A pilot study on the biochemical effects of repeated administration of 24% oral sucrose vs. 30% oral dextrose on urinary markers of adenosine triphosphate degradation.

OBJECTIVES: Premature neonates often receive oral sucrose or dextrose before tissue-damaging procedures (TDPs). Previous work showed that a single dose of sucrose, but not dextrose, increased cellular energy utilization and ATP degradation. This pilot study probes the effects of repeated administration of sucrose or dextrose on energy metabolism. METHODS: Urinary markers of ATP metabolism (hypoxanthine, xanthine, uric acid) are measured in premature neonates randomized to receive: (a) standard of care, (b) 0.2 ml 24% oral sucrose, or (c) 0.2 ml 30% oral dextrose, before every painful procedure on days-of-life 3-7. RESULTS: Standard of care is associated with highest xanthine/creatinine and uric acid/creatinine, likely because of fewer pain treatments. Benefits of repeated oral sucrose are unclear. Neonates receiving oral dextrose had lower xanthine/creatinine and uric acid/creatinine. CONCLUSIONS: Repeated treatments of neonatal procedural pain with 30% oral dextrose are less energetically demanding. Larger clinical studies are needed for comparison with sucrose treatments.

Oral dextrose reduced procedural pain without altering cellular ATP metabolism in preterm neonates: a prospective randomized trial.

OBJECTIVE: To examine the effects of 30% oral dextrose on biochemical markers of pain, adenosine triphosphate (ATP) degradation, and oxidative stress in preterm neonates experiencing a clinically required heel lance. STUDY DESIGN: Utilizing a prospective study design, preterm neonates that met study criteria (n = 169) were randomized to receive either (1) 30% oral dextrose, (2) facilitated tucking, or (3) 30% oral dextrose and facilitated tucking 2 min before heel lance. Plasma markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the premature infant pain profile-revised (PIPP-R). RESULTS: Oral dextrose, administered alone or with facilitated tucking, did not alter plasma markers of ATP utilization and oxidative stress. CONCLUSION: A single dose of 30% oral dextrose, given before a clinically required heel lance, decreased signs of pain without increasing ATP utilization and oxidative stress in premature neonates.

Oxidative Stress Biomarker Decreased in Preterm Neonates Treated With Kangaroo Mother Care.

OBJECTIVE: Due to physiological and metabolic immaturity, prematurely born infants are at increased risk because of maternal separation in many neonatal intensive care units (NICUs). The stress induced from maternal-infant separation can lead to well-documented short-term physiologic instability and potentially lifelong neurological, sociological, or psychological sequelae. Based on previous studies of kangaroo mother care (KMC) that demonstrated improvement in physiologic parameters, we examined the impact of KMC on physiologic measures of stress (abdominal temperature, heart rate, oxygen saturation, perfusion index, near-infrared spectrometry), oxidative stress, and energy utilization/conservation in preterm infants. METHODS: In this randomized, stratified study of premature neonates, we compared the effects on urinary concentrations of biomarkers of energy utilization and oxidative stress of 1 hr of KMC versus incubator care on Day 3 of life in intervention-group babies (n = 26) and control-group babies (n = 25), respectively. On Day 4, both groups received 1 hr of KMC. Urinary samples were collected 3 hr before and 3 hr after intervention/incubator care on both days. Energy utilization was assessed by measures of adenosine triphosphate (ATP) degradation (i.e., hypoxanthine, xanthine, and uric acid). Oxidative stress was assessed using urinary allantoin. Mixed-models analysis was used to assess differences in purine/allantoin. RESULTS: Mean allantoin levels over Days 3 and 4 were significantly lower in the KMC group than in the control group (p = .026). CONCLUSIONS: Results provide preliminary evidence that KMC reduces neonatal oxidative stress processes and that urinary allantoin could serve as an effective noninvasive marker for future studies.

Differential effects of the retinopathy of prematurity exam on the physiology of premature infants.

