losartan-potassium and Asphyxia

In forensic pathology, while classical morphology remains a core procedure to investigate deaths, a spectrum of ancillary procedures has been developed and incorporated to detail the pathology. Among them, postmortem biochemistry is important to investigate the systemic pathophysiological changes involved in the dying process that cannot be detected by morphology. In addition, recent advances in molecular biology have provided a procedure to investigate genetic bases of diseases that might present with sudden death, which is called 'molecular autopsy'. Meanwhile, the practical application of RNA analyses to postmortem investigation has not been accepted due to rapid decay after death; however, recent experimental and practical studies using real-time reverse transcription-PCR have suggested that the relative quantification of mRNA transcripts can be applied in molecular pathology for postmortem investigation of deaths, which may be called 'advanced molecular autopsy'. In a broad sense, forensic molecular pathology implies applied medical sciences to investigate the genetic basis of diseases, and the pathophysiology of diseases and traumas leading to death at a biological molecular level in the context of forensic pathology. The possible applications include analyses of local pathology, including tissue injury, ischemia/hypoxia and inflammation at the site of insult or specific tissue damage from intoxication, systemic responses to violence or environmental hazards, disorders due to intoxication, and systemic pathophysiology of fatal process involving major life-support organs. A review of previous studies suggests that systematic postmortem quantitative analysis of mRNA transcripts can be established from multi-faceted aspects of molecular biology and incorporated into death investigations in forensic pathology, to support and reinforce morphological evidence.

Topics: Aging; Animals; Asphyxia; Biomarkers; Erythropoietin; Forensic Pathology; Gene Expression; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Hypoxia-Ischemia, Brain; Immunohistochemistry; Postmortem Changes; Pulmonary Surfactant-Associated Proteins; Respiratory Insufficiency; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Shock; Specimen Handling; Vascular Endothelial Growth Factor A; Violence; Wounds and Injuries

An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo.. Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models.. Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo).. In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia.. In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Topics: Asphyxia; Erythropoietin; Humans; Hypothermia; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Seizures

Inconsistent enrollment among hospitals for neonatal clinical trials may lead to study populations that are not representative of the patient population in the neonatal intensive care unit. The High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial was a multisite randomized clinical trial investigating erythropoietin as a neuroprotective treatment for term infants (those born between 37 and 42 complete weeks) with hypoxic ischemic encephalopathy. Substantial variability was noted in enrollment rate by hospital. We developed survey questions across five conceptual domains to understand systems-level issues that might contribute to variation in enrollment rate by hospital. Our study found that hospitals varied in their responses across these five domains. We propose three potential reasons that we found a lack of identifiable hospital-level factors that correlated with enrollment rates: sample-size limitations, methodological concerns, and confounding factors. Future studies with a larger sample size should be considered to evaluate contributors to hospital-level variability. This will lead to more robust recruitment strategies, improved enrollment, and decreases in the waste of research resources.

Topics: Asphyxia; Epoetin Alfa; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Intensive Care Units, Neonatal; Neuroprotection

Hypoxic-ischemic encephalopathy (HIE) remains an important cause of neonatal death and frequently leads to significant long-term disability in survivors. Therapeutic hypothermia, while beneficial, still leaves many treated infants with lifelong disabilities. Adjunctive therapies are needed, and erythropoietin (Epo) has the potential to provide additional neuroprotection.. The aim of this study was to review the current incidence, mechanism of injury, and sequelae of HIE, and to describe a new phase III randomized, placebo-controlled trial of Epo neuroprotection in term and near-term infants with moderate to severe HIE treated with therapeutic hypothermia.. This article presents an overview of HIE, neuroprotective functions of Epo, and the design of a double-blind, placebo-controlled, multicenter trial of high-dose Epo administration, enrolling 500 neonates ≥36 weeks of gestation with moderate or severe HIE diagnosed by clinical criteria.. Epo has robust neuroprotective effects in preclinical studies, and phase I/II trials suggest that multiple high doses of Epo may provide neuroprotection against brain injury in term infants. The High Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) Trial will evaluate whether high-dose Epo reduces the combined outcome of death or neurodevelopmental disability when given in conjunction with hypothermia to newborns with moderate/severe HIE.

