Cerebral Hypoperfusion Research Articles

Impairment of Renal Function in Perinatal Asphyxia with Hypoxic Ischemic Encephalopathy in Term Neonates

Background: Perinatal asphyxia is a major cause of neonatal morbidity and mortality worldwide including in Bangladesh. It causes damage to almost every tissue and organ of the body. In kidneys, renal insufficiency may occur promptly even within 24 hours of asphyxia. So, renal function assessment is essential for accurate management of metabolic derangement in neonates as prolonged hypoxic ischemic episode can lead to irreversible cortical necrosis with onset of acute renal failure.Objectives: To find out renal impairment and to measure serum creatinine, serum electrolyte and eGFR, Also to compare biochemical parameters level and determine the frequency of AKI among the asphyxiated neonates with HIE.Materials and Methods: This cross-sectional study was conducted in the neonatal care unit of Sir Salimullah Medical College Mitford Hospital, Dhaka. A total of 70 term neonates suffered from perinatal asphyxia with different stages of Hypoxic ischaemic encephalopathy. A ‘p’ value <0.05 was considered as statistically significant.Results: Among 70 term neonates having HIE, it was observed that 62.9% neonates had moderate birth asphyxia followed by mild (28.6%) and severe (8.6%). Newborns with SGA (71.4%) had more renal impairment than AGA. Among biochemical variables Blood urea and serum creatinine were high and eGFR was low in stage Π. Among electrolytes, hyponatremia was present in 24.3% of cases and more in stage Π, and hyperkalemia was present in 21.4% of cases and more in stage Ш. AKI was found in 18.6% of cases, Risk (stage 1) was 77%, Injury (stage Π) was 15.3% and Failure (stage 3) was 7.7 %.Conclusion: Renal impairment was found in 18.5% of term asphyxiated neonates with HIE according to pRIFLE and AKIN criteria and Biochemical parameters showed no significant changes between different stages of HIE. KYAMC Journal Volume: 14, No: 04, January 2024: 198-205.

Searching molecular biomarkers correlating with BSID-III at 24months in infants with neonatal hypoxic-ischemic encephalopathy.

An early prediction of outcomes of neonatal hypoxic-ischemic encephalopathy (NE) is of key importance in reducing neonatal mortality and morbidity. The objectives were (i) to analyze the characteristics of miRNA expression and metabolic patterns of neonates with NE and (ii) to assess their predictive performance for neurodevelopmental outcomes. Plasma samples from moderate/severe NE patients (N = 92) of the HYPOTOP study were collected before, during, and after therapeutic hypothermia (TH) and compared to a control group (healthy term infants). The expression of miRNAs and concentrations of metabolites (hypoxia-related and energy, steroid, and tryptophan metabolisms) were analyzed. Neurodevelopmental outcomes were evaluated at 24months postnatal age using Bayley Scales of Infant Development, ed. III, BSID-III. Differences in miRNA and metabolic profiles were found between NE vs. control infants, abnormal (i.e., mildly and moderately abnormal and severe) vs. normal, and severe vs. non-severe (i.e., normal and mildly and moderately abnormal) BSID-III. 4-Androstene-3,17-dione, testosterone, betaine, xanthine, and lactate were suitable for BSID-III outcome prediction (receiver operating characteristic areas under the curve (AUCs) ≥ 0.6), as well as 68 miRNAs (AUCs of 0.5-0.9). Significant partial correlations of xanthine and betaine levels and the expression of several miRNAs with BSID-III sub-scales were found.Conclusion: We have identified metabolites/miRNAs that might be useful to support the prediction of middle-term neurodevelopmental outcomes of NE. What is known and what is new: • The early prediction of outcomes of neonatal hypoxic-ischemic encephalopathy (NE) is of key importance in reducing neonatal mortality and morbidity. • Alterations of the metabolome and miRNAs had been observed in NE. • We performed miRNA sequencing and quantified selected metabolites (i.e., lactate, pyruvate, ketone bodies, Krebs cycle intermediates, tryptophan pathway, hypoxia-related metabolites, and steroids) by GC- and LC-MS. • Specific miRNAs and metabolites that allow prediction of middle-term neurodevelopmental outcomes of newborns with NE undergoing hypothermia treatment were identified.

