Lack of evidence of neuropathology in the locus coeruleus in autism.
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Autistic Disorder↗
Biomedical subjects
T Kemper
Publications and source records attributed to T Kemper.
Regional cerebral correlates of global motion perception: evidence from unilateral cerebral brain damage.
We used a psychophysical task to measure sensitivity to motion direction in 50 stroke patients with unilateral brain lesions and 85 control subjects. Subjects were asked to discriminate the overall direction of motion in dynamic stochastic random dot displays in which only a variable proportion of the spots moved in a single direction while the remainder moved randomly. Behavioural and neurophysiological evidence shows that the middle temporal (MT/V5) and middle superior temporal (MST) areas in the macaque monkey are indispensably involved in the perception of this type of motion. In human subjects too, lesions in the same region disrupt performance on this task. Here we assessed more extensively the correlation between direction sensitivity for global motion and the anatomical locus of the lesion. Thresholds for perceiving the direction of global motion were impaired in the visual field contralateral to the lesion in patients with lesions in the occipitoparietal and parietotemporal areas involving the human analogue of areas MT/V5 and MST, but not by lesions in the occipito-temporal or anterior frontal areas. Patients with lesions involving the anterior temporal or parietal lobes displayed poor performance for stimuli presented in either visual field, which is consistent with the large and bilateral receptive fields in these areas in monkeys. The perception of global motion was also more impaired in the centripetal than the centrifugal direction in the hemifield contralateral to the MT/V5 lesion. Surprisingly, thresholds were normal in all patients when the displays contained static but not dynamic visual noise, suggesting that their deficit reflects an inability to filter out dynamic noise. Although frequent repeated testing of some patients whose lesion involved the human homologue of MT was accompanied by an improvement in performance, this was no greater than in other patients who received training on different motion tasks.
Adult↗
Replication of naturally occurring woodchuck hepatitis virus deletion mutants in primary hepatocyte cultures and after transmission to naive woodchucks.
Woodchuck hepatitis virus (WHV) mutants with core internal deletions (CID) occur naturally in chronically WHV-infected woodchucks, as do hepatitis B virus mutants in humans. We studied the replication of WHV deletion mutants in primary woodchuck hepatocyte cultures and in vivo after transmission to naive woodchucks. By screening 14 wild-caught, chronically WHV-infected woodchucks, two woodchucks, WH69 and WH70, were found to harbor WHV CID mutants. Consistent with previous results, WHV CID mutants from both animals had deletions of variable lengths (90 to 135 bp) within the middle of the WHV core gene. In woodchuck WH69, WHV CID mutants represented a predominant fraction of the viral population in sera, normal liver tissues, and to a lesser extent, in liver tumor tissues. In primary hepatocytes of WH69, the replication of wild-type WHV and CID mutants was maintained at least for 7 days. Although WHV CID mutants were predominant in fractions of cellular WHV replicative intermediates, mutant covalently closed circular DNAs (cccDNAs) appeared to be a small part of cccDNA-enriched fractions. Analysis of cccDNA-enriched fractions from liver tissues of other woodchucks confirmed that mutant cccDNA represents only a small fraction of the total cccDNA pool. Four naive woodchucks were inoculated with sera from woodchuck WH69 or WH70 containing WHV CID mutants. All four woodchucks developed viremia after 3 to 4 weeks postinoculation (p.i.). They developed anti-WHV core antigen (WHcAg) antibody, lymphoproliferative response to WHcAg, and anti-WHV surface antigen. Only wild-type WHV, but no CID mutant, was found in sera from these woodchucks. The WHV CID mutant was also not identified in liver tissue from one woodchuck sacrificed in week 7 p.i. Three remaining woodchucks cleared WHV. Thus, the presence of WHV CID mutants in the inocula did not significantly change the course of acute self-limiting WHV infection. Our results indicate that the replication of WHV CID mutants might require some specific selective conditions. Further investigations on WHV CID mutants will allow us to have more insight into hepadnavirus replication.
Animals↗
Naturally occurring woodchuck hepatitis virus (WHV) deletion mutants in chronically WHV-infected woodchucks.
