Immunogold study of effects of prenatal exposure to lipopolysaccharide and/or valproic acid on the rat blood-brain barrier vessels.

The involvement of blood microvessels, representing the anatomic site of the blood-brain barrier (BBB), in brain damage induced by prenatal exposure to lipopolysaccharide (LPS) and/or valproic acid (VPA) was studied in four-week-old rats. The immunogold procedure was applied for localization at the ultrastructural level of endogenous albumin and glucose transporter (GLUT-1) in three brain regions: cerebral cortex, cerebellum and hippocampus. Four groups of rats were used: (1) untreated control, (2) prenatally VPA-treated, (3) prenatally LPS-treated, and (4) prenatally LPS- and VPA-treated. The functional state of the BBB was evaluated as follows: (a) by its tightness, i.e., permeability to blood-borne albumin, and (b) by the expression of GLUT-1 in the endothelial cells (ECs). Using morphometry, the labelling density for GLUT-1 was recorded over luminal and abluminal plasma membranes of the ECs, also providing information on their functional polarity. No extensive increase of vascular permeability and/or any considerable dysfunction of the BBB in experimental groups nos. 2 and 3 were observed, although in solitary vascular profiles, increased endocytosis or even transcytosis of albumin by ECs was noted. In experimental group no. 4, some vascular profiles showed scanty leakage (microleakage), manifested by the presence of immunosignals for albumin in the perivascular area. Although some fluctuations in the expression of GLUT-1 occurred in all experimental groups, especially in group no. 3, a most pronounced and significant diminution of the labelling density, in all three regions of the brain, was observed in group no. 4. This finding suggests the synergistic action of prenatally applied LPS and VPA that affects specific transport functions of glucose in the microvascular endothelium. The diminished or disturbed supply of glucose to selected brain regions can be one of the factors leading to previously observed behavioral disturbances in similarly treated rats.

Pathological changes in the liver of a senescence accelerated mouse strain (SAMP8): a mouse model for the study of liver diseases.

Liver disease is characterized by fatty liver, hepatitis, fibrosis and cirrhosis and is a major cause of illness and death worldwide. The prevalence of liver diseases highlights the need for animal models for research on the mechanism of disease pathogenesis and efficient and cost-effective treatments. Here we show that a senescence-accelerated mouse strain (SAMP8 mice), displays severe liver pathology, which is not seen in senescence-resistant mice (SAMR1). The livers of SAMP8 mice show fatty degeneration, hepatocyte death, fibrosis, cirrhotic changes, inflammatory mononuclear cell infiltration and sporadic neoplastic changes. SAMP8 mice also show abnormal liver function tests: significantly increased levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST). Furthermore, titers of murine leukemia virus are higher in livers of SAMP8 than in those of SAMR1 mice. Our observations suggest that SAMP8 mouse strain is a valuable animal model for the study of liver diseases. The possible mechanisms of liver damage in SAMP8 mice are also discussed.

The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease.

The National NeuroAIDS Tissue Consortium (NNTC) was founded in 1998, in response to the scientific need for well-characterized central nervous system (CNS) and peripheral nervous system (PNS) tissues and fluids from HIV-infected individuals. In addition to performing the routine functions of non-transplant anatomic tissue banks, the Consortium offers a unique model for the integration of independent research entities in order to provide well-characterized tissues and fluids for the international research community. Herein, we describe the structure of the Consortium, pointing out the inherent strengths of linking together multiple independent sites for the purpose of banking HIV-infected nervous system tissues. We describe the neuropathology protocol that was adopted and successfully implemented at the four participating banks of the Consortium.

Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination.