Normal value of neuron-specific enolase for predicting good neurological outcomes in comatose out-of-hospital cardiac arrest survivors.

Research on prognostic factors for good outcomes in out-of-hospital cardiac arrest (OHCA) survivors is lacking. We assessed whether normal levels of normal neuron-specific enolase (NSE) value would be useful for predicting good neurological outcomes in comatose OHCA survivors treated with targeted temperature management (TTM). This registry-based observational study with consecutive adult (≥18 years) OHCA survivors with TTM who underwent NSE measurement 48 hours after cardiac arrest was conducted from October 2015 to November 2022. Normal NSE values defined as the upper limit of the normal range by the manufacturer (NSE <16.3 μg/L) and guideline-suggested (NSE < 60 μg/L) were examined for good neurologic outcomes, defined as Cerebral Performance Categories ≤2, at 6 months post-survival. Among 226 OHCA survivors with TTM, 200 patients who underwent NSE measurement were enrolled. The manufacturer-suggested normal NSE values (<16.3 μg/L) had a specificity of 99.17% for good neurological outcomes with a very low sensitivity of 12.66%. NSE <60 μg/L predicted good outcomes with a sensitivity of 87.34% and specificity of 72.73%. However, excluding 14 poor-outcome patients who died from multi-organ dysfunction excluding hypoxic brain injury, the sensitivity and specificity of normal NSE values were 12.66% and 99.07% of NSE < 16.3 μg/L, and 87.34% and 82.24% of NSE < 60 μg/L. The manufacturer-suggested normal NSE had high specificity with low sensitivity, but the guideline-suggested normal NSE value had a comparatively low specificity for good outcome prediction in OHCA survivors. Our data demonstrate normal NSE levels can be useful as a tool for multimodal appropriation of good outcome prediction.

Point of care magnetic resonance neonatal neuroimaging applications and early imaging in infants under active therapeutic hypothermia: a perspective.

As care of the most vulnerable infants in the neonatal intensive care unit (NICU) evolves, improved and real-time understanding of brain health becomes key. The availability of an in-NICU magnetic resonance imaging (MRI) scanner provides unique options to bedside care providers and researchers. We present our perspective on the 1-Tesla MRI unit in our NICU and its utilities and applications both in the clinical and research fields. We also discuss our experience with early and serial MRI in a cohort of infants with hypoxic-ischemic encephalopathy while undergoing therapeutic hypothermia, using a compatible cooling blanket and monitoring apparatus with special insight into the planning and organization between providers, and parental perspectives around early, detailed imaging.

Utility of Point-of-care Ultrasound in Hypoxic-ischemic Brain Injury in Neonates

Utility of Point-of-care Ultrasound in Hypoxic-ischemic Brain Injury in Neonates

Insights from serial magnetic resonance imaging in neonatal encephalopathy in term infants.

Limited serial neuroimaging studies use magnetic resonance imaging (MRI) to define the evolution of hypoxic-ischemic insults to the brain of term infants and encompass both the primary injury and its secondary impact on cerebral development. The optimal timing of MRI to fully evaluate the impact of hypoxic-ischemic encephalopathy on brain development and associated neurodevelopmental sequelae remains unknown. Goals: (a) review literature related to serial neuroimaging in term infants with HIE; (b) describe pilot data in two infants with HIE treated with therapeutic hypothermia who had a brain injury at day 3-5 and underwent four additional MRIs over the next 12 weeks of life and developmental evaluation at 24 months of age. Early MRI defines primary injury on diffusion-weighted imaging, yet the full impact may not be fully apparent until after 1 month of life. The full impact of an ischemic injury on the neonatal brain may not be fully visible until several weeks after the initial insult. This suggests the benefit of obtaining later time points for MRI to fully define the extent of injury and its neurodevelopmental impact. Few studies inform the nature of the evolution of brain injury with hypothermia in HIE, limiting understanding of potential neuroprotection. MRI is the standard of care for prognosis in infants with HIE, however timing for optimal prognostic prediction remains unclear. Insights from MRI after the first week of life may assist in defining the full extent of brain injury and prognostic significance. A pilot study using five MRI timepoints up to 3 months of age, is presented. More data is required with a systematic evaluation of the impact of early brain injury on brain development in term infants with HIE following TH.

