Neuronal apoptosis in the course of human immunodeficiency virus infection

Apart from the unique changes characteristic of "HIV encephalitis", the productive infection of central nervous system by HIV, which involves predominantly the white matter and basal ganglia, evidence is accumulating that the cerebral cortex may also be affected in AIDS patients. Neuronal loss, suspected at microscopical examination, has been demonstrated by a number of morphometric studies. However, the cause and mechanism of neuronal damage in HIV infection, are still unclear. In an attempt to look for an apoptotic process at the origin of neuronal loss in AIDS, we examined samples of frontal cortex, temporal cortex and basal ganglia from 12 patients who died from AIDS and 4 HIV-positive asymptomatic cases using in situ end labelling to demonstrate characteristic DNA fragmentation. These were compared with 5 seronegative asymptomatic controls, and 2 seronegative patients with Alzheimer's disease. We demonstrated neuronal apoptosis in all the AIDS cases and in the Alzheimer's cases. Positive in situ end labelling was usually associated with morphological changes suggestive of neuronal apoptosis. Semiquantitative appreciation of the density of apoptotic neurons showed that neuronal apoptosis was more severe in atrophic brains. In contrast, no correlation was found between the density of apoptotic neurons and the presence of HIV encephalitis or a history of cognitive disorder. Only occasional apoptotic neurons were found in one asymptomatic, HIV-positive case. Apoptosis was never observed in asymptomatic seronegative cases. Experimental studies tend to support our in vivo findings. Infection by HIV of primary cultures of human embryonic central nervous system induced frequent apoptosis of neurons. No apoptotic cell was identified in non infected control cultures.     

Matching patterns of activity in primate prefrontal area 8a and parietal area 7ip neurons during a spatial working memory task

Single-unit recording studies of posterior parietal neurons have indicated a similarity of neuronal activation to that observed in the dorsolateral prefrontal cortex in relation to performance of delayed saccade tasks. A key issue addressed in the present study is whether the different classes of neuronal activity observed in these tasks are encountered more frequently in one or the other area or otherwise exhibit region-specific properties. The present study is the first to directly compare these patterns of neuronal activity by alternately recording from parietal area 7ip and prefrontal area 8a, under the identical behavioral conditions, within the same hemisphere of two monkeys performing an oculomotor delayed response task. The firing rate of 222 posterior parietal and 235 prefrontal neurons significantly changed during the cue, delay, and/or saccade periods of the task. Neuronal responses in the two areas could be distinguished only by subtle differences in their incidence and timing. Thus neurons responding to the cue appeared earliest and were more frequent among the task-related neurons within parietal cortex, whereas neurons exhibiting delay-period activity accounted for a larger proportion of task-related neurons in prefrontal cortex. Otherwise, the task-related neuronal activities were remarkably similar. Cue period activity in prefrontal and parietal cortex exhibited comparable spatial tuning and temporal duration characteristics, taking the form of phasic, tonic, or combined phasic/tonic excitation in both cortical populations. Neurons in both cortical areas exhibited sustained activity during the delay period with nearly identical spatial tuning. The various patterns of delay-period activity-tonic, increasing or decreasing, alone or in combination with greater activation during cue and/or saccade periods-likewise were distributed to both cortical areas. Finally, similarities in the two populations extended to the proportion and spatial tuning of presaccadic and postsaccadic neuronal activity occurring in relation to the memory-guided saccade. The present findings support and extend evidence for a faithful duplication of receptive field properties and virtually every other dimension of task-related activity observed when parietal and prefrontal cortex are recruited to a common task. This striking similarity attests to the principal that information shared by a prefrontal region and a sensory association area with which it is connected is domain specific and not subject to hierarchical elaboration, as is evident at earlier stages of visuospatial processing.     

Progressive neurodegeneration after intracerebroventricular kainic acid administration in rats: implications for schizophrenia?

