Showing papers in "Folia Neuropathologica in 2004"

Oxidative damage to proteins in the spinal cord in amyotrophic lateral sclerosis (ALS).

Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, which has been linked to the generation of free radicals and oxidative stress. Oxidative damage to spinal cord proteins is suggested to be a contributory factor to neuronal death in ALS. Since proteins are the major targets for free radicals and the so-called "reactive species", therefore the objective of our study was to identify oxidatively damaged spinal cord proteins. The material consisted of spinal cords of 8 sporadic ALS cases and 5 controls. We estimated the level of protein carbonyl moieties, which react quantitatively with 2,4-dinitrophenylhydrazine (DNPH). Afterwards proteins were separated by SDS-polyacrylamide gel electrophoresis and the protein bound DNPH moieties were detected immunochemically. We also morphologically examined spinal cords after immune staining against DNPH. The protein carbonyl content of the ALS spinal cords significantly increased in all examined cases. In most ALS patients, proteins with 125 kDa, 70 kDa and 36kDa were highly oxidized. The 70-kDa protein was identified immunochemically to be neurofilament 68. The morphological examination of ALS spinal cords indicated a pronounced anti-DNPH immune reaction in neurones of the anterior horns; the reaction in the posterior horns was less intense. Microglia in the white matter was immunoreactive; astroglia was DNPH-negative. Although the exact mechanism by which reactive oxygen species induce motor neurones to die is not known yet, the presented data indicate that they affect spinal cord cellular proteins, including neurofilament 68. In this study, we successfully examined the neurochemical features accompanying motor neuron injury in ALS, and the results may help to develop a rationale anti-oxidative neuroprotective strategy.

Degeneration of microglial cells in frontal and temporal lobes of chronic schizophrenics.

Abstract: Schizophrenia is a social disease that occurs in 0.5-1% of the population. It shows a high variability in both clinical picture and theory of its pathogenesis. Its clinical manifestations are accompanied by biochemical, immunological and structural changes. A pivotal role in the development of psychotic disorders is attributed to the impaired limbic system. The aim of this study was to find out whether, and if so, to what extent immunocompetent cells of the central nervous system (microglia) are involved in the process of degeneration occuring in these structures. The study was carried out on 12 brains of female chronic schizophrenics. Sections of frontal and temporal cortex were subjected to ultrastructural as well as histochemical and immunohistochemical examinations by light microscopy. In the structures under study, a large number of ramified microglial cells showing on their surface the expression of the major histocompatibility complex class II (MHC II) was observed. Most cells showed degenerative traits (cytoplasm shrinkage, thinning, shortening and fragmentation of their processes) up to apoptotic changes. Perivascular microglia displayed the lowest intensity of degenerative changes. Ultrastructurally, some damaged microglial cells contained phagosomes and/or degenerated mitochondria. Most abnormal microglia showed morphological signs of the former normal function of immunocompetent and phagocytosing cells. Degeneration of microgial cells, resulting most likely from the primary impairment of the neuron-glia communication that damages their immunocompetent function, may lead to the exacerbation of structural damage and psychotic symptoms. Treatment of chronic schizophrenics should involve the supply of agents to prevent degeneration of microglia and/or long-term immunotherapy.

Limbic neuropathology in idiopathic Parkinson's disease with concomitant dementia.