Drug Disposition in Neonatal Göttingen Minipigs: Exploring Effects of Perinatal Asphyxia and Therapeutic Hypothermia.

Asphyxiated neonates often undergo therapeutic hypothermia (TH) to reduce morbidity and mortality. Since both perinatal asphyxia (PA) and TH influence physiology, altered pharmacokinetics (PK) and pharmacodynamics (PD) are expected. Given that TH is the standard of care for PA with moderate to severe hypoxic-ischemic encephalopathy, disentangling the effect of PA versus TH on PK/PD is not possible in clinical settings. However, animal models can provide insights into this matter. The (neonatal) Göttingen Minipig, the recommended strain for nonclinical drug development, was selected as translational model. Four drugs-midazolam (MDZ), fentanyl (FNT), phenobarbital (PHB), and topiramate (TPM)-were intravenously administered under four conditions: control (C), therapeutic hypothermia (TH), hypoxia (H), and hypoxia plus TH (H+TH). Each group included six healthy male neonatal Göttingen Minipigs anesthetized for 24 hours. Blood samples were drawn at 0 (predose) and 0.5, 2, 2.5, 3, 4, 4.5, 6, 8, 12, and 24 hours post drug administration. Drug plasma concentrations were determined using validated bioanalytical assays. The PK parameters were estimated through compartmental and noncompartmental PK analysis. The study showed a statistically significant decrease in FNT clearance (CL; 66% decrease), with an approximately threefold longer half-life (t1/2) in the TH group. The H+TH group showed a 17% reduction in FNT CL, with a 62% longer t1/2 compared with the C group; however, it was not statistically significant. Although not statistically significant, trends toward lower CL and longer t1/2 were observed in the TH and H+TH groups for MDZ and PHB. Additionally, TPM demonstrated a 28% decrease in CL in the H group compared with controls. SIGNIFICANCE STATEMENT: The overarching goal of this study using the neonatal Göttingen Minipig model was to disentangle the effects of systemic hypoxia and TH on PK using four model drugs. Such insights can subsequently be used to inform and develop a physiologically based pharmacokinetic model, which is useful for drug exposure prediction in human neonates.

Amplitude-Integrated EEG in Infants at Risk of Hypoxic-Ischemic Encephalopathy: A Feasibility Study in Road and Air Transport in Western Australia.

Infants at risk of HIE require early identification and initiation of therapeutic hypothermia (TH). Earlier treatment with TH is associated with better outcomes. aEEG is frequently used when making the decision whether to commence TH. As this is often limited to tertiary centers, TH may be delayed if the infant requires transport to a center that provides it. We aimed to provide a method for the application of amplitude-integrated electroencephalogram (aEEG) and to determine the feasibility of acquiring clinically meaningful information during transport. All infants ≥35 weeks, at risk of HIE at referral, were eligible for inclusion. Scalp electrodes were placed in the C3-C4; P3-P4 position on the infant's scalp and connected to the aEEG amplifier. The aEEG amplifier was, in turn, connected to a clinical tablet computer with EEG software to collect and analyze aEEG information. Recordings were reviewed by the chief principal investigator and two independent reviewers (blinded) for background trace and artifact. Predefined criteria for data quality were set to movement artifacts and software impedance notifications. Surveys were completed by healthcare staff and parents for acceptability and ease of use.

Consensus definition and diagnostic criteria for neonatal encephalopathy-study protocol for a real-time modified delphi study.