BACKGROUND: Intracerebroventricular (ICV) administration of kainic acid to rats produces limbic-cortical neuronal damage that has been compared to the neuropathology of schizophrenia. METHODS: Groups of adult rats were administered ICV kainic acid and then assessed for neuronal loss and the expression of proteins relevant to mechanisms of neuronal damage after one and fourteen days. Neuronal loss was assessed by two-dimensional cell counting and protein expression was assessed by immunohistochemistry. RESULTS: ICV kainic acid administration was associated with both immediate (day 1) and delayed (day 14) neuronal loss in the dorsal hippocampus. The immediate injury was largely limited to the CA3 hippocampal subfield, while the delayed injury included the CA1 subfield. Multiple mechanisms of cell death appeared to be involved in the delayed neuronal loss, as evidenced by changes in the expression of glutamate receptor subunits, heat shock protein and jun protein. CONCLUSIONS: ICV kainic acid administration to adult rats produces progressive damage to limbic-cortical neurons, involving both fast and slow mechanisms of cell death. Given the evidence for clinical deterioration, cognitive deficits and hippocampal neuropathy in some cases of schizophrenia, this animal model may be relevant for hypotheses regarding mechanisms of neurodegeneration in that disorder.     

Remodeling of neuronal circuitries in human temporal lobe epilepsy: increased expression of highly polysialylated neural cell adhesion molecule in the hippocampus and the entorhinal cortex

Neuronal loss and axonal sprouting are the most typical histopathological findings in the hippocampus of patients with drug-refractory temporal lobe epilepsy (TLE). It is under dispute, however, whether remodeling of neuronal circuits is a continuous process or whether it occurs only during epileptogenesis. Also, little is known about the plasticity outside of the hippocampus. We investigated the immunoreactivity of the highly polysialylated neural cell adhesion molecule (PSA-NCAM) in the surgically removed hippocampus and the entorhinal cortex of patients with drug-refractory TLE (n=25) and autopsy controls (n=7). Previous studies have shown that the expression of PSA-NCAM is associated with the induction of synaptic plasticity, neurite outgrowth, neuronal migration, and events requiring remodeling or repair of tissue. In patients with TLE, the optical density (OD) of punctate PSA-NCAM immunoreactivity was increased both in the inner and outer molecular layers of the dentate gyrus, compared with controls. The intensity of PSA-NCAM immunoreactivity in the inner molecular layer correlated with the duration of epilepsy, severity of hippocampal neuronal loss, density of mossy fiber sprouting, and astrogliosis. In TLE patients with only mild neuronal loss in the hippocampus, the density of infragranular immunopositive neurons was increased twofold compared with controls, whereas in TLE patients with severe neuronal loss, the infragranular PSA-NCAM-positive cells were not present. In the hilus, the somata and tortuous dendrites of some surviving neurons were intensely stained in TLE. PSA-NCAM immunoreactivity was also increased in CA1 and in layer II of the rostral entorhinal cortex, where immunopositive neurons were surrounded by PSA-NCAM-positive fibers and puncta. Our data provide evidence that synaptic reorganization is an active process in human drug-refractory TLE. Moreover, remodeling is not limited to the dentate gyrus, but also occurs in the CA1 subfield and the entorhinal cortex.     

(Neurological CPC.55). A 60-year-old woman with progressive cerebellar ataxia, myoclonus, and dementia

We report a 60-year-old woman with progressive ataxia, myoclonus, choreoathetosis, and dementia. She was well until 27 years of the age when she noted an onset of gait disturbance and speech disturbance. She noted abnormal involuntary movements in her four limbs at 42 years of the age. Her symptoms had progressively become worse and she fell down frequently by her 52 years of the age. In addition, her family members noted gradual decline in her intelligence. She was admitted to our hospital in February of 1993 when she was 57-year-old. On admission, she showed dementia, scanning speech, ataxic gait, limb ataxia, action myoclonus, and choreic movements which involved her four limbs. Deep tendon reflexes were slightly exaggerated in the lower limbs; no Babinski sign was noted. Sensation was intact. Laboratory findings were unremarkable. Cerebral MRI revealed atrophy of the cerebellar cortex, superior cerebellar peduncle, brain stem, and the cerebral cortex; the third ventricle and the lateral ventricles were dilated; furthermore, T2-high signal lesions were seen in the cerebral white matter and in the pontine base. Her clinical course was one of the progressive deterioration of her ataxia, involuntary movements, and dementia. She expired on April 24, 1996 when she was 60-year-old. She was discussed in a neurologic CPC and the chief discussant arrived at the conclusion that the patient had dentatorubral-pallidoluysian atrophy. A minor opinion was that she might have had myoclonus epilepsy with ragged-red fibers. Postmortem examination revealed atrophy, gliosis, and neuronal loss in the external segment of the globus pallidus, subthalamic nucleus, red nucleus, and in the dentate nucleus. In addition, the gracil and cuneiform nuclei showed neuronal loss and spheroid formation; the spinocerebellar tracts were retained. The substantia nigra and the locus coeruleus were intact. No ragged-red fibers were seen in the muscle biopsy specimen taken in February, 1993. The neuropathologic findings were consistent with the diagnosis of dentatorubral-pallidoluysian atrophy.     