OBJECTIVE: To compare the differential effects of the retinopathy of prematurity (ROP) examination on the physiology of premature infants with and without oxygen support. STUDY DESIGN: We collected data from 42 premature infants (room air = 19, oxygen support = 23) and compared physiological metrics including heart rate (HR), systemic peripheral saturation (SpO2), mesenteric tissue oxygen saturation (StO2) and clinical events (oxygen desaturation episodes, bradycardia events, and gastric residuals). RESULTS: We found significant differences between groups in HR during and briefly after the exam, and in mesenteric StO2, during eye drop administration, eye exam, and up to 8 min after the exam. SpO2 was significantly different between the groups at all time points. Gastric residuals were higher after the exam in infants on oxygen support, compared to baseline. CONCLUSION: Premature infants on oxygen support may be at a higher risk of adverse physiologic effects in response to the ROP exam.

Platelet-Neutrophil Interactions Are Lower in Cord Blood of Premature Newborns.

OBJECTIVE: To quantify platelet-neutrophil interaction by flow cytometry, in newborn cord blood, as a function of gestational age. RATIONALE: Little is known about platelet function markers in the newborn, and developmental variations in these markers are not well described. METHODS: Cord blood samples were obtained from 64 newborns between 23 and 40 weeks' gestation. The neonates were grouped into three categories: preterm (< 34 weeks' gestation, n = 21), late preterm (34 to < 37 weeks' gestation, n = 22), and term (≥37 weeks' gestation, n = 21). We monitored the expression of P-selectin and the formation of platelet-neutrophil aggregates (PNAs) by flow cytometry while using adenosine 5'-diphosphate (ADP) or thrombin receptor-activating peptide (TRAP) as agonists. RESULTS: PNAs were significantly lower in preterm compared to term neonates after TRAP or ADP stimulations (11.5 ± 5.2% vs. 19.9 ± 9.1%, p < 0.001, or 24.0 ± 10.1% vs. 39.1 ± 18.2%, p = 0.008, respectively). The expression of P-selectin also tended to be lower in preterm neonates, with significant positive correlations between P-selectin expression and PNA formation. CONCLUSIONS: The potential formation of PNAs correlates with gestational age. This suggests that the development of functional competencies of platelets and neutrophils continues throughout gestation, progressively enabling interactions between them.

The Energy Costs of Prematurity and the Neonatal Intensive Care Unit (NICU) Experience.

Premature neonates are in an energy deficient state due to (1) oxygen desaturation and hypoxia events, (2) painful and stressful stimuli, (3) illness, and (4) neurodevelopmental energy requirements. Failure to correct energy deficiency in premature infants may lead to adverse effects such as neurodevelopmental delay and negative long-term metabolic and cardiovascular outcomes. The effects of energy dysregulation and the challenges that clinicians in the Neonatal Intensive Care Unit (NICU) face in meeting the premature infant's metabolic demands are discussed. Specifically, the focus is on the effects of pain and stress on energy homeostasis. Energy deficiency is a complex problem and requires a multi-faceted solution to promote optimum development of premature infants.

The relationship of red blood cell transfusion to intestinal mucosal injury in premature infants.

OBJECTIVE: To determine the incidence of intestinal mucosal injury before and after transfusions in premature infants. STUDY DESIGN: Urine was collected throughout the hospital stay of 62 premature infants and specimens obtained within 24h before and after transfusion were assayed for intestinal fatty acid binding protein (iFABP). A urinary iFABP:creatinine ratio (iFABPu:Cru) of 2.0pg/nmol was considered elevated. RESULT: Forty-nine infants were transfused. iFABPu:Cru was elevated following 71 (75.6%) of 94 transfusions for which urine was available. In 51 (71.8%) of these, iFABPu:Cru was also elevated prior to the transfusion. Among four cases of transfusion-associated NEC, iFABPu was elevated following every sentinel transfusion and prior to three of them. CONCLUSION: Subclinical intestinal mucosal injury is frequent following blood transfusions in premature infants and, when present, usually precedes transfusion. This suggests that transfusion may not be a primary mediator of intestinal injury so much as anemia and its associated conditions. LEVEL OF EVIDENCE: Prognosis study/level 3.

Urinary Allantoin Is Elevated in Severe Intraventricular Hemorrhage in the Preterm Newborn.