Topics: Asphyxia; Clinical Trials, Phase III as Topic; Double-Blind Method; Erythropoietin; Female; Humans; Hypothermia, Induced; Hypoxia-Ischemia, Brain; Infant, Newborn; Logistic Models; Male; Multicenter Studies as Topic; Neuroprotection; Neuroprotective Agents; Randomized Controlled Trials as Topic

There is a critical need for development of physiological biomarkers in infants with birth asphyxia to identify the physiologic response to therapies in real time. This is an ancillary single site study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (Wu et al., 2022 [1]) to measure neurovascular coupling (NVC) non-invasively during an ongoing blinded randomized trial.. Neonates who randomized in the HEAL enrolled at a single-center Level III Neonatal Intensive Care Unit were recruited between 2017 and 2019. Neurodevelopmental impairment was blinded and defined as any of the following: cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition (BSID-III), Gross Motor Function Classification Score (GMFCS) ≥1.. All twenty-seven neonates enrolled in HEAL were recruited and 3 died before complete recording. The rank-based analysis of covariance models demonstrated lack of difference in NVC between the two groups (Epo versus Placebo) that was consistent with the observed lack of effect on neurodevelopmental outcomes.. We demonstrate no difference in neurovascular coupling after Epo administration. These findings are consistent with overall negative trial results. Physiological biomarkers can help elucidate mechanisms of neuroprotective therapies in real time in future trials.

Topics: Asphyxia; Asphyxia Neonatorum; Biomarkers; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant; Infant, Newborn; Neuroprotection; Neurovascular Coupling

MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms.. Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using standardised neuroimaging protocols. MRI and MRS data are processed centrally and used to determine a brain injury score and quantitative measures of lactate and n-acetylaspartate. Harmonisation is achieved through standardisation-thereby reducing intrasite and intersite variance, real-time quality assurance monitoring and phantom scans.. IRB approval was obtained at each participating site and written consent obtained from parents prior to participation in HEAL. Additional oversight is provided by an National Institutes of Health-appointed data safety monitoring board and medical monitor.. NCT02811263; Pre-result.

Topics: Asphyxia; Biomarkers; Clinical Trial Protocols as Topic; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Multicenter Studies as Topic; Neuroimaging

Topics: Asphyxia; Asphyxia Neonatorum; Brain Diseases; Erythropoietin; Female; Humans; Infant, Newborn; Pregnancy

Topics: Asphyxia; Asphyxia Neonatorum; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn

Topics: Asphyxia; Asphyxia Neonatorum; Brain Diseases; Erythropoietin; Female; Humans; Infant, Newborn; Pregnancy

Perinatal asphyxia in preterm infants remains a significant contributor to abnormal long-term neurodevelopmental outcomes. Recombinant human erythropoietin has potent non-haematopoietic neuroprotective properties, but there is limited evidence for protection in the preterm brain. Preterm (0.7 gestation) fetal sheep received sham asphyxia (sham occlusion) or asphyxia induced by umbilical cord occlusion for 25 min, followed by an intravenous infusion of vehicle (occlusion-vehicle) or recombinant human erythropoietin (occlusion-Epo, 5000 international units by slow push, then 832.5 IU/h), starting 30 min after asphyxia and continued until 72 h. Recombinant human erythropoietin reduced neuronal loss and numbers of caspase-3-positive cells in the striatal caudate nucleus, CA3 and dentate gyrus of the hippocampus, and thalamic medial nucleus ( P < 0.05 vs. occlusion-vehicle). In the white matter tracts, recombinant human erythropoietin increased total, but not immature/mature oligodendrocytes ( P < 0.05 vs. occlusion-vehicle), with increased cell proliferation and reduced induction of activated caspase-3, microglia and astrocytes ( P < 0.05). Finally, occlusion-Epo reduced seizure burden, with more rapid recovery of electroencephalogram power, spectral edge frequency, and carotid blood flow. In summary, prolonged infusion of recombinant human erythropoietin after severe asphyxia in preterm fetal sheep was partially neuroprotective and improved electrophysiological and cerebrovascular recovery, in association with reduced apoptosis and inflammation.

