Ontogenetic aspects of hypertension development: analysis in the rat.

In this review, we attempt to outline the age-dependent interactions of principal systems controlling the structure and function of the cardiovascular system in immature rats developing hypertension. We focus our attention on the cardiovascular effects of various pharmacological, nutritional, and behavioral interventions applied at different stages of ontogeny. Several distinct critical periods (developmental windows), in which particular stimuli affect the further development of the cardiovascular phenotype, are specified in the rat. It is evident that short-term transient treatment of genetically hypertensive rats with certain antihypertensive drugs in prepuberty and puberty (at the age of 4-10 wk) has long-term beneficial effects on further development of their cardiovascular apparatus. This juvenile critical period coincides with the period of high susceptibility to the hypertensive effects of increased salt intake. If the hypertensive process develops after this critical period (due to early antihypertensive treatment or late administration of certain hypertensive stimuli, e.g., high salt intake), blood pressure elevation, cardiovascular hypertrophy, connective tissue accumulation, and end-organ damage are considerably attenuated compared with rats developing hypertension during the juvenile critical period. As far as the role of various electrolytes in blood pressure modulation is concerned, prohypertensive effects of dietary Na+ and antihypertensive effects of dietary Ca2+ are enhanced in immature animals, whereas vascular protective and antihypertensive effects of dietary K+ are almost independent of age. At a given level of dietary electrolyte intake, the balance between dietary carbohydrate and fat intake can modify blood pressure even in rats with established hypertension, but dietary protein intake affects the blood pressure development in immature animals only. Dietary protein restriction during gestation, as well as altered mother-offspring interactions in the suckling period, might have important long-term hypertensive consequences. The critical periods (developmental windows) should be respected in the future pharmacological or gene therapy of human hypertension.     

Cerebral hemodynamics after traumatic brain injury of immature brain.

These studies were designed to characterize the cerebral hemodynamic effects of fluid percussion brain injury (FPI) in the newborn pig equipped with a closed cranial window. Reductions in cerebral blood flow, pial artery diameter, and cerebral oxygenation following FPI were greater in newborn (1-3 days old) vs. juvenile (3-4 weeks old) pigs, suggesting that newborns were exquisitely sensitive to brain injury. Additionally, in piglets, there was decremented dilation to nitric oxide, cGMP, and cAMP dependent stimuli following FPI. The membrane potential of vascular muscle is an important contributor to vascular tone and the activity of K+ channels is an important regulator of membrane potential. Recent studies indicate that altered dilator responsiveness and cerebral hemodynamic control following FPI results from impaired K+ ATP sensitive (KATP) and calcium sensitive (Kca+2) channel function. Impaired KATP channel function results, at least in part, from protein kinase C activation by the peptide endothelin-1. These observations indicate that the effects of brain injury on cerebral hemodynamics in the newborn are multifaceted and multifactorial.     

Ontogenetic aspects of central cholinergic involvement in spontaneous alternation behavior

Four studies are reported examining the development of spontaneous alternation behavior in rats. Spontaneous alternation was found to increase from a rate of around 20% in 15-16 day old rats to around 90% in 100-day olds. Increasing the length of confinement in the 1st chosen goal arm did not affect alternation rats. Spontaneous alternation could be disrupted or facilitated in mature animals by the administration of either scopolamine hydrobromide or physostigmine sulphate, drugs which had no effect on the typical alternation pattern of 16-day olds, but appeared to begin to have an effect at around 24 days. Dose response curves revealed certain age-dose level interactions which were consistent with the hypothesis that cholinergic inhibitory mechanisms in the brain develop gradually in the rat.     

Astereopsis caused by traumatic brain injury.