Pharmacological and second messenger signalling selectivities of cloned P2Y receptors

An autopsy case of a 67-year-old man with typical clinical features of progressive supranuclear palsy (PSP) characterized by impairment of vertical ocular pursuit movement, pseudobulbar palsy, nuchal stiffness, parkinsonism, and dementia is described. In addition to typical pathological changes of PSP, the present case showed fronto-temporal cortical atrophy, accompanied with various Gallyas/tau-positive neuronal and glial structures such as neurofibrillary tangles, pretangle neurons, glial coiled bodies, astrocytic plaques and argyrophilic threads in the cerebral cortex and subcortical nuclei, and many senile plaques throughout the whole cerebral cortex. The present report suggests that PSP and corticobasal degeneration share a common background in neuronal and glial pathologies, that pathological changes of PSP and Alzheimer's disease are mixed in the entorhinal cortex, amygdala. Meynert nucleus, and hypothalamus, and that dementia with frontal lobe-like syndrome in PSP is related to the frontal and temporal cortical pathologies, and is cortical dementia as well as subcortical dementia.     

Possible regeneration of rat medial frontal cortex following neonatal frontal lesions

The experiments described here show that the cavity left by midline frontal cortex removals at 10 days of age (P10) fills in with neural tissue. Similar changes are not found at earlier and later ages. This neuronal filling is blocked by prior pretreatment by administration of Bromodeoxyuridine (BrdU) on embryonic day 13. Administration of BrdU following the P10 lesion does not interfere with regrowth. Subsequent immunohistochemical staining for BrdU demonstrates the regrown area to be composed of newly generated cells. which include pyramidal and nonpyramidal neurons. Injections of a retrograde tracer into the striatum or posterior parietal cortex shows that the new neurons have connections similar to those of undamaged brains. The regrowth of this tissue is correlated with recovery of function in a test of forelimb use. Thus, the mammalian brain, during some privileged postnatal stages of growth. is capable of extensive reorganization that includes regeneration of lost neurons. These results are discussed in relation to the proximity of the lesion to the stem cells in the lateral ventricle and their postnatal migrational activities.     

Pathogenesis of trimethyltin neuronal toxicity. Ultrastructural and cytochemical observations

The ultrastructural cytopathologic and cytochemical effects of trimethyltin (TMT) neurotoxicity were delineated in hippocampal and pyriform neurons of acutely intoxicated adult rats. TMT produced neuronal necrosis that preferentially involved hippocampal formation pyriform cortex. The first subcellular alterations were multifocal collection of dense-cored vesicles and tubules and membrane-delimited vacuoles in the cytoplasm of the perikaryon and proximal dendrite. Ultrastructural cytochemical examination revealed that the vesicles and tubules had acid phosphatase activity analagous to Golgi-associated endoplasmic reticulum (GERL). Shortly after the appearance of the GERL-like vesicles and tubules, autophagic vacuoles and polymorphic dense bodies accumulated in the neuronal cytoplasm. Some dense bodies appeared to arise from the dense-cored tubules. Neuronal necrosis was characterized by increased electron density of the cytoplasm and large, electron-dense intranuclear masses. Alterations of mitochondria and other organelles were not observed in the early stages of cell injury. No light- or electron-microscopic alterations were found in liver or kidney. Comparable subcellular alterations were observed in adult and neonatal rats chronically intoxicated with TMT. A series of other trialkyl and tricyclic tins and dimethyltin did not produce similar pathologic findings. The GERL-like accumulations are unique in neuronal cytopathology. These findings suggests that GERL and autophagy play an important role in the pathogenesis of TMT-induced neuronal injury.     