Fragile-X syndrome is a common form of mental retardation resulting from the inability to produce the fragile-X mental retardation protein. Qualitative examination of human brain autopsy material has shown that fragile-X patients exhibit abnormal dendritic spine lengths and shapes on parieto-occipital neocortical pyramidal cells. Similar quantitative results have been obtained in fragile-X knockout mice, that have been engineered to lack the fragile-X mental retardation protein. Dendritic spines on layer V pyramidal cells of human temporal and visual cortices stained using the Golgi-Kopsch method were investigated. Quantitative analysis of dendritic spine length, morphology, and number was carried out on patients with fragile-X syndrome and normal age-matched controls. Fragile-X patients exhibited significantly more long dendritic spines and fewer short dendritic spines than did control subjects in both temporal and visual cortical areas. Similarly, fragile-X patients exhibited significantly more dendritic spines with an immature morphology and fewer with a more mature type morphology in both cortical areas. In addition, fragile-X patients had a higher density of dendritic spines than did controls on distal segments of apical and basilar dendrites in both cortical areas. Long dendritic spines with immature morphologies and elevated spine numbers are characteristic of early development or a lack of sensory experience. The fact that these characteristics are found in fragile-X patients throughout multiple cortical areas may suggest a global failure of normal dendritic spine maturation and or pruning during development that persists throughout adulthood.

Characteristics of scrapie isolates derived from hay mites.

Previous epidemiological evidence suggested that in some instances a vector and/or reservoir is involved in the occurrence and spread of transmissible spongiform encephalopathies (TSEs). In a preliminary study, hay mite preparations from five Icelandic farms with a history of scrapie were injected into mice, and some of these mice became sick after long incubation periods. To confirm that the disease was scrapie, subsequent passages in mice were performed. In addition, the characteristics of the disease process in these passages were assessed and the results compared to those findings with standard scrapie strains. As expected for scrapie, subsequent passages in the same host led to shortened incubation periods compared to those in primary isolate mice, and all mice had spongiform changes in brain. Results were similar for three of four isolates with regard to clinical manifestations, the incubation periods in mice of the three scrapie incubation-period genotypes (s7s7, s7p7, p7p7), and the PrPSc Western blot (WB) pattern. The characteristics of the fourth isolate were markedly different from the other three isolates with regard to these parameters. Comparison of the characteristics of standard mouse-adapted scrapie strains and the four isolates revealed differences; these differences were particularly pronounced for the fourth isolate.

Reduction in TrkA-immunoreactive neurons is not associated with an overexpression of galaninergic fibers within the nucleus basalis in Down's syndrome.

Down's syndrome (DS) individuals develop neuropathological features similar to Alzheimer's disease (AD), including degeneration of cholinergic basal forebrain (CBF) neurons. In AD a reduction in CBF/trkA-containing neurons has been suggested to trigger a hyperexpression of galaninergic fibers within the nucleus basalis subfield of the basal forebrain. The present study examined the interrelationship between reductions in CBF/trkA-containing neurons and the overexpression of galaninergic fibers within the nucleus basalis in DS. Within the nucleus basalis stereologic evaluation revealed a 46% reduction in the number of trkA-immunopositive neurons, whereas optical density measurements displayed a nonsignificant 18% reduction in neuronal trkA immunoreactivity in DS as compared with age-matched controls. Western blot analysis also showed a significant reduction in cortical trkA protein levels in DS. A semiquantitative examination of galaninergic fibers in the nucleus basalis revealed only a modest hypertrophy of galaninergic fibers within the nucleus basalis in DS. The present findings indicate a significant reduction in trkA within the nucleus basalis and cortex with only a moderate hypertrophy of galaninergic fibers in DS. These observations suggest that DS may not be an exact genetic model for investigation of changes in the AD basal forebrain.

The therapeutic effect of an herbal formula Badmaev 28 (padma 28) on experimental allergic encephalomyelitis (EAE) in SJL/J mice.