'Neonatal encephalopathy' (NE) describes a group of conditions in term infants presenting in the earliest days after birth with disturbed neurological function of cerebral origin. NE is aetiologically heterogenous; one cause is peripartum hypoxic ischaemia. Lack of uniformity in the terminology used to describe NE and its diagnostic criteria creates difficulty in the design and interpretation of research and complicates communication with families. The DEFINE study aims to use a modifiedDelphi approach to form a consensus definition for NE, and diagnostic criteria. Directed by an international steering group, we will conduct a systematic review of the literature to assess the terminology used in trials of NE, and with their guidance perform an online Real-time Delphi survey to develop a consensus diagnosis and criteria for NE. A consensus meeting will be held to agree on the final terminology and criteria, and the outcome disseminated widely. A clear and consistent consensus-based definition of NE and criteria for its diagnosis, achieved by use of a modifiedDelphi technique, will enable more comparability of research results and improved communication among professionals and with families. The terms Neonatal Encephalopathy and Hypoxic Ischaemic Encephalopathy tend to be used interchangeably in the literature to describe a term newborn with signs of encephalopathy at birth. This creates difficulty in communication with families and carers, and between medical professionals and researchers, as well as creating difficulty with performance of research. The DEFINE project will use a Real-time Delphi approach to create a consensus definition for the term 'Neonatal Encephalopathy'. A definition formed by this consensus approach will be accepted and utilised by the neonatal community to improve research, outcomes, and parental experience.

Electrical impedance tomography provides information of brain injury during total aortic arch replacement through its correlation with relative difference of neurological biomarkers

Postoperative neurological dysfunction (PND) is one of the most common complications after a total aortic arch replacement (TAAR). Electrical impedance tomography (EIT) monitoring of cerebral hypoxia injury during TAAR is a promising technique for preventing the occurrence of PND. This study aimed to explore the feasibility of electrical impedance tomography (EIT) for warning of potential brain injury during total aortic arch replacement (TAAR) through building the correlation between EIT extracted parameters and variation of neurological biomarkers in serum. Patients with Stanford type A aortic dissection and requiring TAAR who were admitted between December 2021 to March 2022 were included. A 16-electrode EIT system was adopted to monitor each patient’s cerebral impedance intraoperatively. Five parameters of EIT signals regarding to the hypothermic circulatory arrest (HCA) period were extracted. Meanwhile, concentration of four neurological biomarkers in serum were measured regarding to time before and right after surgery, 12 h, 24 h and 48 h after surgery. The correlation between EIT parameters and variation of serum biomarkers were analyzed. A total of 57 TAAR patients were recruited. The correlation between EIT parameters and variation of biomarkers were stronger for patients with postoperative neurological dysfunction (PND(+)) than those without postoperative neurological dysfunction (PND(−)) in general. Particularly, variation of S100B after surgery had significantly moderate correlation with two parameters regarding to the difference of impedance between left and right brain which were MRAIabs and TRAIabs (0.500 and 0.485 with p < 0.05, respectively). In addition, significantly strong correlations were seen between variation of S100B at 24 h and the difference of average resistivity value before and after HCA phase (ΔARVHCA), the slope of electrical impedance during HCA (kHCA) and MRAIabs (0.758, 0.758 and 0.743 with p < 0.05, respectively) for patients with abnormal S100B level before surgery. Strong correlations were seen between variation of TAU after surgery and ΔARVHCA, kHCA and the time integral of electrical impedance for half flow of perfusion (TARVHP) (0.770, 0.794 and 0.818 with p < 0.01, respectively) for patients with abnormal TAU level before surgery. Another two significantly moderate correlations were found between TRAIabs and variation of GFAP at 12 h and 24 h (0.521 and 0.521 with p < 0.05, respectively) for patients with a normal GFAP serum level before surgery. The correlations between EIT parameters and serum level of neurological biomarkers were significant in patients with PND, especially for MRAIabs and TRAIabs, indicating that EIT may become a powerful assistant for providing a real-time warning of brain injury during TAAR from physiological perspective and useful guidance for intensive care units.