Topics: Animals; Asphyxia; Electroencephalography; Erythropoietin; Female; Gray Matter; Humans; Neurons; Neuroprotective Agents; Pregnancy; Sheep; White Matter

To study the protective effect of erythropoietin (EPO) on brain tissue with cardiac arrest-cardiopulmonary resuscitation (CA-CPR) and its mechanism.. 120 male Sprague-Dawley (SD) rats were randomly divided into three groups (each n = 40), namely: sham group, routine chest compression group, and conventional chest compression + EPO group (EPO group). The rats in each group were subdivided into CA and 6, 12, 24, 48 hours after restoration of spontaneous circulation (ROSC) five subgroups (each n = 8). The model of CA was reproduced according to the Hendrickx classical asphyxia method followed by routine chest compression, and the rats in sham group only underwent anesthesia, tracheostomy intubation and venous-puncture without asphyxia and CPR. The rats in EPO group were given the routine chest compression + EPO 5 kU/kg (2 mL/kg) after CA. Blood sample was collected at different time points of intervention for the determination the content of serum S100 β protein by enzyme linked immunosorbent assay (ELISA). All the rats were sacrificed at the corresponding time points, and the hippocampus was harvested for the calculation of the number of S100 β protein positive cells, and to examine the pathological changes and their scores at 24 hours after ROSC by light microscopy.. With prolongation of ROSC time, the serum levels of S100 β protein (µg/L) in the routine chose compression group and the EPO group were significantly elevated, peaking at 24 hours (compared with CA: 305.7 ± 29.2 vs. 44.4 ± 6.2 in routine chest compression group, and 276.7 ± 28.9 vs. 44.7 ± 5.6 in the EPO group, both P < 0.05), followed by a fall. The levels of S100 β protein at each time point after ROSC in EPO group were significanthy lower than those of the routine chest compression group (83.2 ± 7.5 vs. 114.3 ± 15.3 at 6 hours, 123.9 ± 20.2 vs. 184.9 ± 22.2 at 12 hours, 276.7 ± 28.9 vs. 305.7 ± 29.2 at 24 hours, 256.3 ± 26.6 vs. 283.2 ± 23.6 at 48 hours, all P < 0.05). With the prolongation of ROSC time, the S100 β protein positive cell number in brain (cells/HP) in the routine chest compression group and the EPO group was significantly increased, peaking at 24 hours (compared with CA: 14.3 ± 2.2 vs. 6.7 ± 0.7 in the routine chest compression group, 11.3 ± 1.3 vs. 6.8 ± 0.9 in the EPO group, both P < 0.05), then it began to fall. The S100 β protein positive cell number in brain at each time point after ROSC in the EPO group was significantly lower than that of the routine chest compression group (7.0 ± 0.9 vs. 7.9 ± 1.9 at 6 hours, 8.4 ± 1.1 vs. 10.2 ± 2.2 at 12 hours, 11.3 ± 1.3 vs. 14.3 ± 2.2 at 24 hours, 8.3 ± 0.8 vs. 10.8 ± 2.0 at 48 hours, all P < 0.05). Under the light microscope, a serious brain cortex injury was found after reproduction of the model, and the degree of injury was reduced after EPO intervention. The pathological score at 24 hours after ROSC in EPO group was lower than that of routine chest compression group (3.83 ± 0.73 vs. 4.17 ± 0.75, P < 0.05).. The S100 β protein level in serum and brain tissue was increased early in asphyxia CA-CPR rats. EPO intervention can reduce the expression of S100 protein and reduce the degree of brain injury.

Topics: Animals; Asphyxia; Brain; Brain Injuries; Cardiopulmonary Resuscitation; Erythropoietin; Heart Arrest; Male; Random Allocation; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein beta Subunit

