Hemmen Sabir

Neutrophils, traditionally viewed as first responders to microbial invasion, also play a pivotal role in sterile inflammation associated with tissue injury or stress in the absence of pathogens. In this context, they are recruited by danger-associated molecular patterns (DAMPs) released from damaged or dying cells, rather than by microbial signals. Once at the site of injury, neutrophils clear debris, release proteases and reactive oxygen species contributing to tissue damage, and shape the inflammatory environment through cytokine and chemokine secretion. However, because their antimicrobial arsenal is nonspecific, their activity in sterile settings can be a double-edged sword: essential for initiating repair but also capable of exacerbating tissue injury if not properly regulated. Neutrophils have been implicated in many diseases of neonates, particularly neonatal encephalopathy (NE). Recently, this has been demonstrated using different hypoxic-ischemic encephalopathy (HIE) animal models. Harnessing the roles of neutrophils, both good and bad, can potentially influence future clinical therapies. This review summarizes the current knowledge about the role of neutrophils following perinatal hypoxic-ischemic brain injuries. Impact: This study elucidates the association between neutrophil activity and neonatal hypoxic-ischemic encephalopathy, thereby reinforcing emerging evidence from animal models and elucidating the underlying mechanisms of this prevalent neonatal condition. Neutrophils play a pivotal role in sterile inflammation, underscoring their dual function in both tissue repair and damage. This duality reshapes the understanding of injury, extending beyond the traditional focus on infection. Neutrophils have been recognized as potential therapeutic targets, and the modulation of their responses may achieve a balance between protection and injury. This approach could pave the way for novel, mechanism-based treatments for perinatal brain injury.

Neonatal hypoxic–ischemic encephalopathy (HIE) is a major cause of neonatal mortality and long-term neurological disability, affecting 1–3 per 1000 live births in developed countries and occurring at substantially higher rates in developing countries. Neuroinflammation is a key contributor to disease progression, with growing evidence implicating the activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome following hypoxic–ischemic (HI) injury. In this study, we investigated the role and regulation of the NLRP3 inflammasome in neonatal HIE using in vitro and in vivo models. Primary microglial cultures subjected to oxygen–glucose deprivation and the Vannucci neonatal rat model of HI were used to characterize NLRP3 activation and its contribution to injury. We demonstrated that HI induces NLRP3 inflammasome activation, whereas pharmacological inhibition of NLRP3 enhances cell viability and attenuates brain damage. Our findings identify microglia as a central mediator of NLRP3-driven neuroinflammation and highlight microglial NLRP3 signaling as a promising therapeutic target for neuroinflammatory diseases. Collectively, this study provides an integrated view of NLRP3 regulation in neonatal HIE and supports inflammasome-directed strategies for neuroprotection following neonatal HI injury.

Aim: There is a wide treatment heterogeneity for asphyxiated newborn infants between hospitals in Germany. This study aimed to identify the leading entry criteria initiating therapeutic hypothermia (TH) using data from the German Hypothermia Registry. Methods: We retrospectively analyzed 262 asphyxiated newborn infants treated with TH across 74 neonatal units in Germany. Clinical and metabolic parameters and neurological assessments were recorded before the initiation of TH using a standardised electronic form in REDCap, a secure web‐based platform for clinical research. Correlations between metabolic indicators (pH, base deficit, lactate) and neurological assessments, including Sarnat score, Thompson score and initial amplitude‐integrated electroencephalography (aEEG) were examined. Results: Mean gestational age was 39.4 ± 1.7 weeks. Acidosis and abnormal aEEG patterns were the most frequent criteria initiating treatment. Lower pH was strongly associated with abnormal aEEG (odds ratio 0.02, 95% confidence interval 0.002–0.19, p < 0.01). Base deficit and lactate showed weaker, non‐significant associations. Lower 10‐min Apgar scores predicted abnormal aEEG (odds ratio 0.77, 95% confidence interval 0.69–0.87, p < 0.001). Conclusion: Severe acidosis (pH < 7.0) was significantly associated with abnormal aEEG patterns, the main determinant initiating TH. Identifying abnormal aEEG patterns is essential for confirming moderate to severe encephalopathy and guiding treatment.

Objective: Magnetic-resonance-imaging (MRI) after brain injury is crucial for providing therapeutic strategies and prognosis. Serial MRI increases the prognostic value by revealing changes present at different time points after the initial injury and aids to study pathology and potential therapeutic strategies. Mobile ultralow-field MRI provides a unique opportunity to offer both bed-side and serial MRI in seriously sick patients. Design: We investigated whether serial bedside MRI, including quantitative Apparent Diffusion Coefficient (ADC) measurements are feasible in an infant with hypoxic-ischemic brain injury and how the appearance of brain injury evolves on MRI sequences. Setting/patients/interventions: We performed serial bed-side ultralow-field MRI with ADC measurements in an infant with hypoxic-ischemic brain injury over 11 days. Main results: We demonstrated that morphological changes associated with hypoxic-ischemic brain injury detected using standard MRI could be verified in an ultralow-field scan. We documented how hypoxic-ischemic brain injury develops in T1, T2, FLAIR and DWI sequences over a time span of 11 days and how signal intensity changes over this period. We show that ultralow-field imaging visualizes the pathophysiology known by experimental data. We report quantitative serial ADC-measurement in lesions. Conclusion: Ultralow-field MRI enables the detection of hypoxic-ischemic brain injury in infants and has the potential to significantly broaden access to MRI. Its application may provide more timely, comprehensive diagnostic information related to hypoxic-ischemic brain injury. Serial ultralow-field MRI enables quantitative assessment of ADC values, which may support the establishment of clinically relevant cutoff values. This not only enhances diagnostic and prognosis precision in hypoxic-ischemic brain injury, but also provides a framework for evaluating the efficacy of emerging therapeutic strategies.