Impaired depth perception (astereopsis) has been observed in a variety of cerebral pathologies affecting the posterior parietal lobe. In the current study of 93 consecutive head trauma admissions, 24% had complete astereopsis and 41% performed more than 2 SDs below the orthopedic control group mean. Degree of impairment was related to Glascow Coma Scale score, length of posttraumatic amnesia, reduced visuospatial and memory abilities, and the presence of intracranial pathology of the parietal lobes. Impairment was also related to trauma severity in patients without any visualized intracranial pathology, presumably due to diffuse axonal shearing. Clinically meaningful impairment was observed in 25% of this group; 10% had complete astereopsis. Stereoacuity screening requires 1 to 2 minutes. Undetected astereopsis may increase risk for subsequent motor vehicle accidents or falls.     

Personality disturbances associated with traumatic brain injury.

Personality disturbances associated with traumatic brain injury are reviewed. The varied structural pathology of the brain in this patient group makes it difficult to specify how different brain lesions may result in specific emotional and motivational disturbances. However, an attempt to clarify terms and review empirical findings is made. Longitudinal prospective studies that utilize appropriate control groups are needed. Future research may especially benefit by considering the long-term effects of early agitation following traumatic brain injury as well as the problem of aspontaneity and impairment of self-awareness.     

Persistent neurobehavioral problems following mild traumatic brain injury.

Accumulating research documents typical rates in the range of 85% of mild traumatic brain injury (MTBI) showing prompt, complete resolution with 15% suffering from persistent neurobehavioral impairments. Studies of neurobehavioral symptoms of MTBI have not separated these two populations, resulting in either inconclusive or contradictory conclusions concerning the relationship of MTBI with residual behavioral problems. This project studied 70 MTBI patients with persistent neurobehavioral problems at two time intervals post-injury to determine whether there are consistent neurobehavioral patterns considered to be sequelae of MTBI. A matched group of 40 normal subjects provided control data. While most behavioral problems showed improvement, 21% tended to show significant behavioral impairment compared to controls at 12 or more months post-injury. Neurochemical bases of neuronal degeneration may account for some of the behavioral deterioration following MTBI.     

Disturbance of social cognition after traumatic orbitofrontal brain injury.

A patient with traumatic orbitomedial frontal lobe damage demonstrated good neurocognitive recovery but a lasting, profound disturbance of emotional regulation and social cognition. Initial neuropsychological findings included a complete anosmia, mildly reduced fluency and disturbed motor regulation. The impairments of fluency and motor regulation resolved, and formal measures of "frontal lobe" functioning were generally intact. However, she remained impaired on tasks requiring the interpretation of social situations, which mirrored her impairment in real life functioning. This disturbance in social cognition appeared related to difficulty appreciating and integrating the relatively subtle social and emotional cues required for the appropriate interpretation of events. The patient's presentation represents an intermediate position between patients with profound neurobehavioral deficits and patients with impaired real-life social cognition despite intact neuropsychological performance following orbitofrontal damage. Variations in the orbitofrontal behavioral syndrome may be related to extent of lesion, time post injury and the course of recovery in different patients.     

The effects of traumatic brain injuries on information processing.

Many individuals experience memory impairment subsequent to traumatic brain injuries (TBI). These memory deficits may result from general impairment of information processing rather than damage to memory critical neurological systems. The investigators examined learning time and recall errors for easy and hard word pairs in a distraction and no-distraction condition to examine learning patterns. Although results indicated that individuals with and without TBI generally showed the same learning and retrieval patterns, individuals with TBI did so in an accentuated manner. This suggests that attentional deficits associated with TBI are not responsible for subsequent memory deficits.     

NMDA and age dependent cerebral hemodynamics after traumatic brain injury.