A herbal formula, Badmaev 28, was evaluated in the treatment of an induced attack in a chronic relapsing model of experimental allergic encephalomyelitis (EAE) in SJL/J mice. Chronic EAE was induced by immunization of 8 week old mice with an emulsion of syngeneic spinal cords with incomplete Freund's adjuvant supplemented with Mycobacterium tuberculosis. Therapy with Badmaev 28 was started on day 25 after the immunization, and the formula was administered in the drinking water at doses of 7, 21, 83 and 166 mg/kg/day. The treatment resulted in significantly decreased mortality compared with the untreated control animals and the therapeutic effect occurred in one experiment in a dose-dependent fashion. Based on the experimental results it is difficult to name one particular mechanism responsible for the therapeutic effectiveness of the formula in the EAE model. Rather this protective effect could be explained by a broad protective mechanism of action discussed in the literature as nonspecific resistance (NSR) to the diversified biological and psychological stressors. The increase in NSR characterizes the action of pharmacological compounds termed adaptogens or bioprotectants.

Entorhinal cortex of aged subjects with Down's syndrome shows severe neuronal loss caused by neurofibrillary pathology.

In Alzheimer's disease (AD), neurofibrillary degeneration of neurons starts in the transentorhinal cortex and spreads in a time-dependent manner to the entorhinal cortex, which provides a major input to the hippocampus--a key structure of the memory system. People with Down's syndrome (DS) develop neurofibrillary changes more than 30 years earlier than those with sporadic AD. To characterize AD-related pathology in the entorhinal cortex in DS, we examined seven subjects with DS of 60-74 years of age who died in the end stage of AD, and four age-matched control subjects. The volume of the entorhinal cortex in brains of subjects with DS was 42% less than that in control cases; however, the total number of neurons free of neurofibrillary changes was reduced in DS by 90%: from 9,619,000 +/- 914,000 (mean +/- standard deviation) to 932,000 +/- 504,000. The presence of 2,488,000 +/- 544,000 neurofibrillary tangles in the entorhinal cortex of people with DS, the prevalence of end-stage tangles, and the significant negative correlation between the total number of intact neurons and the percentage of neurons with neurofibrillary changes indicate that neurofibrillary degeneration is a major cause of neuronal loss in the entorhinal cortex of people with DS. The relatively low amyloid load (7 +/- 1%) and lack of correlation between the amyloid load and the volumetric or neuronal loss suggest that the contribution of beta-amyloid to neuronal loss in the entorhinal cortex is unsubstantial.

Microencephaly in children congenitally infected with human immunodeficiency virus--a gross-anatomical morphometric study.

A quantitative technique involving serial sectioning and semiautomatic morphometric analysis was used to assess the severity of the reduction in size of the major brain structures in cerebral hemispheres of children congenitally infected with HIV-1. Cerebral hemispheres from 12 children (18-48 months of age) who died of AIDS were sectioned into 5-mm-thick serial slabs and photographed. The cross-sectional areas of grossly recognizable brain structures were digitized, and the volumes were calculated according to Cavalieri's principle. The results were compared with those of an identically processed group of control brains from non-AIDS children. Analysis of the brain weight showed that there was a significant reduction in supratentorial and infratentorial weight in the AIDS group. The results of the morphometric study revealed that the loss in brain mass was associated with a statistically significant reduction in the total volume of both hemispheres, the entire cortex, white matter, and basal ganglia. Detailed analysis of individual brain structures also showed a significant reduction in volume of all cortical regions and most of the subcortical gray matter (e.g., caudate nucleus, putamen, globus pallidus, claustrum, and thalamus). It appears that in the microencephaly observed as a frequent sequel in pediatric AIDS, the loss of brain tissue is global and includes an almost proportional loss of cortex, subcortical gray matter and white matter.

The white matter changes in microencephalic HIV infected infants. A preliminary report.

The brains of six infants 14-34 months of age and with microencephaly (brain weight deficit 20-55.5%) were chosen from a group of cases vertically infected with HIV. The center of our investigations was focused on the white matter changes of which two types were observed in the examined brains. Within the periventricular white matter of four cases evident lesions consisting of myelin pallor and concomitant gliosis were recognized as HIV-1 infection related leukoencephalopathy. In all those cases myelination delay was also noted. In one case HIV encephalitis was diagnosed. Our observations suggest that in the majority of HIV infected infants changes resulting in the brain "too small for age" corelate with myelination delay coexisting with early-onset leukoencephalopathy. Because of the small number of cases in this study the results should be considered preliminary, and will require further investigations.