Evidence of an increasing prevalence of diagnosed diabetes mellitus in the Poole area from 1983 to 1996

Significant progress in understanding and treating acquired immunodeficiency syndrome (AIDS) has been made over the last 5 years. Current multi drug therapies prolong patients' lives and reduce the incidence of neurobehavioural symptoms. However, the impact of therapy on human immunodeficiency virus type one (HIV-1), the causative agent of AIDS, in the brain, is unknown. Some patients develop dementia in spite of the multi drug therapies and others develop subtle neurobehavioural changes that diminish the quality of their prolonged lives. Thus, HIV-1 infection of the central nervous system remains an important clinical concern. Although much is known about neuropathology of HIV-1 infection, major questions about neuropathogenesis remain. How does HIV-1 reach the brain? Is it present in neurons and glial cells? What is the biological and therapeutic significance of neurotropism of HIV-1? What causes neuronal damage and loss? And, is CNS a reservoir of HIV-1? More research in vivo and in situ in humans and in animals, is needed to answer these outstanding questions. Specific experiments addressing these questions are proposed.     

Photoaffinity labeling of peroxisome proliferator binding proteins in rat hepatocytes; dehydroepiandrosterone sulfate- and bezafibrate-binding proteins

Neuronal nitric oxide synthase produces nitric oxide, a radical involved in neurotransmission as well as in cytotoxicity during stroke and neurodegenerative diseases. In the adult Wistar rat neuronal nitric oxide synthase-positive neurons are inhomogenously distributed along defined cortical areas, with highest densities (18 cells/mm2) in cingular area 1, piriform cortex, frontal motor area Fr 2 and in the medial visual association area Oc 2MM. A medium packing density of neuronal nitric oxide synthase neurons (10/mm2) characterizes primary sensory areas, whereas retrosplenial cortices contain lowest cell numbers (3-5/mm2). The data suggest that functions of certain cortical areas are more dependent on intracortically produced nitric oxide than others, and that cortical injury may cause more severe nitric oxide related cytotoxicity in areas with higher numbers of neuronal nitric oxide synthase-positive neurons.     

Progressive atrophy of pyramidal neuron dendrites in autoimmune MRL-lpr mice

The autoimmune-prone MRL-lpr substrain of mice develop an autoimmunity-associated behavioral syndrome (AABS) which resembles in many respects the behavior of animals exposed to chronic stress. The present study examined whether these mice show changes in the morphology of neuronal dendrites, as found in animals exposed to chronic stress. A modified Golgi-Cox procedure was used to visualize the dendrites of pyramidal neurons in the parietal cortex and in the CA1 hippocampal field of 5-week and 14-week old MRL-lpr mice and MRL + / + controls. Reduced dendritic branching and length, and an up to 20% loss of dendritic spines were observed in parietal and hippocampal pyramidal neurons of MRL-lpr mice at both ages. In the parietal cortex, there was an age-dependent potentiation in the reduction of basilar, but not apical, dendrite branching and length, as well as in the loss of spines on basilar segments. Loss of spines in the hippocampus followed an age-related course for apical but not basilar dendrites. Moreover, compared to age-matched controls, brain weight was smaller in MRL-lpr mice at 14 but not 5 weeks of age. Considering that dendritic atrophy becomes more extensive when autoimmune disease is florid in MRL-lpr mice, it is proposed that immune/inflammatory factor(s) produce dendritic loss. Reduced dendritic complexity may represent, at least in part, a structural basis for the altered behavioral profile of MRL-lpr mice.     

Quantitative distribution of parvalbumin, calretinin, and calbindin D-28k immunoreactive neurons in the visual cortex of normal and Alzheimer cases

The distribution of parvalbumin (PV), calretinin (CR), and calbindin (CB) immunoreactive neurons was studied with the help of an image analysis system (Vidas/Zeiss) in the primary visual area 17 and associative area 18 (Brodmann) of Alzheimer and control brains. In neither of these areas was there a significant difference between Alzheimer and control groups in the mean number of PV, CR, or CB immunoreactive neuronal profiles, counted in a cortical column going from pia to white matter. Significant differences in the mean densities (numbers per square millimeter of cortex) of PV, CR, and CB immunoreactive neuronal profiles were not observed either between groups or areas, but only between superficial, middle, and deep layers within areas 17 and 18. The optical density of the immunoreactive neuropil was also similar in Alzheimer and controls, correlating with the numerical density of immunoreactive profiles in superficial, middle, and deep layers. The frequency distribution of neuronal areas indicated significant differences between PV, CR, and CB immunoreactive neuronal profiles in both areas 17 and 18, with more large PV than CR and CB positive profiles. There were also significantly more small and less large PV and CR immunoreactive neuronal profiles in Alzheimer than in controls. Our data show that, although the brain pathology is moderate to severe, there is no prominent decrease of PV, CR and CB positive neurons in the visual cortex of Alzheimer brains, but only selective changes in neuronal perikarya.     