Deletion mutants of hepatitis B virus (HBV) are often found in chronically HBV-infected patients. It has not been possible to study the significance of such deletion mutants on liver diseases in a suitable animal model. In this study, we characterized naturally occurring deletion mutants of woodchuck hepatitis virus (WHV) in 11 chronically WHV-infected woodchucks. Deletions within the WHV preS region (nt 2992-338) had a length of 72 or 84 bp and were located in the amino terminal part of preS1. Internal deletions within the core gene (CID) had variable lengths (103 to 312 bp) and were identified within the center of this gene (nt 2021-2587). Four of seven CIDs were in-frame deletions, whereas the remaining three CIDs were out-of-frame deletions and led to the interruption of the reading frame. Sequence analysis of cloned PCR products of CIDs showed that heterogeneous WHV deletion mutants coexisted in single woodchucks. In addition, WHV genomes with double deletions in the preS1 and the core region could be found. We were unable to detect the expression of truncated core proteins in transfection experiments. The CID mutations led to a marked increase of the expression of the luciferase gene which was fused to the start codon of WHV polymerase, probably due to the shortening of the untranslated region or the removal of AUGs preceding the polymerase start codon. The characterization of naturally occurring WHV deletion mutants will allow us to study their biological and pathogenic properties in the woodchuck model in the future.
Animals↗
Astrocytic hypertrophy and altered GFAP degradation with age in subcortical white matter of the rhesus monkey.
Reactive astrocytosis is a well known phenomenon that occurs in the normal aging process of the brain. While many studies indicate astrocytic hypertrophy and glial fibrillary acidic protein (GFAP) content increase with age in the hippocampal formation of certain animal models, it is unclear whether these findings are generalizable to the primate and to other areas of the brain. In this study, we quantitatively assessed age-related changes in astrocytic cell size and density in a rhesus monkey model of normal aging. By GFAP immunohistochemistry, we observed an increase in GFAP(+) cell size but not density in all subcortical white matter areas of the frontal, temporal, and parietal cortices. No significant increases in astrocyte hypertrophy were observed in any gray matter area examined. In addition, Western blotting experiments showed increases in total and degraded GFAP content with age, suggesting altered degradation and possibly production of GFAP occur with age.
Aging↗
Microinfarction as a result of hypertension in a primate model of cerebrovascular disease.
Ten adult cynomolgus monkeys were studied as a non-human primate model of hypertensive cerebrovascular disease. Seven were made hypertensive by surgical coarctation of the aorta and three served as unoperated controls. After survival periods of 8-30 months, the brains were serially sectioned and surveyed for neuropathological changes. The most conspicuous change was minute areas of microinfarction in the white and gray matter. The lesions were of irregular shape with an average maximum diameter of less than 0.5 mm. They were slightly larger in the gray than in the white matter and appeared to be of different ages. Their area of predilection was the white matter of the forebrain, with smaller numbers in the cerebral cortex and scattered lesions elsewhere in the forebrain, brain stem and cerebellum. These microinfarcts did not correspond to usually described lesions in the human brain in hypertension or in other animal models of hypertensive cerebrovascular disease. We suggest that they represent an early change in the natural history of hypertensive neuropathology.
Age Factors↗
Immunization of woodchucks with plasmids expressing woodchuck hepatitis virus (WHV) core antigen and surface antigen suppresses WHV infection.
DNA vaccination can induce humoral and cellular immune response to viral antigens and confer protection to virus infection. In woodchucks, we tested the protective efficacy of immune response to woodchuck hepatitis core antigen (WHcAg) and surface antigen (WHsAg) of woodchuck hepatitis virus (WHV) elicited by DNA-based vaccination. Plasmids pWHcIm and pWHsIm containing WHV c- or pre-s2/s genes expressed WHcAg and WHsAg in transient transfection assays. Pilot experiments in mice revealed that a single intramuscular injection of 100 microgram of plasmid pWHcIm DNA induced an anti-WHcAg titer over 1:300 that was enhanced by boost injections. However, two injections of 100 microgram of pWHcIm did not induce detectable anti-WHcAg in woodchucks. With an increase in the dose to 1 mg of pWHcIm per injection, transient anti-WHcAg response and WHcAg-specific proliferation of peripheral mononuclear blood cells (PMBCs) appeared in woodchucks after repeated immunizations. Four woodchucks vaccinated with pWHcIm were challenged with 10(4) or 10(5) of the WHV 50% infective dose. They remained negative for markers of WHV replication (WHV DNA and WHsAg) in peripheral blood and developed anti-WHs in week 5 after challenge. In contrast, woodchucks not immunized or immunized with the control vector pcDNA3 developed acute WHV infection. Two woodchucks immunized with 1 mg of pWHsIm developed WHsAg-specific proliferative response of PBMCs but no measurable anti-WHsAg response. A rapid anti-WHsAg response developed during week 2 after virus challenge. Neither woodchuck developed any signs of WHV infection. These data indicate that DNA-based vaccination with WHcAg and WHsAg can elicit immunity to WHV infection.