Oxytocin Exhibits Neuroprotective Effects on Hippocampal Cultures under Severe Oxygen-Glucose Deprivation Conditions.

Perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy can result in severe, long-lasting neurological deficits. In vitro models, such as oxygen-glucose deprivation (OGD), are used experimentally to investigate neuronal response to metabolic stress. However, multiple variables can affect the severity level of OGD/PA and may confound any measured treatment effect. Oxytocin (OXT) has emerged as a potential neuroprotective agent against the deleterious effects of PA. Previous studies have demonstrated OXT's potential to enhance neuronal survival in immature hippocampal cultures exposed to OGD, possibly by modulating gamma-aminobutyric acid-A receptor activity. Moreover, OXT's precise impact on developing hippocampal neurons under different severities of OGD/PA remains uncertain. In this study, we investigated the effects of OXT (0.1 µM and 1 µM) on 7-day-old primary rat hippocampal cultures subjected to 2 h OGD/sham normoxic conditions. Cell culture viability was determined using the resazurin assay. Our results indicate that the efficacy of 1 µM OXT treatment varied according to the severity of the OGD-induced lesion, exhibiting a protective effect (p = 0.022) only when cellular viability dropped below 49.41% in non-treated OGD cultures compared to normoxic ones. Furthermore, administration of 0.1 µM OXT did not yield significant effects, irrespective of lesion severity (p > 0.05). These findings suggest that 1 µM OXT treatment during OGD confers neuroprotection exclusively in severe lesions in hippocampal neurons after 7 days in vitro. Further research is warranted to elucidate the mechanisms involved in OXT-mediated neuroprotection.

Underlying Mechanism of Lysosomal Membrane Permeabilization in CNS Injury: A Literature Review.

Lysosomes play a crucial role in various intracellular pathways as their final destination. Various stressors, whether mild or severe, can induce lysosomal membrane permeabilization (LMP), resulting in the release of lysosomal enzymes into the cytoplasm. LMP not only plays a pivotal role in various cellular events but also significantly contributes to programmed cell death (PCD). Previous research has demonstrated the participation of LMP in central nervous system (CNS) injuries, including traumatic brain injury (TBI), spinal cord injury (SCI), subarachnoid hemorrhage (SAH), and hypoxic-ischemic encephalopathy (HIE). However, the mechanisms underlying LMP in CNS injuries are poorly understood. The occurrence of LMP leads to the activation of inflammatory pathways, increased levels of oxidative stress, and PCD. Herein, we present a comprehensive overview of the latest findings regarding LMP and highlight its functions in cellular events and PCDs (lysosome-dependent cell death, apoptosis, pyroptosis, ferroptosis, and autophagy). In addition, we consolidate the most recent insights into LMP in CNS injury by summarizing and exploring the latest advances. We also review potential therapeutic strategies that aim to preserve LMP or inhibit the release of enzymes from lysosomes to alleviate the consequences of LMP in CNS injury. A better understanding of the role that LMP plays in CNS injury may facilitate the development of strategic treatment options for CNS injury.

Changes in the Treatment and Outcomes of Different Severities of Neonatal Hypoxic Ischemic Encephalopathy in California: A Retrospective Cohort Study.

Evaluate the changes in management and outcomes of Californian infants with hypoxic ischemic encephalopathy (HIE). Infants with HIE were identified from a California administrative birth cohort using ICD codes and divided into two epochs, Epoch 1 (2010-2015) and Epoch 2 (2016-2019). Risk ratios (RR) for therapeutic hypothermia (TH) in each epoch and their outcomes were calculated using log-linear regression. In this cohort, 4779 infants with HIE were identified. Incidence of HIE in California increased yearly from 0.5/1,000 California births to a peak of 1.5/1,000 births in 2018. The use of TH in infants with mild HIE increased in Epoch 2 compared to Epoch 1. There was no significant difference in outcomes between epochs for infants with mild HIE that received TH. Significantly more infants with mild HIE received TH since 2015 in California, but no difference in outcomes was found for these patients.