Strategies for graft immunomodulation in islet transplantation

BACKGROUND: The cortex of patients with schizophrenia exhibits a deficit in neuropil, but the nature and extent of cellular abnormalities remain unclear. To gain further insight into this abnormality, neuronal and glial somal size were analyzed in postmortem brains from 9 patients with schizophrenia, 10 normal (control) patients, and 7 patients with Huntington disease, the latter representing a known neurodegenerative disorder. METHODS: A 3-dimensional image analyzer was used to measure the perimeters of 10722 neuronal and 19913 glial profiles in Brodmann areas 9 and 17. Neurons and glia were classified by size and layer to assess specific vulnerabilities with respect to cortical architecture and circuitry. RESULTS: The schizophrenic prefrontal cortex was characterized by a downward shift in neuronal sizes accompanied by 70% to 140% per layer increases in the density of small neurons. In layer III only, a significant reduction in mean neuronal size was associated with a significant decrease in the density of very large neurons in sublayer Illc. Neither neuronal size in occipital area 17 nor glial size in prefrontal or occipital cortexes were reduced. In cortex with Huntington disease, neuronal degeneration was evidenced by concurrence of reduced neuronal size, decreased density of large neurons, and dramatic elevation in density of large glia. CONCLUSIONS: Distinct cytometric abnormalities support the hypothesis that neuronal degeneration in the prefrontal cortex is not a prominent feature of the neuropathological changes in schizophrenia, although an ongoing process in Huntington disease. Rather, schizophrenia appears to involve more subtle abnormalities, with the largest corticocortical projection neurons of layer IIIc expressing the greatest somal reduction.     

A histochemical examination of the staining of kainate-induced neuronal degeneration by anionic dyes

Anionic dyes, notably acid fuchsine, strongly stain the nuclei and cytoplasm of neurons severely damaged by injury or disease. We provide detailed instructions for staining nervous tissue with toluidine blue and acid fuchsine for optimal demonstration of injured neurons. Degeneration was induced in the hippocampus of the mouse by systemic administration of kainic acid, and the resulting acidophilia was investigated using paraffin sections of the Carnoy- or Bouin-fixed brains. The affected cells were bright red with the toluidine blue-acid fuchsine sequence. Their nuclei were stainable also with alkaline Biebrich scarlet and with the 1,2-naphthoquinone-4-sulfonic acid-Ba(OH)2 method; all staining was blocked by benzil but was relatively refractory to deamination by HNO2. These properties indicated an arginine-rich protein. The nuclei were strongly acidophilic in the presence of a high concentration of DNA (strong Feulgen reaction), and acidophilia could not be induced in normal neuronal nuclei by chemical extraction of nucleic acids. The cytoplasmic acidophilia of degenerating hippocampal neurons was due to a protein rich in lysine (extinguished by alkalinity, easily prevented by deamination, and unaffected by benzil). Stainable RNA was absent from the perikarya of the affected cells, but normal neuronal cytoplasm did not become acidophilic after extraction of nucleic acids. We suggest that kainate-induced cell death is preceded by increased production of basic proteins, which become concentrated in the nucleus and perikaryon. Groups of small, darkly staining neurons were seen in the cerebral cortex in control and kainate-treated mice. These shrunken cells were purple with the toluidine blue-acid fuchsine stain, and were attributed to local injury incurred during removal of the unfixed brain.     

The mechanism of movement instrumental learning in a Hopfield environment in the feline motor cortex

A model of the neuronal processes in the motor cortex is proposed, which provides the mechanism for instrumentalization (voluntary reproduction) of movements primarily evoked by stimulation of the parietal cortex. The main propositions of the model are as follows: the late NMDA-dependent response of the motor cortex neurons to stimulation of the parietal cortex reflects the discharges in the recurrent collaterals of the pyramidal cell axons; learning processes in the motor cortex are based on the long-term potentiation of the efficiency of the recurrent collaterals; the Hopfield's theory of neuronal nets is applied to the processes of motor learning in the cortex. The movement instrumentalization is viewed as the stable state formation in the collaterally linked neuronal structure; the voluntary reproduction of the previously learned movement in considered as the process of transition of the neuronal structure into the stable state. The data on acetylcholine and dopamine modulatory influences on the reactions of motor cortex neurons are discussed.     