Up to 65% of untreated infants suffering from moderate to severe hypoxic-ischemic encephalopathy (HIE) are at risk of death or major disability. Therapeutic hypothermia (HT) reduces this risk to approximately 50% (number needed to treat: 7-9). Erythropoietin (Epo) is a neuroprotective treatment that is promising as an adjunctive therapy to decrease HIE-induced injury because Epo decreases apoptosis, inflammation, and oxidative injury and promotes glial cell survival and angiogenesis. We hypothesized that HT and concurrent Epo will be safe and effective, improve survival, and reduce moderate-severe cerebral palsy (CP) in a term nonhuman primate model of perinatal asphyxia.. Thirty-five Macaca nemestrina were delivered after 15-18 min of umbilical cord occlusion (UCO) and randomized to saline (n = 14), HT only (n = 9), or HT+Epo (n = 12). There were 12 unasphyxiated controls. Epo (3,500 U/kg × 1 dose followed by 3 doses of 2,500 U/kg, or Epo 1,000 U/kg/day × 4 doses) was given on days 1, 2, 3, and 7. Timed blood samples were collected to measure plasma Epo concentrations. Animals underwent MRI/MRS and diffusion tensor imaging (DTI) at <72 h of age and again at 9 months. A battery of weekly developmental assessments was performed.. UCO resulted in death or moderate-severe CP in 43% of saline-, 44% of HT-, and 0% of HT+Epo-treated animals. Compared to non-UCO control animals, UCO animals exhibit poor weight gain, behavioral impairment, poor cerebellar growth, and abnormal brain DTI. Compared to UCO saline, UCO HT+Epo improved motor and cognitive responses, cerebellar growth, and DTI measures and produced a death/disability relative risk reduction of 0.911 (95% CI -0.429 to 0.994), an absolute risk reduction of 0.395 (95% CI 0.072-0.635), and a number needed to treat of 2 (95% CI 2-14). The effects of HT+Epo on DTI included an improved mode of anisotropy, fractional anisotropy, relative anisotropy, and volume ratio as compared to UCO saline-treated infants. No adverse drug reactions were noted in animals receiving Epo, and there were no hematology, liver, or kidney laboratory effects.. HT+Epo treatment improved outcomes in nonhuman primates exposed to UCO. Adjunctive use of Epo combined with HT may improve the outcomes of term human infants with HIE, and clinical trials are warranted.

Topics: Animals; Asphyxia; Brain; Disease Models, Animal; Epoetin Alfa; Erythropoietin; Humans; Hypothermia; Hypoxia-Ischemia, Brain; Infant; Macaca nemestrina; Recombinant Proteins; Treatment Outcome

To examine the effects of EPO administration on the integrity of myocardium in a rat model of asphyxia-induced cardiac arrest/CPR.. 24 male Sprague-Dawley (SD) rats were randomly divided into three groups (8 each) to receive (1) cardiac arrest (induced by tracheal catheter clamping for 8 minutes)/CPR (by chest compressions and mechanical ventilation 8 minutes after cardiac arrest), (2) cardiac arrest/CPR +EPO (5 kU/kg, i.v, 3 minutes after restoration of spontaneous circulation (ROSC), and (3) no-treatment (control). The left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximal positive/negative filling pressure change versus time (±dp/dt max) in the animals were recorded 30, 60, 90, and 120 minutes after ROSC. Blood and heart tissue samples were collected 120 minutes after ROSC for the examination of serum troponin I (cTnI) level, myocardium pathological change (by light/electronic microscopy), and myocardium apoptosis [by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL) staining].. The LVSP, +dp/dt max and - dp/dt max absolute value in CPR group and EPO group were significantly lower than those of baseline at 30, 60, 90, 120 minutes after ROCS. In comparison with the control group, the LVSP( mm Hg, 1 mm Hg = 0.133 kPa: 119.52±12.68, 134.32±15.78 vs. 165.82±7.05), +dp/dt max (mm Hg/sec: 4457.14±826.22, 6019.85±1192.19 vs. 10325.93±773.09), and - dp/dt max ( mm Hg/sec: - 3956.04±952.37, - 4957.22±838.60 vs. - 8421.33±886.65) were significant lower (all P < 0.01) in the CPR and EPO group 30 minutes after ROSC, and such tendency remained till 120 minutes after ROSC: (LVSP: 124.62±8.07, 145.61±16.70 vs. 162.34±7.63; +dp/dt max: 4977.67±350.40, 7471.62±998.32 vs. 9999.39±727.96; - dp/dt max: - 4145.51±729.77, - 5895.64±787.30 vs. - 8089.75±981.52). Compared to the CPR group, the value of LVSP, + dp/dt max and - dp/dt max at all time points were significantly higher in EPO group (all P < 0.05). The LVEDP value was significantly higher ( P < 0.01) in both CPR and EPO group in comparison with the control (mm Hg/sec: 22.94±3.94, 11.18±2.58 vs. 2.89±0.70) 120 minutes after ROSC, and it was significantly lower in EPO group in comparison with CPR group ( P < 0.05). Light/electronic microscopy revealed myocardial necrosis, inflammatory cell infiltration, myocardial cell membrane integrity loss, mitochondrial swelling, and increased number of apoptotic cardiomyocyte (314.1±30.7 vs. 165.2±45.9 as in control) in CPR group samples. In contrast, the cardiomyocyte morphologic damages were significantly fewer in EPO group, so is the numbers of apoptotic cardiomyocyte (242.1±20.0 vs. 314.1±30.7, P < 0.05). In comparison with the control, the serum cTnI 120 minutes after ROSC was significantly higher (all P < 0.01) in CPR and EPO group (μg/L: 20.70±5.96,16.98±3.81 vs. 2.60±0.86), but no such difference was found between these two groups.. EPO can attenuate the post resuscitation myocardial injury probably through its mitochondrial protective, anti-apoptotic effect.

