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Jerome Y Yager

Publications and source records attributed to Jerome Y Yager.

12 recordsLinked to original sources
PubMed2006

The influence of aging on recovery following ischemic brain damage.

Stroke is a health hazard that affects all age groups, however the impact of age on brain injury following ischemia remains largely unexamined. We examined the extent to which age, from the newborn to mature adult, affects behavioral recovery following similar degrees of ischemic brain damage. We utilized a model that produces comparable volumes of brain damage between the different ages. Endothelin-1, a potent vasoconstrictor, was injected into the brain of 10, 63 and 180-day-old rats, at the level of the right middle cerebral artery. On days 3, 7, 14, 28 and 56 post-insult, behavioral tests including rota-rod, foot-fault, open-field, inclined screen, tape-removal test and postural reflex were performed. Control animals underwent sham surgery, but ischemia was not induced. Neuropathology was assessed on day 63 post-insult. Volume of damage was determined for each brain as a percentage of the contralateral hemisphere (which remains undamaged). Our results indicated that the volume of damage for each age group was 22.97, 19.97, and 18.85% for 10, 63 and 180-day-old rats, respectively, and were not significantly different from each other. Overall, ischemic animals did significantly more poorly on behavioral testing than did controls. When broken down by age, the difference between ischemics and controls was only evident in the 63 and 180-day-old animals. The tape-removal test revealed main effects of age, group, and day (p<0.001). In addition, significant interactions were noted for day of testing by age (p<0.001), day of testing by group with ischemics performing more slowly than controls, and an age by group interaction which indicated that the 63 and 180-day-old ischemic rats did not recover completely during the testing period and remained significantly slower than their controls (p<0.001). In the foot-fault task, the 63 and 180-day-old ischemic animals performed significantly more poorly on days 3, 7, and 14 of recovery, returning to control values by day 28. The 180-day olds performed more poorly on day 3 of recovery, but then returned to control values. For open-field testing, the results indicate an overall difference between ischemics and controls, with the 63 and 180-day-old animals improving with time though they did not achieve control values. In conclusion our data suggest functional performance is poorly and inconsistently correlated with the extent of morphologic injury across all age groups. The immature rat clearly recovers more completely and more rapidly than do older, more mature rats. The findings may imply a greater degree of brain plasticity in the infant rat compared to the adult, and have important implications related to the underlying mechanisms of recovery and the association between brain damage and functional improvement.

Age Factors↗
PubMed2006

Translational stroke research in the developing brain.

Preclinical animal models can help guide the development of clinical pediatric and newborn stroke trials. Data obtained using currently available models of hypoxia-ischemia and focal stroke have demonstrated the need for age-appropriate models. There are age-related differences in susceptibility of the immature brain to oxidative stress and inflammation, as well as in the rate and degree of apoptotic neuronal death. These issues need to be carefully addressed in designing future clinical trials.

Adult↗
PubMed2005

Moderate hypothermia in neonatal encephalopathy: efficacy outcomes.

Therapeutic hypothermia holds promise as a rescue neuroprotective strategy for hypoxic-ischemic injury, but the incidence of severe neurologic sequelae with hypothermia is unknown in encephalopathic neonates who present shortly after birth. This study reports a multicenter, randomized, controlled, pilot trial of moderate systemic hypothermia (33 degrees C) vs normothermia (37 degrees C) for 48 hours in neonates initiated within 6 hours of birth or hypoxic-ischemic event. The trial tested the ability to initiate systemic hypothermia in outlying hospitals and participating tertiary care centers, and determined the incidence of adverse neurologic outcomes of death and developmental scores at 12 months by Bayley II or Vineland tests between normothermic and hypothermic groups. Thirty-two hypothermic and 33 normothermic neonates were enrolled. The entry criteria selected a severely affected group of neonates, with 77% Sarnat stage III. Ten hypothermia (10/32, 31%) and 14 normothermia (14/33, 42%) patients expired. Controlling for treatment group, outborn infants were significantly more likely to die than hypoxic-ischemic infants born in participating tertiary care centers (odds ratio 10.7, 95% confidence interval 1.3-90). Severely abnormal motor scores (Psychomotor Development Index < 70) were recorded in 64% of normothermia patients and in 24% of hypothermia patients. The combined outcome of death or severe motor scores yielded fewer bad outcomes in the hypothermia group (52%) than the normothermia group (84%) (P = 0.019). Although these results need to be validated in a large clinical trial, this pilot trial provides important data for clinical trial design of hypothermia treatment in neonatal hypoxic-ischemic injury.