Germinal matrix intraventricular hemorrhage (IVH) is the most common type of intracranial hemorrhage observed in preterm neonates. It is a precursor of poor neurocognitive development, cerebral palsy, and death. The pathophysiology is not well defined, but damage to the fragile germinal matrix vasculature may be due to free radicals generated during inflammation and as a consequence of ischemia followed by reperfusion. Assessment of the oxidative stress status in these infants is therefore important. Urinary allantoin concentration was measured in preterm neonates as a marker of oxidative stress associated with IVH. Urine was collected from 44 preterm neonates at four time points between 24 and 72 hours of life (HOL), and the allantoin content was determined by gas chromatography mass spectrometry (GCMS). Records were retrospectively reviewed, and the incidence and severity of IVH was categorized as follows: no IVH (n = 24), mild (grade 1-2) IVH (n = 13), and severe (grade 3-4) IVH (n = 7). Neonates with severe IVH showed significantly elevated allantoin levels vs subjects with no IVH from 36 HOL (0.098 ± 0.013 µmol and 0.043 ± 0.007 µmol, respectively, p = 0.002). The allantoin concentration remained elevated even at 72 HOL (0.079 ± 0.014 µmol and 0.033 ± 0.008 µmol, respectively, p = 0.021). There were no significant differences in allantoin levels in the no IVH and mild IVH groups. IVH was diagnosed by head imaging on average at about 11th postnatal day. Urinary allantoin levels were significantly elevated during the first 3 days of life in the neonates subsequently diagnosed with severe IVH, suggesting that oxidative stress might be a crucial factor in IVH pathogenesis. Further studies are needed to assess the usefulness of urinary allantoin in early identification of preterm infants at risk for or with severe IVH and monitoring of the response to interventions designed to prevent or treat it.

Oral sucrose for heel lance enhances adenosine triphosphate use in preterm neonates with respiratory distress.

OBJECTIVE: To examine the effects of oral sucrose on procedural pain, and on biochemical markers of adenosine triphosphate utilization and oxidative stress in preterm neonates with mild to moderate respiratory distress. STUDY DESIGN: Preterm neonates with a clinically required heel lance that met study criteria (n = 49) were randomized into three groups: (1) control (n = 24), (2) heel lance treated with placebo and non-nutritive sucking (n = 15) and (3) heel lance treated with sucrose and non-nutritive sucking (n = 10). Plasma markers of adenosine triphosphate degradation (hypoxanthine, xanthine and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured using the Premature Infant Pain Profile. Data were analyzed using repeated measures analysis of variance, chi-square and one-way analysis of variance. RESULTS: We found that in preterm neonates who were intubated and/or were receiving ⩾30% FiO2, a single dose of oral sucrose given before a heel lance significantly increased markers of adenosine triphosphate use. CONCLUSION: We found that oral sucrose enhanced adenosine triphosphate use in neonates who were intubated and/or were receiving ⩾30% FiO2. Although oral sucrose decreased pain scores, our data suggest that it also increased energy use as evidenced by increased plasma markers of adenosine triphosphate utilization. These effects of sucrose, specifically the fructose component, on adenosine triphosphate metabolism warrant further investigation.

Urinary Hypoxanthine as a Measure of Increased ATP Utilization in Late Preterm Infants.

OBJECTIVE: To examine the effect of neonatal morbidity on ATP breakdown in late preterm infants. STUDY DESIGN: Urinary hypoxanthine concentration, a marker of ATP breakdown, was measured from 82 late preterm infants on days of life (DOL) 3 to 6 using high-performance liquid chromatography. Infants were grouped according to the following diagnoses: poor nippling alone (n = 8), poor nippling plus hyperbilirubinemia (n = 21), poor nippling plus early respiratory disease (n = 26), and respiratory disease alone (n = 27). RESULTS: Neonates with respiratory disease alone had significantly higher urinary hypoxanthine over DOL 3 to 6 when compared with neonates with poor nippling (P = .020), poor nippling plus hyperbilirubinemia (P < .001), and poor nippling plus early respiratory disease (P = .017). Neonates with poor nippling who received respiratory support for 2 to 3 days had significantly higher hypoxanthine compared with infants who received respiratory support for 1 day (P = .017) or no days (P = .007). CONCLUSIONS: These findings suggest that respiratory disorders significantly increase ATP degradation in late premature infants.

Oral sucrose for heel lance increases adenosine triphosphate use and oxidative stress in preterm neonates.