Differential use of immunoglobulin light chain genes and B lymphocyte expansion at sites of disease in rheumatoid arthritis (RA) compared with circulating B lymphocytes

Patients infected with HIV-1 often exhibit cognitive deficits that are related to progressive neuronal degeneration and cell death. The protein Tat, which is released from HIV-1-infected cells, was recently shown to be toxic toward cultured neurons. We now report that Tat induces apoptosis in cultured embryonic rat hippocampal neurons. Tat induced caspase activation, and the caspase inhibitor zVAD-fmk prevented Tat-induced neuronal death. Tat induced a progressive elevation of cytoplasmic-free calcium levels, which was followed by mitochondrial calcium uptake and generation of mitochondrial-reactive oxygen species (ROS). The intracellular calcium chelator BAPTA-AM and the inhibitor of mitochondrial calcium uptake ruthenium red protected neurons against Tat-induced apoptosis. zVAD-fmk suppressed Tat-induced increases of cytoplasmic calcium levels and mitochondrial ROS accumulation, indicating roles for caspases in the perturbed calcium homeostasis and oxidative stress induced by Tat. An inhibitor of nitric oxide synthase, and the peroxynitrite scavenger uric acid, protected neurons against Tat-induced apoptosis, indicating requirements for nitric oxide production and peroxynitrite formation in the cell death process. Finally, Tat caused a delayed and progressive mitochondrial membrane depolarization, and cyclosporin A prevented Tat-induced apoptosis, suggesting an important role for mitochondrial membrane permeability transition in Tat-induced apoptosis. Collectively, our data demonstrate that Tat can induce neuronal apoptosis by a mechanism involving disruption of calcium homeostasis, caspase activation, and mitochondrial calcium uptake and ROS accumulation. Agents that interupt this apoptotic cascade may prove beneficial in preventing neuronal degeneration and associated dementia in AIDS patients.     

Optic flow processing in monkey STS: a theoretical and experimental approach

How does the brain process visual information about self-motion? In monkey cortex, the analysis of visual motion is performed by successive areas specialized in different aspects of motion processing. Whereas neurons in the middle temporal (MT) area are direction-selective for local motion, neurons in the medial superior temporal (MST) area respond to motion patterns. A neural network model attempts to link these properties to the psychophysics of human heading detection from optic flow. It proposes that populations of neurons represent specific directions of heading. We quantitatively compared single-unit recordings in area MST with single-neuron simulations in this model. Predictions were derived from simulations and subsequently tested in recorded neurons. Neuronal activities depended on the position of the singular point in the optic flow. Best responses to opposing motions occurred for opposite locations of the singular point in the visual field. Excitation by one type of motion is paired with inhibition by the opposite motion. Activity maxima often occur for peripheral singular points. The averaged recorded shape of the response modulations is sigmoidal, which is in agreement with model predictions. We also tested whether the activity of the neuronal population in MST can represent the directions of heading in our stimuli. A simple least-mean-square minimization could retrieve the direction of heading from the neuronal activities with a precision of 4.3 degrees. Our results show good agreement between the proposed model and the neuronal responses in area MST and further support the hypothesis that area MST is involved in visual navigation.     

Preliminary technique of laparoscopic extraperitoneal infrarenal paraaortic lymphadenectomy in the porcine model

The prevalence of Parkinson's disease (PD) is higher in whites than in nonwhites and it increases with advancing age. The pathological hallmarks of PD are loss of pigmented neurons in the substantia nigra pars compacta (SNpc) and presence of Lewy bodies. With increasing age, a similar loss of pigmented neurons in the SNpc has been reported. Hence, age and race possibly play a role in the pathogenesis of PD. The objectives of this study were to count the number of melanized neurons in the SNpc in normal human brains from India and study the change in neuronal count with advancing age and to compare the neuronal counts from this Indian population with counts reported in normal brains from the United Kingdom. Melanized neurons in the SNpc were counted in 84 normal human brains (age range, 5-84 years) in a single 7-microm section at the level of emergence of the oculomotor nerve. In the brains from India, there was no loss of melanized nigral neurons with advancing age. The absolute number of these melanized neurons was about 40% lower than the brains from UK. Despite a low number of melanized nigral neurons in the brains from India, individuals function normally and have dopamine levels comparable with their Western counterparts, suggesting that it is not the absolute number of melanized nigral neurons but the percent loss of nigral neurons that results in dopaminergic deficiency in PD. There is no significant loss of pigmented nigral neurons with age, suggesting that the loss seen in PD is exclusively due to the disease process itself. Indians have a lower prevalence of PD despite having a low count of melanized nigral neurons, suggesting that better protective mechanisms may be present in the Indians to prevent the loss of nigral neurons.     