Magnetic resonance imaging scanning susceptibility weighted imaging sequences in the diagnosis and prognostic evaluation of neonatal hypoxic-ischemic encephalopathy

BACKGROUND Magnetic resonance imaging (MRI) scanning with susceptibility weighted imaging (SWI) sequences plays a significant role in the diagnosis and prognostic evaluation of neonatal hypoxic-ischemic encephalopathy (HIE). AIM To observe the role of MRI multi-parameter quantitative indexes in the diagnosis of neonatal HIE. METHODS The imaging data from 23 cases of neonatal HIE admitted to the Imaging Department of Ganyu District People's Hospital of Lianyungang City and 23 neonates without HIE admitted during the same period were analyzed retrospectively from August, 2021 to December, 2023. The results of clinical judgment were compared with the results of computed tomography (CT) and MRI examinations. RESULTS The degree of cerebral edema (more than moderate), the number of damaged brain regions (&gt; 2), the number of cerebral hemorrhages (&gt; 2), and the percentage of small venous dilatation detected were higher in MRI than in CT examination, and the differences were statistically significant (P &lt; 0.05). The total area of the largest region of cerebral damage and of cerebral hemorrhage observed by MRI examination were significantly larger than those of CT examination (P &lt; 0.01). Multiparametric quantitative MRI combined with diffusion weighted imaging and SWI had higher sensitivity and accuracy than CT diagnosis, and the difference was statistically significant (P &lt; 0.05). The difference in the specificity of the two modes of diagnosis was not significant (P &gt; 0.05). CONCLUSION The use of MRI multi-parameter quantitative indexes can accurately diagnose and evaluate neonatal HIE.

Oral Clonidine-Based Strategy to Reduce Opiate Use During Cooling for Neonatal Encephalopathy: An Observational Study

To determine whether an enteral, clonidine-based sedation strategy (CLON) during therapeutic hypothermia (TH) for hypoxic-ischemic encephalopathy would decrease opiate use while maintaining similar short-term safety and efficacy profiles to a morphine-based strategy (MOR). This was a single-center, observational study conducted at a level IV neonatal intensive care unit from January 1, 2017, to October 1, 2021. From April 13, 2020, to August 13, 2020, we transitioned from MOR to CLON. Thus, patients receiving TH for hypoxic-ischemic encephalopathy were grouped to MOR (before April 13, 2020) and CLON (after August 13, 2020). We calculated the total and rescue morphine milligram equivalent/kg (primary outcome) and frequency of hemodynamic changes (secondary outcome) for both groups. The MOR and CLON groups (74 and 25 neonates, respectively) had similar baseline characteristics and need for rescue sedative intravenous infusion (21.6% MOR and 20% CLON). Both morphine milligram equivalent/kg and need for rescue opiates (combined bolus and infusions) were greater in MOR than CLON (P<.001). As days in TH advanced, a lower percentage of patients receiving CLON needed rescue opiates (92% on day 1 to 68% on day 3). Patients receiving MOR received a greater cumulative dose of dopamine and more frequently required a second inotrope and hydrocortisone for hypotension. MOR had a lower respiratory rate during TH (P=.01 vs CLON). Our CLON protocol is noninferior to MOR, maintaining perceived effectiveness and hemodynamic safety, with an apparently reduced need for opiates and inotropes.