OBJECTIVE: To examine the effects of sucrose on pain and biochemical markers of adenosine triphosphate (ATP) degradation and oxidative stress in preterm neonates experiencing a clinically required heel lance. STUDY DESIGN: Preterm neonates that met study criteria (n = 131) were randomized into 3 groups: (1) control; (2) heel lance treated with placebo and non-nutritive sucking; and (3) heel lance treated with sucrose and non-nutritive sucking. Plasma markers of ATP degradation (hypoxanthine, xanthine, and uric acid) and oxidative stress (allantoin) were measured before and after the heel lance. Pain was measured with the Premature Infant Pain Profile. Data were analyzed by the use of repeated-measures ANOVA and Spearman rho. RESULTS: We found significant increases in plasma hypoxanthine and uric acid over time in neonates who received sucrose. We also found a significant negative correlation between pain scores and plasma allantoin concentration in a subgroup of neonates who received sucrose. CONCLUSION: A single dose of oral sucrose, given before heel lance, significantly increased ATP use and oxidative stress in premature neonates. Because neonates are given multiple doses of sucrose per day, randomized trials are needed to examine the effects of repeated sucrose administration on ATP degradation, oxidative stress, and cell injury.

Procedural pain and oxidative stress in premature neonates.

UNLABELLED: Preterm neonates exposed to painful procedures in the neonatal intensive care unit exhibit increased pain scores and alterations in oxygenation and heart rate. It is unclear whether these physiological responses increase the risk of oxidative stress. Using a prospective study design, we examined the relationship between a tissue-damaging procedure (TDP; tape removal during discontinuation of an indwelling central arterial or venous catheter) and oxidative stress in 80 preterm neonates. Oxidative stress was quantified by measuring uric acid (UA) and malondialdehyde (MDA) concentration in plasma before and after neonates (n = 38) experienced a TDP compared to those not experiencing any TDP (control group, n = 42). Pain was measured before and during the TDP using the Premature Infant Pain Profile (PIPP). We found that pain scores were higher in the TDP group compared to the control group (median scores, 11 and 5, respectively; P < .001). UA significantly decreased over time in control neonates but remained stable in TDP neonates (132.76 to 123.23 µM versus 140.50 to 138.9 µM; P = .002). MDA levels decreased over time in control neonates but increased in TDP neonates (2.07 to 1.81 µM versus 2.07 to 2.21 µM, P = .01). We found significant positive correlations between PIPP scores and MDA. Our data suggest a significant relationship between procedural pain and oxidative stress in preterm neonates. PERSPECTIVE: This article presents data describing a significant relationship between physiological markers of neonatal pain and oxidative stress. The method described in this paper can potentially be used to assess the direct cellular effects of procedural pain as well the effectiveness of interventions performed to decrease pain.

Biochemical measurement of neonatal hypoxia.

Neonatal hypoxia ischemia is characterized by inadequate blood perfusion of a tissue or a systemic lack of oxygen. This condition is thought to cause/exacerbate well documented neonatal disorders including neurological impairment. Decreased adenosine triphosphate production occurs due to a lack of oxidative phosphorylation. To compensate for this energy deprived state molecules containing high energy phosphate bonds are degraded. This leads to increased levels of adenosine which is subsequently degraded to inosine, hypoxanthine, xanthine, and finally to uric acid. The final two steps in this degradation process are performed by xanthine oxidoreductase. This enzyme exists in the form of xanthine dehydrogenase under normoxic conditions but is converted to xanthine oxidase (XO) under hypoxia-reperfusion circumstances. Unlike xanthine dehydrogenase, XO generates hydrogen peroxide as a byproduct of purine degradation. This hydrogen peroxide in combination with other reactive oxygen species (ROS) produced during hypoxia, oxidizes uric acid to form allantoin and reacts with lipid membranes to generate malondialdehyde (MDA). Most mammals, humans exempted, possess the enzyme uricase, which converts uric acid to allantoin. In humans, however, allantoin can only be formed by ROS-mediated oxidation of uric acid. Because of this, allantoin is considered to be a marker of oxidative stress in humans, but not in the mammals that have uricase. We describe methods employing high pressure liquid chromatography (HPLC) and gas chromatography mass spectrometry (GCMS) to measure biochemical markers of neonatal hypoxia ischemia. Human blood is used for most tests. Animal blood may also be used while recognizing the potential for uricase-generated allantoin. Purine metabolites were linked to hypoxia as early as 1963 and the reliability of hypoxanthine, xanthine, and uric acid as biochemical indicators of neonatal hypoxia was validated by several investigators. The HPLC method used for the quantification of purine compounds is fast, reliable, and reproducible. The GC/MS method used for the quantification of allantoin, a relatively new marker of oxidative stress, was adapted from Gruber et al. This method avoids certain artifacts and requires low volumes of sample. Methods used for synthesis of MMDA were described elsewhere. GC/MS based quantification of MDA was adapted from Paroni et al. and Cighetti et al. Xanthine oxidase activity was measured by HPLC by quantifying the conversion of pterin to isoxanthopterin. This approach proved to be sufficiently sensitive and reproducible.