Child Development↗
PubMed2005

Moderate hypothermia in neonatal encephalopathy: safety outcomes.

Hypoxic-ischemic injury may cause multisystem organ damage with significant aberrations in clotting, renal, and cardiac functions. Systemic hypothermia may aggravate these medical conditions, such as bradycardia and increased clotting times, and very little safety data in neonatal hypoxic-ischemic injury is available. This study reports a multicenter, randomized, controlled pilot trial of moderate systemic hypothermia (33 degrees C) vs normothermia (37 degrees C) for 48 hours in infants with neonatal encephalopathy instituted within 6 hours of birth or hypoxic-ischemic event. The best outcome measures of safety were determined, comparing rates of adverse events between normothermia and hypothermia groups. A total of 32 hypothermia and 33 normothermia neonates were enrolled in seven centers. Adverse events and serious adverse effects were collected by the study team during the hospital admission, monitored by an independent study monitor, and reported to Institutional Review Boards and the Data and Safety Monitoring Committee. The following adverse events were observed significantly more commonly in the hypothermia group: more frequent bradycardia and lower heart rates during the period of hypothermia, longer dependence on pressors, higher prothrombin times, and lower platelet counts with more patients requiring plasma and platelet transfusions. Seizures as an adverse event were more common in the hypothermia group. These observed side effects of 48 hours of moderate systemic hypothermia were of mild to moderate severity and manageable with minor interventions.

Acidosis↗
PubMed2004

Preventing hyperthermia decreases brain damage following neonatal hypoxic-ischemic seizures.

Neonatal seizures are the most common manifestation of underlying cerebral dysfunction. Hypoxic-ischemic encephalopathy is the cause of seizures in 40-60% of newborns. Previous work from our laboratory demonstrates that seizures associated with a hypoxic-ischemic insult results in aggravation of neuronal cell death, specifically within the hippocampus. The latter occurs in the setting of spontaneously occurring hyperthermia of 1.5 degrees C. The purpose of this study was to determine whether preventing the onset of seizure induced hyperthermia would be neuroprotective. Three groups of 10-day old rat pups received unilateral hypoxic-ischemic insults for 30 min followed by KA-induced seizures. Hyperthermia was prevented by lowering the environmental temperature ("relative hypothermia") to 29 degrees C such that the seizuring rat pups were normothermic. In one group, the prevention of hyperthermia occurred immediately following hypoxia-ischemia, whereas in the other group it occurred at the onset of seizures. The third group of rat pups (controls) remained at their nesting temperature and therefore became hyperthermic during seizures. Early (3 days) and late (20 days) neuropathology was assessed. Rat pups in whom hyperthermia was prevented during seizures displayed a significant reduction in brain damage compared to controls (p<0.05). Assessment of hippocampal brain damage also showed a significant improvement in neuronal necrosis at 20 days of recovery compared to 3 days of recovery (p<0.05). The results indicate that preventing spontaneous hyperthermia in this model of hypoxic-ischemic seizures in the newborn is neuroprotective.

Analysis of Variance↗
PubMed2004

Animal models of hypoxic-ischemic brain damage in the newborn.