Risk of Adverse Neonatal Events in Pregnancies Complicated by Severe Maternal Morbidity

To investigate the risk of adverse neonatal events after a pregnancy complicated by severe maternal morbidity. We analyzed a population-based cohort of deliveries in Quebec, Canada, between 2006 and 2021. The main exposure measure was severe maternal morbidity, comprising life-threatening conditions such as severe hemorrhage, cardiac complications, and eclampsia. The outcome included adverse neonatal events such as very preterm birth (gestational age <32weeks), bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, and neonatal death. Using log-binomial regression models, we estimated adjusted relative risks (RRs) and 95% confidence intervals (CIs) for the association between severe maternal morbidity and adverse neonatal events. Among 1 199 112 deliveries, 29 992 (2.5%) were complicated by severe maternal morbidity and 83 367 (7.0%) had adverse neonatal events. Severe maternal morbidity was associated with 2.96 times the risk of adverse neonatal events compared with no morbidity (95% CI 2.90-3.03). Associations were greatest for mothers who required assisted ventilation (RR 5.86, 95% CI 5.34-6.44), experienced uterine rupture (RR 4.54, 95% CI 3.73-5.51), or had cardiac complications (RR 4.39, 95% CI 3.98-4.84). Severe maternal morbidity was associated with ≥3 times the risk of neonatal death and hypoxic-ischemic encephalopathy and ≥10 times the risk of very preterm birth and bronchopulmonary dysplasia. Severe maternal morbidity is associated with an elevated risk of adverse neonatal events. Better prevention of severe maternal morbidity may help reduce burden of severe neonatal morbidity.

Mesenchymal Stromal Cell therapy for Hypoxic Ischemic Encephalopathy: Future directions for combination therapy with hypothermia and/or melatonin

Hypoxic ischemic encephalopathy (HIE) remains a leading cause of neonatal mortality and lifelong disability across the world. While therapeutic hypothermia (HT) is beneficial, it is only partially protective and adjuvant treatments that further improve outcomes are urgently needed. In high-income countries where HT is standard care, novel treatments are tested in conjunction with HT. Mesenchymal stromal cells (MSC) represent a paradigm shift in brain protection, uniquely adapting to the host cellular microenvironment. MSC have low immunogenicity and potent paracrine effects stimulating the host tissue repair and regeneration and reducing inflammation and apoptosis. Preclinical studies in perinatal brain injury suggest that MSC are beneficial after hypoxia-ischemia (HI) and most preclinical studies of MSC with HT show protection. Preclinical and early phase clinical trials have shown that allogenic administration of MSC to neonates with perinatal stroke and HIE is safe and feasible but further safety and efficacy studies of HT with MSC in these populations are needed. Combination therapies that target all stages of the evolution of injury after HI (eg HT, melatonin and MSC) show promise for improving outcomes in HIE.

A novel rat model of cerebral small vessel disease based on vascular risk factors of hypertension, aging, and cerebral hypoperfusion.

Cerebral small vessel disease (CSVD) is a major cause of vascular cognitive impairment and functional loss in elderly patients. Progressive remodeling of cerebral microvessels due to arterial hypertension or other vascular risk factors, such as aging, can cause dementia or stroke. Typical imaging characteristics of CSVD include cerebral microbleeds (CMB), brain atrophy, small subcortical infarctions, white matter hyperintensities (WMH), and enlarged perivascular spaces (EPVS). Nevertheless, no animal models that reflect all the different aspects of CSVD have been identified. Here, we generated a new CSVD animal model using D-galactose (D-gal) combined with cerebral hypoperfusion in spontaneously hypertensive rats (SHR), which showed all the hallmark pathological features of CSVD and was based on vascular risk factors. SHR were hypodermically injected with D-gal (400 mg/kg/d) and underwent modified microcoil bilateral common carotid artery stenosis surgery. Subsequently, neurological assessments and behavioral tests were performed, followed by vascular ultrasonography, electron microscopy, flow cytometry, and histological analyses. Our rat model showed multiple cerebrovascular pathologies, such as CMB, brain atrophy, subcortical small infarction, WMH, and EPVS, as well as the underlying causes of CSVD pathology, including oxidative stress injury, decreased cerebral blood flow, structural and functional damage to endothelial cells, increased blood-brain barrier permeability, and inflammation. The use of this animal model will help identify new therapeutic targets and subsequently aid the development and testing of novel therapeutic interventions. Main process of the study: Firstly, we screened for optimal conditions for mimicking aging by injecting D-gal into rats for 4 and 8 weeks. Subsequently, we performed modified microcoil BCAS intervention for 4 and 8 weeks in rats to screen for optimal hypoperfusion conditions. Finally, based on these results, we combined D-gal for 8 weeks and modified microcoil BCAS for 4 weeks to explore the changes in SHR.