The role of morphine in a rat model of hypoxic-ischemic injury.

We investigated whether morphine plays a neuroprotective role in a neonatal rat pup model of bilateral carotid artery occlusion with hypoxia. At postnatal day 10, rats received either morphine (n = 7), naloxone (n = 7), or saline placebo (n = 15) after hypoxic-ischemic injury. Survival (days), weight gain and animal testing (negative geotaxis, surface righting, and rotarod) were compared between treatment groups. Lesion volume was delineated with magnetic resonance imaging at days 7 and 28-57 after injury. Survival in rats treated with morphine, naloxone, or saline was, respectively, 14, 29, and 73%. Median number of days of survival after bilateral carotid artery occlusion with hypoxia treated with morphine was 4 (95% confidence interval 4 to 22), with naloxone was 3 (95% confidence interval -1.4 to 21), and with placebo was 28 (95% confidence interval 18 to 28). There were no statistically significant differences in magnetic resonance imaging-derived ischemic lesion volumes, weight gain, or behavioral testing measures between the groups. Morphine was ineffective as a neuroprotectant in rat pups with severe hypoxic-ischemic injury and may have contributed to their decreased survival.

An animal model for measuring the effect of common NICU procedures on ATP metabolism.

Neonates exposed to common neonatal intensive care unit (NICU) procedures show alterations in heart rate, blood pressure, and oxygen saturation. However, it is unclear if these physiologic changes increase adenosine triphosphate (ATP) utilization, thus potentially increasing the risk for tissue hypoxia in medically fragile neonates. Plasma uric acid is a commonly used marker of increased ATP utilization because uric acid levels increase when ATP consumption is enhanced. To examine the effect of a common NICU procedure on plasma uric acid concentration, we developed a model that allows for acute monitoring of this biochemical marker in plasma in 7- to 9-day-old rabbits. In our pilot study, we exposed neonatal rabbits to a single heel lance 2.5 hr after catheter placement. We measured uric acid concentration before and 30 min after the heel lance and compared findings to levels in control animals not exposed to the heel lance. Our pilot data shows a significant difference in uric acid concentration over time between the control and heel lance groups (46.2 ± 7.1 µM vs. 54.7 ± 5.8 µM, respectively, p = .027). Calculation of percentage change from baseline showed uric acid concentration increasing in rabbits exposed to heel lance and decreasing in control rabbits (1.5 ± 4.7% vs. -16.1 ± 4.2%, respectively, p = .03). These data suggest that this animal model can be successfully used to examine the biochemical effect of common NICU procedures, such as heel lance, on markers of ATP breakdown and purine metabolism.

Necrotizing enterocolitis is associated with neonatal intestinal injury.

PURPOSE: We hypothesized that a subset of premature newborns has subclinical, intestinal mucosal compromise that predisposes to the development of necrotizing enterocolitis (NEC) days or weeks later. METHODS: Fifty-five newborns of 23 to 36 weeks' gestational age were identified, and urine was collected over the first 90 hours of life. The urinary concentration of intestinal fatty acid binding protein (iFABP(u)), a sensitive marker for intestinal injury, was determined. The diagnosis of NEC was based upon clinical condition, pathology, and/or imaging findings. RESULTS: Neonatal iFABP(u) exceeded 800 pg/mL in 27 subjects, including 9 of 9 who subsequently developed stage 2 or 3 NEC. This degree of iFABP(u) elevation, but not asphyxia, was significantly associated with the development of NEC (P < .01). CONCLUSION: In this population of premature newborns, there was a substantial incidence of intestinal mucosal compromise. All infants who subsequently developed stage 2 or 3 NEC had an elevated iFABP(u). This finding suggests a model for the pathogenesis of some cases of NEC, whereby perinatal mucosal injury predisposes to further damage when feedings are initiated. In addition, neonatal iFABP(u) assessment may represent a tool to identify infants at the highest risk for NEC and allow for the institution of focused, preventive measures.