Fibrin sealant: scientific rationale, production methods, properties, and current clinical use

Morphological analysis of the brains from 100 cases of full blown AIDS patients observed in the course of 1987-1995 years was performed. The material comprised 96 males, 3 females and 1 infant, 11 months old. Early material consisted almost exclusively of homo- and bisexuals, while in the last years heterosexual drug addicts prevailed. Gross brain examination revealed focal changes in 25% of cases, most of them being connected either with opportunistic infections or primary proliferating malignancies. Brain atrophy with an evident regional differences was observed macroscopically in 35 cases. Microscopic examination allowed detection of pathological changes in the brains of 87 cases, although in the remaining 13 cases there occurred some slight abnormalities taking the form of non-specific neuronal degeneration and loss, considered as resulting from perimortal cardio-pulmonary insufficiency or bleeding. Specific HIV-related changes in the form of HIV-encephalitis, HIV-encephalopathy or coexistence of both and HIV-leptomeningitis as well as HIV-vasculitis were present in 35 cases. They were accompanied by HIV-associated changes (vacuolar myelopathy, vacuolar leukoencephalopathy and selective poliodystrophy). Very seldom they appeared as independent pathological features and were characterized by very low frequency. Opportunistic infections composed the largest group of 59 cases. Proliferative malignancies occurred altogether in eleven cases, 10 of which were primary and secondary brain lymphomas. One case of Kaposi sarcoma completed the neoplastic series. Sixteen cases revealed various types of brain pathology such as hepatogenic encephalopathy, traumatic cortical scars, central pontine myelinolysis etc. The 59 cases of opportunistic infections consisted of a wide spectrum of viral and bacterial as well as fungal and protozoan infections. Among viral infections cytomegalovirus encephalitis was the most common, way ahead the progressive multifocal leukoencephalopathy. The second in frequency among opportunistic infections was brain toxoplasmosis and some fungal infections such as cryptococcosis and aspergillosis. Bacterial infections were in fact limited to tuberculosis, taking the form of granulomatous leptomeningitis with severe vascular pathology and/or tuberculoma formation. Many pathological processes appearing in a single case was characteristic feature of our collection. There was coexistence of HIV-specific CNS pathology and opportunistic infections, malignant neoplastic growth and other types of pathology. Various opportunistic infections coexisted without HIV-specific changes as well as malignant proliferation with opportunistic infections. Similarities and differences of our series were compared with data characterizing other, earlier collections of NeuroAIDS.     

Hereditary form of parkinsonism--dementia

In four generations of a family, 13 members were afflicted with an autosomal dominant disorder characterized by young age at onset, early weight loss, and rapidly progressive dopa-responsive parkinsonism, followed later by dementia and, in some, by hypotension. Intellectual dysfunction began with subjective memory loss and objective visuospatial dysfunction and was followed later by decline of frontal lobe cognitive and memory functions. Neuropathological examination in 4 autopsied cases showed neuronal loss in the substantia nigra and locus ceruleus and widespread Lewy bodies, many of them in the cerebral cortex; those in the hypothalamus and locus ceruleus were often of bizarre shapes. Other findings were vacuolation of the temporal cortex, unusual neuronal loss and gliosis in the hippocampus (CA 2/3), and neuronal loss in the nucleus basalis. There were no neuritic plaques, neurofibrillary tangles, or amyloid deposits. Positron emission tomography in 3 patients showed decreased striatal uptake of fluorodopa. Neurochemical analysis of an autopsied brain showed a pronounced decrease in choline acetyltransferase activity in the frontal and temporal cortices and hippocampus and a severe depletion of striatal dopamine with a pattern not typical of classic Parkinson's disease.