Topics: Animals; Asphyxia; Cardiopulmonary Resuscitation; Erythropoietin; Heart Arrest; Male; Myocardium; Rats; Rats, Sprague-Dawley; Troponin I

Circulating erythropoietin (EPO) is mainly produced in the kidneys, depending on blood oxygen level. The present study investigated the postmortem serum EPO levels with regard to the cause of death and survival time. Serial medicolegal autopsy cases of postmortem time within 48 h (n = 536) were examined. Serum EPO levels were within the clinical reference range in most cases. Uremic patients with medical administration of an EPO agent (n = 11) showed a markedly high level (140-4,850 mU/ml; median, 1,798 mU/ml). Otherwise, an elevation in serum EPO level (>30 mU/ml) was mainly seen in protracted deaths due to blunt injury and fire fatality, depending on the survival time (r = 0.69, p < 0.0001, and r = 0.45, p < 0.0001, respectively), and in subacute deaths from gastrointestinal bleeding and infectious diseases. However, mildly to moderately elevated serum EPO levels were sporadically found in acute deaths due to mechanical asphyxiation, fire fatality, and acute ischemic heart disease, and in fatal hypothermia cases, especially for elderly subjects. Protracted deaths due to mechanical asphyxiation and ischemic heart disease did not show any survival time-dependent increase in serum EPO level (p > 0.05). EPO was immunohistochemically detected in the tubular epithelia and interstitial cells, showing no evident difference among the causes of death, independent of survival time or serum level. These findings suggest that serum EPO can be used as a marker for investigating anemia and/or hypoxia as a consequence of fatal insult in subacute or prolonged deaths, or a predisposition to traumatic deaths or fatal heart attacks in acute deaths.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asphyxia; Biomarkers; Communicable Diseases; Drowning; Erythropoietin; Female; Fires; Forensic Pathology; Gastrointestinal Hemorrhage; Humans; Hypothermia; Immunohistochemistry; Kidney; Male; Middle Aged; Myocardial Ischemia; Postmortem Changes; Sensitivity and Specificity; Time Factors; Uremia; Wounds, Nonpenetrating; Young Adult

To investigate the effect of erythropoietin for the management of postresuscitation myocardial dysfunction following asphyxia-induced cardiac arrest. Male adult Wistar rats were used for the prospective controlled animal study. Asphyxia-induced cardiac arrest was performed by turning-off the ventilator and clamping the endotracheal tube. Cardiopulmonary resuscitation with an intravenous injection of 0.01 mg/kg epinephrine and mechanical ventilation were started after 6.5 minutes of asphyxia. The resuscitated animals received either erythropoietin (5000 U/kg) or equivalent volume of 0.9% saline as placebo intravenously 3 minutes after return of spontaneous circulation. The erythropoietin treatment produced better left ventricular dP/dt40 and -dP/dt in the invasive hemodynamic measurements, and left ventricular fraction shortening by echocardiography. Administration of erythropoietin also improved three days survival among those successfully resuscitated. The molecular effects of erythropoietin were shown by activation of its down streaming Akt and ERK 42/44 signaling pathways. EPO has the potential to improve postresuscitation myocardial dysfunction and short term survival in rats after asphyxia-induced cardiac arrest.