Amino Acid Sequence↗
Effects of prenatal protein malnutrition on mossy fibers of the hippocampal formation in rats of four age groups.
The present study was undertaken to investigate the effect of prenatal protein deprivation on the postnatal development of the mossy fiber plexus of the hippocampal formation on postnatal (P) days 15, 30, 90, and 220. Although there is extensive information about the effects of malnutrition on cell body and dendrite morphology, little attention has been paid to axons or axon plexuses. The mossy fiber plexus represents the dentate gyrus granule cell axonal projection to areas CA4 and CA3 of the hippocampal formation and is readily demonstrated with Timm's heavy metal stain. With the use of this stain, the plexus was measured at 13 levels throughout the hippocampal complex. There was no effect of the diet on the anatomical distribution of the plexus. The current study, however, does show significant effects of prenatal protein malnutrition on postnatal development of the mossy fiber plexus that are age dependent. The prenatally malnourished rats show significant deficits in the total rostro-caudal extent and volume of the plexus on P15, P90, and P220, with the most marked dietary effect on P220. There was no significant diet effect on P30 in either extent or volume.
Analysis of Variance↗
Effects of prenatal protein malnutrition on hippocampal CA1 pyramidal cells in rats of four age groups.
The present study was undertaken to investigate the effect of prenatal protein deprivation on area CA1 hippocampal pyramidal cells on postnatal (P) days 15, 30, 90 and 220 using Golgi techniques. Age related changes in both groups and diet related changes between groups were assessed. There were significant diet effects at all four ages, with one of 12 different measurements showing a significant diet effect on P15, five on P30, one on P90, and seven on P220. The most marked effect of the diet was on pyramidal cell dendrite spine density in the stratum moleculare and stratum radiatum, with a different pattern of diet effects in the two strata. In pyramidal cell dendrites in the stratum moleculare, there was a deficit in spine density that was significant at three of the four ages and there were similar age-related changes in the two diet groups. Spines on pyramidal cell dendrites in the stratum radiatum showed a lack of synchrony of age-related changes in the two diet groups, with an increased spine density in the malnourished rats on P30 and a widening deficit in this parameter on P90 and P220. The bimodal distribution to these changes, with most marked deficits occurring on P30 and P220, with an intervening period of apparent "catch-up" on P90, is of interest and may be a significant brain adaptation to malnutrition. The present study is the final of three morphometric studies on the effect of prenatal protein restriction on three key neurons in the hippocampal trisynaptic circuit. When compared to our previous studies on the dentate granule cell and the CA3 pyramidal cell, it is noted that there is an effect of the low protein diet on all these neurons, with the most marked effect on the predominantly postnatally generated dentate granule cells.
Analysis of Variance↗
Lack of correlation between plaque burden and cognition in the aged monkey.
To assess whether amyloid plaque accumulation in the monkey brain can account for age-related cognitive impairment that begins at about 20 years of age, we measured plaque content in the brains of 14 rhesus monkeys aged 5-30 years. We used immunohistochemistry employing the monoclonal antibody 6E10, which is specific to amino acids 1-17 of the amyloid beta peptide to identify amyloid plaques in serial coronal sections of the forebrain. Amyloid plaques accumulate with age, starting at 25 years of age and escalating after 30 years. Until the age of 30, plaques are only found in a few monkeys and are relatively sparse. Results from our group and others show that plaque content and the proportion of individuals afflicted with amyloid plaques increase with age. Although both cognitive dysfunction and plaque content increase with age, amyloid plaque content does not correlate with the cognitive dysfunction observed in elderly monkeys since even in very old subjects some cognitively impaired animals have few amyloid plaques and others with abundant plaques show only minor cognitive impairments. In summary, amyloid plaques appear to accumulate significantly only in monkeys over 25 years of age but do not appear to be a causal factor in age-related cognitive decline of the normal aging rhesus monkey.
Aging↗
[Large nodular, multicenter, juvenile xanthogranuloma with ulceration].
We report on a patient with multicentric juvenile xanthogranuloma, whose unusual clinical and histological pattern initially obscured the diagnosis. Spontaneous remission of the tumour, which has now been maintained for over 2 years, the change from the primary monomorphological fibrocytic appearance to a polymorphological histiocytic picture with multiple fat-storing giant cells, and the lacking dermonstration of specific cell organelles finally allowed the nature of the disease to the definitely diagnosed.