Opportunistic infections of the central nervous system in children with HIV infection: report of 9 autopsy cases and review of literature.

Central nervous system (CNS) abnormalities attributed to direct effects of HIV infection are seen in most of children with acquired immunodeficiency syndrome (AIDS). Secondary CNS infections with opportunistic and common pathogens are infrequent in this age group. We report 9 cases of opportunistic infection of the CNS found among 65 autopsy cases of pediatric AIDS. These included 4 cases of cytomegalovirus (CMV) infection, 1 of which was associated with aspergillosis, and 2 cases of candidiasis, 1 of which coexisted with Mycobacterium avium intracellulare (MAI) infection. There were also 2 cases of leptomeningitis, 1 due to Mycobacterium tuberculosis (MTB) and the other to Cryptococcus neoformans. In 1 child progressive multifocal leukoencephalopathy (PML) coexisted with mycotic encephalitis caused by an Aspergillus sp.

[Nervous system changes in infants with HIV virus. Neuropathological picture]. / Zmiany w ukladzie nerwowym dzieci zakazonych wirusem HIV. Obraz neuropatologiczny.

The neuropathologic examination of symptomatic perinatal HIV infection was performed using a large group of cases from New York Medical Centers. Macroscopic evaluation demonstrated many cases with microencephaly and others with brain atrophy. Microscopically in a part of them, as far as in others without microencephaly/atrophy changes corresponding to HIV encephalitis were found, including multinucleated giant cells, microglial nodules and perivascular infiltrations. In other brains in which inflammatory changes were minimal, myelin lesions were also observed and the picture corresponded to the diagnosis of encephalopathy. In addition lesions of cortico-spinal tracts, mineralization within the basal ganglia and changes of vascular walls with secondary parenchymal lesions were found. Opportunistic infections and neoplastic changes were rare. The review demonstrated the picture of neuropathological changes in pediatric cases that died of AIDS.

[Central nervous system changes in infants with HIV infection. Epidemiology and neurology]. / Zmiany w ukladzie nerwowym dzieci zakazonych wirusem hiv. epidemiologia i zaburzenia neurologiczne.

The increase of HIV infected population reaching worldwide 10 million of cases leads to a great number of infected women in reproductive age. Finally the perinatally acquired HIV infection has become a great problem. The number of infants with AIDS is estimated at about 160,000. The diagnosis and evaluation of significant clinical symptoms of HIV infection in infants are briefly described in this study. The nervous system being one of targets of HIV infection the neurological manifestation occurring in infants were more extensively discussed. Microencephaly or brain atrophy and psycho-motor developmental delay resulting in progressive or static encephalopathy syndromes were presented.

The insular claustrum in the methylazoxymethanol acetate (MAM) treated rats shows two different populations of neurons.

Methylazoxymethanol acetate (MAM) is a substance that inhibits migration of neurons in the embryonic brain. After intraperitoneal injection of two different doses of MAM to pregnant rats, microcephaly with or without complete development of the cerebral cortex was observed in every litter. High MAM doses (30 mg/kg) resulted in the lack of superficial layers (II-IV) of the cerebral cortex when the deep layers (V, VI) were seen. The claustrum was present but composed of loosely packed, medium-size, triangular or fusiform neurons with anarchic oriented long axes. After administration of low MAM doses (14 mg/kg) two different parts (medial and lateral) of the insular claustrum were observed. Our results suggest that neurons of the insular claustrum create two different subpopulations of cells, which were similar to that observed in primitive insectivore (e.g., hedgehog), but fuse in development.

Cerebral edema formation in dogs following hypotension induced with isoflurane and labetalol.