Topics: Animals; Asphyxia; Cardiopulmonary Resuscitation; Cardiotonic Agents; Disease Models, Animal; Erythropoietin; Heart; Heart Arrest; Male; Rats; Rats, Wistar; Recombinant Proteins; Signal Transduction; Ventricular Dysfunction, Left

Our objective was to establish a nonhuman primate model of perinatal asphyxia appropriate for preclinical evaluation of neuroprotective treatment strategies under conditions that closely resemble human neonatal emergencies, and to begin testing the safety and efficacy of erythropoietin neuroprotective treatment. Prior to delivery by hysterotomy, the umbilical cords of near term Macaca nemestrina (n = 8) were clamped for times ranging between 12 and 15 min. Animals received erythropoietin (5,000 U/kg/dose x 2 i.v., n = 3), or vehicle (n = 5) after resuscitation. We assessed physiologic parameters, continuous electroencephalogram, magnetic resonance imaging/spectroscopy, safety parameters and behavior. Animals were euthanized at 4 months of age. Mean birth weight was 507 +/- 62 g. Initial arterial pH ranged from 6.75 to 7.12, with base deficits of 17-25 mEq. Animals were flaccid at birth, with attenuated electroencephalograms, and seizures occurred in 3 of 8 animals. We demonstrated magnetic resonance imaging/spectroscopy changes consistent with hypoxia (elevated lactate levels were present in some animals), significant motor and behavioral abnormalities (particularly with 15 min of cord clamping), and evidence of gliosis at the time of death. We have established a reproducible model of moderate to severe perinatal hypoxic-ischemic injury in M. nemestrina newborns. This model, which combines structural, biochemical, and behavioral assessments over time can be used to assess the safety and efficacy of neuroprotective strategies.

Topics: Animals; Animals, Newborn; Asphyxia; Brain; Disease Models, Animal; Electroencephalography; Erythropoietin; Female; Fetal Monitoring; Gliosis; Hypoxia-Ischemia, Brain; Lactic Acid; Macaca nemestrina; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Neuroprotective Agents; Placental Circulation; Pregnancy; Seizures; Umbilical Cord

Accumulating studies demonstrate that the expressions of hypoxia-inducible factor 1 (HIF-1), erythropoietin (EPO) and vascular endothelial growth factor (VEGF) depend on cellular oxygen tension, which is involved in the pathological process of tissue hypoxia and/or ischemia. The present study investigated hypoxia-inducible factor-1alpha (HIF-1alpha), EPO and VEGF mRNA expressions in the kidney with regard to the cause of death in medicolegal autopsy. Relative quantifications of HIF-1alpha, EPO and VEGF mRNAs, based on real-time TaqMan reverse transcription-polymerase chain reaction (RT-PCR), were performed on tissue specimens obtained from consistent sites of the bilateral renal cortices. The cases (total, n=245, 6-48h postmortem) included fatal blunt/sharp instrument injuries (n=53/31), asphyxia (n=28: aspiration, n=8; strangulation/hanging, n=20), drowning (n=27), fire fatality (n=62), acute myocardial infarction/ischemia (AMI, n=39), and gastrointestinal hemorrhage (n=5). Both HIF-1alpha and EPO mRNA levels were significantly lower in drowning cases. More characteristic findings were found for VEGF mRNA: it showed higher expression levels for AMI, acute blunt/sharp instrument injury, and aspiration, whereas it was lower for neck compression (strangulation/hanging), drowning, fire fatality with higher blood carboxyhemoglobin (COHb) levels (>60%), peracute blunt injury, and gastrointestinal hemorrhage. Quantitative assays of renal HIF-1alpha, EPO and VEGF mRNA transcripts are potentially useful for investigating the pathophysiology of death, and VEGF mRNA may be especially useful as an indication of acute circulatory failure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asphyxia; Child; Drowning; Erythropoietin; Female; Fires; Forensic Pathology; Gastrointestinal Hemorrhage; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Kidney; Male; Middle Aged; Myocardial Ischemia; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vascular Endothelial Growth Factor A; Wounds, Nonpenetrating; Wounds, Penetrating

Topics: Abortion, Therapeutic; Acid-Base Equilibrium; Amniotic Fluid; Asphyxia; Bilirubin; Chromosome Aberrations; Chromosome Disorders; Culture Techniques; Erythroblastosis, Fetal; Erythropoietin; Estriol; Female; Fetal Diseases; Gestational Age; Humans; Hydrogen-Ion Concentration; Lactates; Porphyrins; Pregnancy; Proteins; Spectrophotometry