Diagnosis, Differential↗
A synthetic dural prosthesis constructed from hydroxyethylmethacrylate hydrogels.
Hydroxyethylmethacrylate (HEMA) hydrogels were investigated for their suitability as a dural prosthesis. Poly-HEMA has many characteristics required for an artificial dural substitute: it is durable, flexible, easily prepared, inexpensive, easily sterilized and handled, easily shaped, and known to be chemically inert and nontoxic. Sheets made of plain HEMA were evaluated as dural substitutes in rats and rabbits after either craniotomy or laminectomy with durectomy. Histological evaluations of the prostheses and the underlying tissues were undertaken at various time points from 2 to 9 weeks postoperatively. There was minimal tissue response to the implanted HEMA gel in contrast to marked thickening of the overlying leptomeninges and cortical herniation in the control animals. It is concluded that HEMA gels fulfill the essential criteria for an effective dural substitute.
Animals↗
Heterogeneity of brain gene expression in Alzheimer's disease.
We have examined the expression of several genes whose transcripts have increased levels in Alzheimer's disease and have found heterogeneity in these levels in different patients with this condition. The level of expression of these genes was compared to different clinical and pathological aspects of the disease. A case with markedly elevated alpha 1-antichymotrypsin mRNA levels demonstrated prominent neuronal accumulation of this protein. Many of the neurons which demonstrated alpha 1-antichymotrypsin staining did not have neurofibrillary tangles, and vice versa. This suggests that alpha 1-antichymotrypsin staining might identify a different facet of the pathology of Alzheimer's disease than does neurofibrillary tangle staining and may provide new information in the study of this condition.
Aged↗
Treatment of smoke inhalation in five horses.
Five horses were admitted for treatment of smoke-inhalation injuries sustained in a barn fire. Three of the horses were mildly affected, with high respiratory rates (24 to 36 breaths/min) and normal to low arterial oxygen tensions (77.0 to 94.1 mm of Hg), and responded well to administration of diuretics, bronchodilators, corticosteroids, and antibiotics. The 2 remaining horses were severely affected. Both were in respiratory distress, with markedly low arterial oxygen tensions (50.4 and 57.1 mm of Hg) and cyanosis. These 2 horses required fluid resuscitation in addition to the treatments given to the less severely affected horses. Tracheostomy was performed to facilitate removal of large, obstructive, pseudomembranous tracheobronchial casts. Oxygen was administered by nasal or tracheal insufflation or by use of a high-frequency jet ventilator. The most severely affected horse developed hemorrhagic colitis and was euthanatized. The 4 surviving horses recovered in 2 to 5 months and resumed working without reduction in performance capability.
Adrenal Cortex Hormones↗
Prenatal malnutrition and development of the brain.
In this review, we have summarized various aspects as to how prenatal protein malnutrition affects development of the brain and have attempted to integrate several broad principles, concepts, and trends in this field in relation to our findings and other studies of malnutrition insults. Nutrition is probably the single greatest environmental influence both on the fetus and neonate, and plays a necessary role in the maturation and functional development of the central nervous system. Prenatal protein malnutrition adversely affects the developing brain in numerous ways, depending largely on its timing in relation to various developmental events in the brain and, to a lesser extent, on the type and severity of the deprivation. Many of the effects of prenatal malnutrition are permanent, though some degree of amelioration may be produced by exposure to stimulating and enriched environments. Malnutrition exerts its effects during development, not only during the so-called brain growth spurt period, but also during early organizational processes such as neurogenesis, cell migration, and differentiation. Malnutrition results in a variety of minimal brain dysfunction-type syndromes and ultimately affects attentional processes and interactions of the organism with the environment, in particular producing functional isolation from the environment, often leading to various types of learning disabilities. In malnutrition insult, we are dealing with a distributed, not focal, brain pathology and various developmental failures. Quantitative assessments show distorted relations between neurons and glia, poor formation of neuronal circuits and alterations of normal regressive events, including cell death and axonal and dendritic pruning, resulting in modified patterns of brain organization. Malnutrition insult results in deviations in normal age-related sequences of brain maturation, particularly affecting coordinated development of various cell types and, ultimately, affecting the formation of neuronal circuits and the commencing of activity of neurotransmitter cell types and, ultimately, affecting the formation of neuronal circuits and the commencing of activity of neurotransmitter systems. It is obvious that such diffuse type "lesions" can be adequately assessed only by interdisciplinary studies across a broad range of approaches, including morphological, biochemical, neurophysiological, and behavioral analyses.