The effects of induced hypotension with isoflurane and labetalol on cerebral edema formation were compared following a cryogenic brain injury in dogs. Thirteen dogs received a maintenance anesthetic of 70% N2O, 0.5% isoflurane in O2 and a fentanyl infusion (3 micrograms.kg-1 x hr-1). All dogs were normoventilated (PaCO2 of 35-40 mmHg) and monitored for temperature, arterial blood pressure, central venous pressure (maintained between 7-10 mmHg), end-tidal CO2, end-tidal anesthetic level, and urine output. Following a right parietal craniectomy, a standard sized cryogenic brain lesion was made. The animals were randomly allocated in two groups. Group I (n = 6) received maintenance anesthesia, but within a 30 minute period, mean arterial pressure (MAP) was reduced to 60 mmHg with isoflurane varying in inspired concentration from 2 to 4%. Thereafter, the MAP was maintained at this level for 60 minutes. The inspired concentration of isoflurane was decreased, then discontinued to allow the MAP to return to baseline during the next 30 minutes. Group II (n = 7) received maintenance anesthesia, and MAP was reduced to 60 mmHg during a 30 minute period with intravenous labetalol (20 mg.kg-1). This MAP was maintained for one hour with a continuous labetalol infusion. The infusion was discontinued and the MAP returned to baseline during the next 30 minutes. The wounds were surgically closed. Anesthesia was discontinued, paralysis was reversed, and the animals were extubated and transported to a recovery room. Forty-eight hours postoperatively, all animals were reanesthetized, injected with Evans' blue dye and sacrificed. The brain was removed, fixed in formalin, and sent "blindly" coded for neuropathologic evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)

Amebic meningoencephalitis in a patient with AIDS caused by a newly recognized opportunistic pathogen. Leptomyxid ameba.

A fatal case of meningoencephalitis due to a leptomyxid ameba in a patient with the acquired immunodeficiency syndrome is presented. This opportunistic organism has not been previously recognized as a human pathogen. A 36-year-old male intravenous drug abuser died after an 18-day hospital course heralded by fever and headache and followed by nuchal rigidity and hemiparesis. Computed tomography of the head showed multiple hypodense lesions. Neuropathologic examination showed that in addition to human immunodeficiency virus encephalomyelitis, there was multifocal meningoencephalitis with trophozoites and cysts morphologically indistinguishable from those of Acanthamoeba. These organisms were also found in the kidneys and adrenal glands. By immunofluorescence, the parasites showed antigenic identity with a free-living leptomyxid ameba and failed to react with any of a spectrum of antiacanthamoeba antisera. This emphasizes the importance of immunofluorescence identification of morphologically indistinguishable ameba species.

Sequelae of perinatal central nervous system damage after long-term survival.

We presented the case of a 78-year-old man with mental retardation and spastic paraparesis diagnosed early in life as cerebral palsy. Six years prior to demise he had post-traumatic subdural hematoma, which was removed surgically. The neuropathological examination revealed the sequelae of the recent trauma, superimposed on the extensive old lesions. Cavitary changes in the periventricular white matter and cortical ulegyria in the border zones of the major cerebral arteries vascularization were characteristic of perinatal hypoxic-ischemic lesions. Peculiar in the ulegyria were extensive areas with numerous corpora amylacea adjacent to the areas of fibrillar and cellular gliosis. Another sequelae of involution processes was the atrophy of brain hemispheres (secondary microcephaly). The case appears to be an example of the late degenerative involution changes developing on the background of lesions originated from the perinatal period.

Skeletal muscle pathology in AIDS: an autopsy study.

A survey of skeletal muscle pathology in 92 autopsied cases of AIDS revealed microscopic alterations in 64 cases. There were 40 cases of disuse atrophy, 8 of denervation atrophy, 2 of cryptococcal myositis, 1 of Mycobacterium avium intracellulare (MAI) infection and 2 of necrotizing myopathy associated with hyperkalemia. A second group of cases with changes of unknown etiology was found. These were tentatively ascribed to the direct or indirect action of HIV. This category includes 8 cases of inflammatory myopathy, 8 of necrotizing myopathy in absence of a known etiological factor, 3 of extreme atrophy and 4 of "regenerating" myopathy.