Background: Mild hypoxic-ischemic encephalopathy (HIE) often goes undected due to the narrow therapeutic window, subtle or absent clinical signs, and the lack of standardized diagnostic criteria. A broader umbilical cord blood pH threshold may help identifying at-risk neonates. Long-term developmental outcomes of term-born infants with isolated acidosis are lacking.Objective: To examine the long-term non-verbal cognitive and language development at two years of term-born infants with an umbilical cord blood pH between 7.0 and 7.15 but no apparent clinical signs of mild HIE.Study design: Retrospective observational study of 101 term-born infants. Developmental outcome was assessed using the Parent Report of Children's Abilities—Revised (PARCA-R) questionnaire for infants aged between 23 months and 27 months. Standardized PARCA-R scores are interpreted as follows: ≥85 = normal development, 70–84 = mild developmental delay, <70 = moderate developmental delay.Results: PARCA-R Scores <85 in either non-verbal cognitive or language delay occurred in 39% of the cohort: 32% of them in non-verbal cognitive and 16% in language domain. No significant differences in developmental outcomes between the pH subgroups were found. Our outcomes were highly consistent with reported outcomes of infants diagnosed with mild HIE.Conclusion: Term-born infants with isolated perinatal acidosis may be at increased risk of developmental impairments at two years, despite being considered clinically healthy at birth.

Background: Inflammation-sensitized hypoxic-ischemic brain injury significantly contributes to neonatal mortality as affected neonates do not benefit from standard cooling treatments. To get further insight into inflammatory responses involved, we experimentally investigated the immune response of microglia in an inflammation-sensitized neonatal hypoxia-ischemia (HI) model. Results: Transcriptomic analysis of microglia isolated from brains following inflammation-sensitized HI brain injury revealed a strong upregulation of leukocyte recruitment and pro-inflammatory markers. Specifically, markers associated with neutrophil-mediated immune responses and chemotaxis were upregulated in the inflammation-sensitized HI group compared to the non-inflammation-sensitized HI and control groups. Serpine 1 and Selp could be identified as specifically upregulated markers indicating an acute inflammatory condition before HI injury. Conclusion: Our study revealed preliminary data about a microglia population which is primed to recruit peripheral neutrophils to infiltrate the brain and mediate neutrophil immune response. We showed a contribution to neutrophil activation in case of inflammation following HI in the brain. Targeting microglia-mediated neutrophil recruitment can indicate a possible treatment approach in case of inflammation-sensitized HI brain injury.

Purpose: This study aims to assess the applicability of ultralow-field (ULF) magnetic resonance imaging (MRI) in the neonatal intensive care unit (NICU), its impact on both the neonate being scanned and neighboring patients, and its effects on medical procedures and early parent-child interaction. Background: Neonatal MRI is crucial for diagnosis and treatment in the NICU, but access is limited, both in high-income countries and low- and middle-income countries. Portable ULF MRI presents an opportunity to expand access, but its applicability and potential impacts on neonates and nearby patients have not been studied, including its effects on medical care and early parent-child interaction. Methods: We assessed applicability, safety and stress levels of neonates during ULF MRI at a NICU by measuring heart rate, oxygen saturation and blood pressure of the neonate scanned and neighboring patients and by measuring subjective stress levels assessed by attending physicians, nurses and parents. Using questionnaires, we assessed whether medical care and early parent-child interaction was affected. Results: No significant differences were found in the physiological measures of the scanned and neighboring neonates. Medical care and parent-child interaction were not affected by ULF MRI. Conclusions: ULF MRI can be safely performed in the NICU without causing stress to neonates or affecting medical care or parent-child interaction. It can be performed at the bedside during natural sleep, requiring fewer resources compared to high-field MRI, making it a viable point-of-care option in both the NICU and low-resource settings. This could significantly increase MRI accessibility.

Background: Understanding the mechanisms of injury following neonatal hypoxic-ischemic encephalopathy (HIE) is a major goal in neonatal research. HIE can have severe effects on cognitive and motor development in newborns, including an increased risk of death. As the incidence is 10–20 times higher in low- and middle-income countries compared to developed countries, the interest in a therapy exists worldwide. Therapeutic hypothermia (HT) is the only effective treatment after HIE. However, TH is not universally effective, particularly in cases of inflammation-sensitized hypoxia-ischemia (HI); it provides limited benefit. Methods: To identify proteins that may contribute to the reduced efficacy of HT in the case of pre-HI inflammation sensitization, the proteomic profiles of animals subjected to HI and HT combined with lipopolysaccharide (LPS) were analyzed via liquid chromatography mass spectrometry (LC-MS/MS). Results: We identified proteins that potentially support the efficacy of HT and those that prevent the success of the therapy in the neonatal rat model of inflammation-sensitized HI. Conclusion: This study represents a step forward in identifying proteins related to the efficacy of HT following inflammation-sensitized HI. Impact: Therapeutic hypothermia is the only available treatment for neonatal hypoxic-ischemic encephalopathy, but not effective in models of inflammation-sensitized hypoxic-ischemic brain injury. Using liquid chromatography mass spectrometry, we identified proteins possibly having an effect on the treatment success of therapeutic hypothermia following experimental inflammation-sensitized hypoxic-ischemic brain injury. This proteomic analysis reveals proteins as potential markers that could prevent or support the efficacy of therapeutic hypothermia in experimental neonatal inflammation-sensitized hypoxic-ischemic encephalopathy.