Activation of N-methyl-D-aspartate (NMDA) glutamatergic receptors elicits cerebrovascular dilation, may couple local cerebral metabolism to blood flow but contribute to excitotoxic neuronal cell death. While cerebral hemodynamics following traumatic brain injury may correlate with neurologic status, the role of NMDA vascular activity is uncertain in the sequelae of brain injury. NMDA dilation was impaired following fluid percussion brain injury (FPI) in an age dependent manner in the pig and the newly described opioid nociceptin/orphanin FQ (NOC/ oFQ) contributes to such impairment via the cyclooxygenase dependent generation of superoxide. Further, hypotensive pial artery dilation (PAD) was blunted after FPI but partially protected by pretreatment with the NMDA antagonist MK801. Cerebral blood flow (CBF) was reduced during normotension by FPI, further reduced by hypotension, but both were partially protected by MK801 in the newborn. In contrast, blunted hypotensive PAD was protected significantly less by MK801 in the juvenile pig. Similarly, MK801 had less protective effect on normotensive and hypotensive CBF values post FPI in the juvenile. These data indicate that NMDA receptor activation contributes to impaired hypotensive cerebral hemodynamics following FPI in an age dependent manner. Further, these data suggest that NMDA receptor activation, NOC/oFQ, and prostaglandins dynamically interact to impair cerebral hemodynamics following FPI.     

Neuropsychiatric sequelae of traumatic brain injury

The authors review the psychiatric disturbances associated with traumatic brain injury. They highlight the close link between traumatic brain injury and psychiatry and provide an overview of the epidemiology, risk factors, classification, and mechanisms of traumatic brain injury. They describe various neuropsychiatric sequelae, and the respective treatments are outlined with emphasis on a multidisciplinary approach.     

Ontogenetic aspects of sexual dimorphism and the primary immune response to sheep erythrocytes in hamsters from prepuberty through senescence.

Ontogeny of the primary response to sheep erythrocytes of age-matched groups of male and female hamsters was studied at various chronological ages ranging from prepuberty to senescence. Selected organs were likewise weighed upon sacrifice to obtain developmental patterns. Adrenal weights were higher in the male, and pituitary weights were higher in the female; for both organs typical dimorphism was demonstrable by 36 days. Spleen weight and index favored the female by 46 days. Immunological sex dimorphism first appeared in groups injected at 53 days and autopsied at 58 days and persisted through senescence. Sexual dimorphism of antibody-mediated immunity, previously shown to favor the female in both the primary and secondary immune responses, thus follows the dimorphism of total amount of splenic lymphoid tissue and occurs shortly after realization of sexual maturity in the male. These findings support our previous suggestion of the suppressive effect of androgens on the antibody-mediated immune responsiveness of the male hamster.     

Verbal IQ-performance IQ differentials in traumatic brain injury samples.

Several studies of head trauma utilizing the Wechsler Adult Intelligence Scale (WAIS) reported large sample differentials between verbal IQ (VIQ) and performance IQ (PIQ), leading some writers to claim that the VIQ is largely unaffected by traumatic brain injury (TBI), and that a superiority of VIQ over PIQ should be expected. In contrast, our review of Wechsler Adult Intelligence Scale-Revised (WAIS-R) studies indicates that although TBI sample PIQ means are often depressed relative to VIQ means, the differences are small and sometimes in the opposite direction. Possible reasons for the discrepancy between our WAIS-R review and those of an earlier review of WAIS studies are discussed. Clinically, the lack of a VIQ-PIQ difference should never be used to infer that a TBI has not occurred.     

Porteus Maze performance following traumatic brain injury in children.

To investigate planning in traumatically brain injured children, the authors gave the Porteus Maze Test (PMT; S. D. Porteus, 1959) to 276 pediatric patients who had sustained a traumatic brain injury (TBI) at least 3 years previously. Sensitivity of the PMT to TBI severity, age at test, and volume of focal brain lesions detected by magnetic resonance imaging was also studied. The Peabody Picture Vocabulary Test-Revised (L. M. Dunn & L. M. Dunn, 1981) was also administered as a control measure. Results indicated that the PMT was highly sensitive to TBI severity and to volume of circumscribed prefrontal lesions. In contrast to the PMT data, receptive vocabulary was related to injury severity but not to discrete prefrontal lesions. Implications for mechanisms of cognitive deficit after TBI in children are discussed.