Controversy continues over which animal model to use as a reflection of human disease states. With respect to perinatal brain disorders, scientists must contend with a disease in evolution. In that regard, the perinatal brain is at risk during a time of extremely rapid development and maturation, involving processes that are required for normal growth. Interfering with these processes, as part of therapeutic intervention must be efficacious and safe. To date, numerous models have provided tremendous information regarding the pathophysiology of brain damage to term and preterm infants. Our challenges will continue to be in identifying those infants at greatest risk for permanent injury, and adapting therapies that provide more benefit than harm. Using animal models to conduct these studies will bring us closer to that goal.

Animals↗
PubMed2003

Group A streptococcal meningitis as a complication of an infected capillary haemangioma.

UNLABELLED: We report a case of group A streptococcal meningitis in an infant resulting from an infected capillary haemangioma. The child suffered significant morbidity including cerebral infarction, epilepsy, and developmental delay. Treatment of infected capillary haemangiomas remains controversial and inconsistent. CONCLUSION: Our experience of this infant, resulting in profound neurological morbidity suggests that group A Streptococcus can be a virulent organism in the young child and that capillary haemangiomas must be treated aggressively at the first sign of infection.

Brain Diseases↗
PubMed2002

Hypoglycemic injury to the immature brain.

Despite the fact that hypoglycemia is an extremely common disorder of the newborn, consensus has been difficult to reach regarding definition, diagnosis, outcome, and treatment. With improved neuroradiologic techniques, such as MRI and PET scanning becoming increasingly available, studies to determine the correlation between hypoglycemia and outcome will help to clarify issues surrounding the effects of hypoglycemia on brain pathology. Long-term epidemiologic studies correlating the severity and duration of hypoglycemia with neurologic consequences are required, and can be complemented by appropriate parallel investigations in animal models of neonatal hypoglycemia.

Age Factors↗
PubMed2002

Neurologic manifestations of iron deficiency in childhood.

Iron deficiency is a common disorder in pediatric patients. Although the most common manifestation is that of anemia, iron deficiency is frequently the source of a host of neurologic disorders presenting to general pediatric neurologic practices. These disorders include developmental delay, stroke, breath-holding episodes, pseudotumor cerebri, and cranial nerve palsies. Although frequent, the identification of iron deficiency as part of the differential diagnosis in these disorders is uncommon and frequently goes untreated. The purpose of the current review is to highlight what is understood regarding iron deficiency and it's underlying pathophysiology as it relates to the brain, and the association of iron deficiency with common neurologic pediatric disease.

Anemia, Iron-Deficiency↗
PubMed2002

Prolonged neonatal seizures exacerbate hypoxic-ischemic brain damage: correlation with cerebral energy metabolism and excitatory amino acid release.