Animals↗
The effects of hypertension on cerebral atherosclerosis in the cynomolgus monkey.
BACKGROUND AND PURPOSE: There is substantial clinical, pathological, and experimental evidence that hypertension aggravates atherosclerosis of the extracranial vessels. The present study assesses the effects of hypertension on the development of cerebral atherosclerosis in nonhuman primates fed an atherogenic diet. METHODS: The extent and severity of cerebral atherosclerosis were evaluated morphologically, morphometrically, and biochemically in atherosclerotic monkeys with and without hypertension. Atherosclerosis was induced by feeding a hypercholesterolemic diet for 12 months; hypertension was produced by surgical coarctation of the thoracic aorta. RESULTS: At autopsy, gross atherosclerotic lesions of the major cerebral arteries were observed in 15 of 16 atherosclerotic monkeys with hypertension compared with 5 of 16 atherosclerotic animals without hypertension. In the hypertensive-atherosclerotic group, 38.5% of the vessels examined showed gross involvement compared with only 3.4% of the vessels involved in the atherosclerotic group (P < .001). The lesions in the atherosclerotic group were generally mild, whereas those in the hypertensive-atherosclerotic group were severe and resulted in significant luminal narrowing and occlusion of vessels (P < .001). The small branches of the cerebral arteries also showed severe disease with luminal obstruction in the hypertensive-atherosclerotic group. The extent and severity of cerebral atherosclerosis were significantly related to the severity of the hypertension (P < .05). CONCLUSIONS: Hypertension is an important factor in cerebral atherosclerosis because of its accelerating effect on the disease. Nonhuman primate models may be useful in clarifying the role of hypertension and atherosclerosis in cerebral vascular disease.
Animals↗
Effects of prenatal protein deprivation on postnatal development of granule cells in the fascia dentata.
The effect of prenatal protein deprivation on the postnatal development of granule cells in the fascia dentata in the rat was studied at 15, 30, 90, and 220 days of age. The granule cells showed a significant reduction in cell size, decreased number of synaptic spines throughout their dendritic extent, and reduced complexity of dendritic branching in the outer two-thirds of the molecular layer. All of these deficits were present at 15 days and persisted throughout the study (220 days). The least deficits in synaptic spine density occurred at 90 days and in dendritic branching at 30 days. Partial restitution of earlier, more severe deficits was associated primarily with maturational events occurring in the protein deprived rats, whereas later increases in deficits were related primarily to a failure of the protein deprived rats to keep pace with neuronal development occurring in the controls. The present results are similar to those noted in our previous study in this journal of the effect of a low protein diet (8% casein) on these neurons that extended from pregnancy until the time of sacrifice at 30, 90, and 220 days of age (Cintra et al., '90; 532:271-277). Taken together, these two studies suggest that the postnatal adaptation of the granule cells to prenatal protein deprivation is primarily due to events that occur during pregnancy and that the site of predilection for the deficit is their dendrites in the outer two-thirds of the molecular layer of the fascia dentata.
Aging↗
Effects of protein undernutrition on the dentate gyrus in rats of three age groups.
The effect of an 8% casein and a control 25% casein diet on the granule cells in the dorsal blade of the dentate gyrus of the rat hippocampal formation was studied at 30, 90 and 220 days of age. Female rats were fed either an 8% or 25% casein diet 5 weeks prior to conception and the litters were maintained on these respective diets until killed. In rapid-Golgi-impregnated cells, we measured major and minor axes of the soma of the dentate granule neurons, the number of spines on 50-microns segments of proximal, middle and terminal regions of the largest dendrite per granule cell and the number of dendrites intersecting 8 concentric rings 38 microns apart. At all 3 ages studied undernourished rats showed, when compared to controls, significant reductions of the major and minor axes of the somata and significant reductions in the number of spines on dendrites in the middle and terminal dendritic segments. Dendritic branching was significantly reduced in undernourished rats compared to controls in all but the 4th concentric rings, with the greatest effect being seen on the outer 3 concentric rings at 90 and 220 days of age. The location of the deficit in dendritic synaptic spines and the greatest deficit in dendritic branching correspond to the sites of termination of the lateral and medial perforant pathway projection to the dentate gyrus on the terminal and middle dendritic segments of the granule cells. The deficits noted in the granule cells of the dentate gyrus in this study were more severe than those found in our previous studies on the effect of the low protein diet in these same rats on visual cortical pyramidal cells and on the 3 cell types in the nucleus raphe dorsalis and nucleus locus coeruleus.
Analysis of Variance↗