Relationship between opioid therapy, tissue-damaging procedures, and brain metabolites as measured by proton MRS in asphyxiated term neonates.

To examine the effects of opioid and tissue-damaging procedures (TDPs) [i.e. procedures performed in the neonatal intensive care unit (NICU) known to result in pain, stress, and tissue damage] on brain metabolites, we reviewed the medical records of 28 asphyxiated term neonates (eight opioid-treated, 20 non-opioid treated) who had undergone magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (MRS) within the first month of life as well as eight newborns with no clinical findings of asphyxial injury. We found that lower creatine (Cr), myoinositol (Ins), and N-acetylaspartate (NAA)/choline (Cho) (p < or = 0.03) and higher Cho/Cr and glutamate/glutamine (Glx) Cr (p < or = 0.02) correlated with increased TDP incidence in the first 2 d of life (DOL). We also found that occipital gray matter (OGM) NAA/Cr was decreased (p = 0.03) and lactate (Lac) was present in a significantly higher amount (40%; p = 0.03) in non-opioid-treated neonates compared with opioid-treated neonates. Compared with controls, untreated neonates showed larger changes in more metabolites in basal ganglia (BG), thalami (TH), and OGM with greater significance than treated neonates. Our data suggest that TDPs affect spectral metabolites and that opioids do not cause harm in asphyxiated term neonates exposed to repetitive TDPs in the first 2-4 DOL and may provide a degree of neuroprotection.

Effect of dopamine on vascular reactivity in near-term lamb carotids: role of the endothelium.

Many neonates are diagnosed with hypotension in the first 24 hr of life. Those with severe hypotension are often given high doses of dopamine at 10 to 20 microg/kg/min. This study examined the hypothesis that dopamine, a vasoactive drug commonly used in the neonatal intensive care unit, alters vascular reactivity. Vascular reactivity was measured by comparing 5HT dose-response characteristics in untreated near-term lamb common carotid arteries and arteries treated with 15 microg/kg/min of dopamine. The authors found that dopamine pretreatment for 60 min significantly potentiated 5HT-induced contractile tone by approximately 100% ( p < .05). This observed increase in tone was accompanied by a significant decrease in the affinity of 5HT to its receptor ( p < .05), suggesting an activation of a separate contractile pathway, or a mechanism downstream from agonist-receptor binding. Interestingly, an increase in contractility was observed only in endothelium-intact arteries. In arteries with denuded endothelium, dopamine pretreatment resulted in a small but significant decrease in tone compared to control arteries ( p < .05), suggesting a vasodilatory mechanism unmasked by endothelium removal. Although multiple mechanisms can increase vascular resistance, these data described the in vitro effects of high doses of dopamine on vascular tone as well as the role of the endothelium in dopaminemediated vasoconstriction.

Dexamethasone alters vascular reactivity by enhancing COX-related vasodilatation in fetal ovine carotids.

Based on preliminary studies that contractile efficacy was altered in vertebral and basilar arteries from neonatal donors treated with postnatal glucocorticoids, we examined the hypothesis that postnatal dexamethasone (DEX), a glucocorticoid used for respiratory disease in neonates, can alter vascular reactivity. Using near-term fetal lamb carotids, we measured 5-hydroxytryptamine (5-HT) dose-response relationship in DEX-treated and untreated arteries. We found that DEX incubation for 1 h had no effect on 5-HT sensitivity and agonist affinity but significantly reduced 5-HT contractile efficacy, a response that became even more pronounced after 4 h of DEX treatment. Coincubation of DEX-treated arteries with INDO for 4 h reversed this DEX-induced attenuation in 5-HT contractile efficacy, although DEX had no significant effects on cyclooxygenase (COX)-1 and COX-2 protein abundance. This data suggests that DEX alters vascular reactivity through a COX-related mechanism, with possible repercussions to neurological injury.