BACKGROUND: Perinatal hypoxia-ischemia (HI) is the most common precipitant of seizures in the first 24-48 h of a newborn's life. In a previous study, our laboratory developed a model of prolonged, continuous electrographic seizures in 10-day-old rat pups using kainic acid (KA) as a proconvulsant. Groups of animals included those receiving only KA, or HI for 15 or 30 min, followed by KA infusion. Our results showed that prolonged electrographic seizures following 30 min of HI resulted in a marked exacerbation of brain damage. We have undertaken studies to determine alterations in hippocampal high-energy phosphate reserves and the extracellular release of hippocampal amino acids in an attempt to ascertain the underlying mechanisms responsible for the damage promoted by the combination of HI and KA seizures. METHODS: All studies were performed on 10-day-old rats. Five groups were identified: (1) group I--KA alone, (2) group II--15 min of HI plus KA, (3) group III--15 min of HI alone, (4) group IV--30 min of HI plus KA, and (5) group VI--30 min of HI alone. HI was induced by right common carotid artery ligation and exposure to 8% oxygen/balance nitrogen. Glycolytic intermediates and high-energy phosphates were measured. Prior to treatment, at the end of HI (both 15 and 30 min), prior to KA injection, and at 1 (onset of seizures), 3, 5 (end of seizures), 7, 24 and 48 h, blood samples were taken for glucose, lactate and beta-hydroxybutyrate. At the same time points, animals were sacrificed by decapitation and brains were rapidly frozen for subsequent dissection of the hippocampus and measurement of glucose, lactate, beta-hydroxybutyrate, adenosine triphosphate (ATP) and phosphocreatine (PCr). In separate groups of rats as defined above, microdialysis probes (CMA) were stereotactically implanted into the CA2-3 region of the ipsilateral hippocampus for measurement of extracellular amino acid release. Dialysate was collected prior to any treatment, at the end of HI (15 and 30 min), prior to KA injection, and at 1 (onset of seizures), 3, 5 (end of seizures), 7 and 9 h. Determination of glutamate, serine, glutamine, glycine, taurine, alanine, and GABA was accomplished using high-performance liquid chromatography with EC detection. RESULTS: Blood and hippocampal glucose concentrations in all groups receiving KA were significantly lower than control during seizures (p < 0.05). beta-Hydroxybutyrate values displayed the inverse, in that values were significantly higher (p < 0.01) in all KA groups compared with pretreatment controls during seizure activity. Values returned to control by 2 h following the cessation of seizures. Lactate concentrations in brain and blood mimicked those of beta-hydroxybutyrate. ATP values declined to 0.36 mmol/l in both the 15 and 30 min hypoxia groups compared with 1.85 mmol/l for controls (p < 0.01). During seizures, ATP and PCr values declined significantly below their homologous controls. Following seizures, ATP values only for those animals receiving KA plus HI for 30 min remained below their homologous controls for at least 24 h. Determination of amino acid release revealed elevations of glutamate, glycine, taurine, alanine and GABA above pretreatment control during HI, with a return to normal prior to KA injections. During seizures and for the 4 h of recovery monitored, only glutamate in the combined HI and KA group rose significantly above both the 15 min of HI plus KA and the KA alone group (p < 0.05). CONCLUSION: Under circumstances in which there is a protracted depletion of high-energy phosphate reserves, as occurs with a combination of HI- and KA-induced seizures, excess amounts of glutamate become toxic to the brain. The latter may account for the exacerbation of damage to the newborn hippocampus, and serve as a target for future therapeutic intervention.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

A new model for determining the influence of age and sex on functional recovery following hypoxic-ischemic brain damage.

Stroke is a disorder affecting the lives of all age groups, and particularly those at the opposite ends of the age spectrum. It is generally believed that the immature brain is more resistant to damage resulting from a hypoxic/ischemic injury, and that it is also more 'plastic' in terms of its ability to recover. Evidence from our laboratory, and a host of others, has indicated, however, that the developing brain may in fact be more sensitive to injury resulting from hypoxia-ischemia. The question remains, however, whether the immature brain has a greater capacity for recovery. In order to determine the relative capability for functional recovery between age groups, a stroke model of comparable injury is required. This paper describes a new rodent model of ischemic injury allowing for comparisons of behavioral recovery spanning the spectrum of ages between newborn and the elderly. Endothelin-1, a potent vasoconstrictor, was stereotactically injected into the brains of 10-, 63-, and 180-day-old Wistar rats, immediately adjacent to the middle cerebral artery. Regionally, the cortex, caudate, and thalamus were most significantly affected, with sparing of the hippocampus. Pathologic assessment indicated a similar degree of injury across age groups affecting the territorial distribution of the middle cerebral artery, with a predominance of damage in the anterior sections of the cortex and caudate (p < 0.05), compared to the posterior sections including the cortex and thalamus. There were no regional differences in the extent of damage between age groups. Interestingly, however, there were significant differences between males and females regarding the overall extent of brain damage (p < 0.05), with males showing greater damage than females. In addition, there were significant regional differences in the extent of damage between males and females, particularly regarding cortical damage (p < 0.05), both anteriorly and posteriorly, and the caudate anteriorly (p < 0.05). Our findings provide an important new model for comparison of brain damage among the entire spectrum of ages affected by stroke. Importantly, this will allow for further investigations regarding both functional recovery and gender difference comparisons. This may have important ramifications for the development of therapeutic interventions that are age and gender specific.

Age Factors↗