Ultrasonic vocalization emission is altered following neonatal hypoxic-ischemic brain injury in mice

Neonatal hypoxic-ischemic (HI) brain injury leads to cognitive impairments including social communication disabilities. Current treatments do not sufficiently target these impairments, therefore new tools are needed to examine social communication in models for neonatal brain injury. Ultrasonic vocalizations (USVs) during early life show potential as a measurement for social development and reflect landmark developmental stages in neonatal mice. However, changes in USV emission early after HI injury have not been found yet. Our current study examines USV patterns and classes in the first 3 days after HI injury. C57Bl/6 mice were subjected to HI on postnatal day (P)9 and USVs were recorded between P10 and P12. Audio files were analyzed using the VocalMat automated tool. HI-injured mice emitted less USVs, for shorter durations, and at a higher frequency compared to control (sham-operated) littermates. The HI-induced alterations in USVs were most distinct at P10 and in the frequency range of 50–75 kHz. At P10 HI-injured mouse pups also produced different ratios of USV class types compared to control littermates. Moreover, alterations in the duration and frequency were specific to certain USV classes in HI animals compared to controls. Injury in the striatum and hippocampus contributed most to alterations in USV communication after HI. Overall, neonatal HI injury leads to USV alterations in newborn mice which could be used as a tool to study early HI-related social communication deficits.

Disease characterization in cloned foals in Colombia, the effect of placental pathologies on the success and survival of cloned foalsfrom two different cell lines

Cloned foals born in the different cloning programs in the USA, Argentina, and recently in Colombia have experienced several pathological entities during their pregnancy and neonatal period. These entities include abortions, stillbirths, hypoxic-ischemic encephalopathy, large umbilical remanent, and angular deformity on the fore limb. The objectives of this study were to determine whether cloned foals suffer similar diseases and have the same mortality rate as noncloned ones and the differences between cloned foals from two different cell lines (fibroblastic and bone marrow cells) and, to establish whether mares carrying cloned foals from different cell lines have ultrasonographic, paraclinical, and hormonal profile parameters equal to traditional pregnancies and to determine whether there are differences between the cloned foals from the two different cell lines. In the analysis of the continuous variables, significant mean differences were established in the three groups of mares in PCV, hemoglobin, erythrocyte count, MCV, MCH, serum proteins and globulins, and in lymphocyte counts p&lt;0.05. A risk analysis was made for morbidity and mortality associated with the cell origin of the clone and its pregnancy using chi-square sequential tests and logistic regression, and it was considered statistically significant at p&lt; 0.05. A principal component analysis of the paraclinical findings of the mares with the outcome of the foal and the paraclinical parameters of the foals divided by the origin of gestation was performed to evaluate the components of the response variable and their dynamics. Thirty-four pregnancies of clones of fibroblastic origin, 26 of clones of bone marrow origin, and 32 of non-clones were studied. The presentation of placental diseases compatible with placentitis was significantly more frequent (p= 0.026) in mares with cloned foals from fibroblastic cell lines. Neonatal sepsis was determined to be the most frequent disease and was diagnosed more commonly in foals of fibroblastic cell origin—an increase in the risk (OR 37) (p=0.0006). The risk of death was positive and significant with the fibroblast cell line foals (OR: 9.1. P&lt;0.01) compared to the cloned foals of marrow cell origin and non-cloned foals. The risk of death can be predicted in the neonatal period, and some indicators found in this study, such as signs related to placentitis, are associated with increased neonatal mortality and are more frequent in foals of fibroblastic cell origin.