged use may necessitate a transition to clonidine during the weaning process. Dexmedetomidine can be administered intravenously as a bolus or infusion or intranasally. Indications include sedation and analgesia for mechanical ventilation, therapeutic hypothermia, procedural premedication, and as an adjunct to inhalational anesthesia and nerve-blocking agents. Research across varying age groups has demonstrated that dexmedetomidine shortens periods of invasive ventilation and decreases the need for other sedatives. Neonatal studies suggest that dexmedetomidine may help accelerate the achievement of full enteral feeds and can be safely administered within specific dosage ranges without causing significant adverse events that would necessitate abrupt discontinuation. Conclusions: Dexmedetomidine can be used alone or in combination with other agents. By increasing the use of dexmedetomidine, it is possible to reduce the dosage of concurrent medications, thereby minimizing the risk of complications while still achieving the desired sedation and analgesia. Full article

Background: The aim of the study was to evaluate a novel EEG scoring system as a diagnostic and prognostic tool for brain injury in infants who had experienced perinatal asphyxia. Methods: The scoring system, based on a semi-quantitative approach, encompassed seven EEG parameters and their aggregate Dammiss score (DS) measured across seven time points (6 h, 12 h, 24 h, 48 h, 72 h, 78 h, and 2 weeks). The EEGs of 61 full-term newborns affected by perinatal asphyxia and treated with therapeutic hypothermia were evaluated. Results: The EEG parameters were correlated with the outcome at 2 years of age: 41 infants showed normal development; 16 presented with mild neurological abnormalities; and 4 developed cerebral palsy. Key EEG features—such as maturational patterns, sleep states, interburst interval, burst morphology and DS at 6 h of life—were highly predictive of outcomes. Correlations were also observed for sleep states, burst morphology, and DS at 12 and 24 h. Notably, burst amplitude and seizure did not correlate with outcome. Additionally, EEG recovery—observed in all patients—was temporarily impaired by seizures in 18% of the cooled infants. Conclusions: The EEG findings within the first 6 h of life were the most predictive of neurodevelopmental outcomes. The DS and EEG maturational features emerged as the most robust indicators of prognosis. Full article