Abstract: To study pathological background of dementia in idiopathic Parkinson’s disease (PD), 41 autopsy brains (31 cases with and 10 cases without dementia) were investigated The severity of degenerative changes was evaluated in selected limbic regions (trans- and entorhinal cortex, hippocampus, and amygdala) The densities of Lewy bodies (LBs), Lewy neurites (LNs), neurofibrillary tangles (NFTs), and amyloid neuritic plaques (NPs) were determined on immunohistochemically stained sections using antibodies against α-synuclein, tau-protein, and amyloid-β Precisely defined modern criteria for selecting study cohort (Newcastle, CERAD and Braak et al) ensured homogeneity of the study sample and reliability of the results Comparisons between the cases of Parkinson’s disease with dementia (PDD) and those without (PD-only) revealed that the former were characterised by significantly higher densities of LBs and LNs in transentorhinal and entorhinal cortices as well as in the CA2–3 region of the hippocampus and cortical complex of amygdala In the PDD sub-set we found statistically significant correlation of LBs with LNs counts in CA2–3 region of hippocampus as well as of LBs counts in transentorhinal cortex with LNs counts in CA2–3 hippocampal region The relationship was also observed between LBs counts in CA2–3 region of the hippocampus and LNs counts in cortical complex of amygdala Our studies suggest that dementia in PD may be associated with the presence of degenerative changes of PD-type in leading limbic structures, without co-existent Alzheimer’s disease (AD) They also imply that LBs and LNs may appear to be morphological hallmarks of the pathological process associated with dementia in PD LBs and LNs distribution pattern and correlations of LBs with LNs counts in limbic regions observed in our study suggest the cumulative patomechanism of changes dependent on transsynaptic α-syn pathology and indicate the spread of the pathological process via axonal transport The coexistence of the small number of changes of AD-type may exacerbate cognitive deficits in PDD

The concentration of thyroid hormones and activities of iodothyronine deiodinases are altered in human brain gliomas.

Abstract: We have determined the cellular concentration of thyroxine (T4) and triiodothyronine (T3) and the activities of two brain iodothyronine deiodinases, type II (5’-D2) and type III (5-D3), in two types of tissues — tumour (26) and non-tumour (5), derived either from human gliomas with various histological malignancies or from non-tumoural surrounding brain tissue. As it has been established, all patients before the surgery had the Non-Thyroidal Illness Syndrome (NTIS). The concentration of serum T3 was therefore significantly decreased in all the examined patients. It was over 2.5 times lower than that before surgery and 4.0 times lower at surgery than that seen in healthy controls. The serum concentration of T4 was found to be below normal range in 4/26 cases and in low levels of normal range in 6/26 cases, whereas TSH serum concentration in all patients was within normal range. The concentrations of T3 and T4 (expressed as pg of hormone/mg tissues protein) in 22/26 brain tissue samples were significantly lower in gliomas than in 5 non-tumoural brain tissue samples. As expected, the alternation in brain 5’D II activity in gliomas was seen in most cases with astrocytomas (5/8 cases), gliosarcomas (8/8 cases) and glioblastoma multiforme (10/10 cases). In general, the mean enzyme activity in tumour tissue was significantly higher than that found in non-tumoural tissue of human brain (21.79 fmol of newly generated T3/h/mg of protein vs. 4.88 fmol of T3/h/mg protein, respectively). The highest 5’D2 activity with a range from 10.82 to 45.96 (mean 23.61 fmol T3/h/mg protein) was found in gliosarcomas. The activity of 5-D3 was increased (in 8/8 cases of gliosarcoma and in 9/10 cases of glioblastoma multiforme) or decreased (in 3/3 cases of astrocytoma II, 5/5 cases of astrocytoma III) when compared to mean activity of this enzyme found in non-tumoural brain tissue. In summary, our results suggest that the concentration of brain iodothyronines and metabolism of thyroid hormones in the examined human brain tumours are altered. These changes may be related to malignant progression.

Toll-like receptors in rat brains injured by hypoxic-ischaemia or exposed to staphylococcal alpha-toxin.

Abstract: Some data suggest that the central nervous system (CNS) is the main target of Staphylococcus alpha-toxin. Since this pathogen cannot penetrate the blood-brain barrier (BBB), the exact mechanism by which alphatoxin affects the CNS remains unclear. Recent studies on the role of the innate immune system have shed light on how bacterial infections initiate inflammatory responses within the CNS. The aim of this study was to investigate the immunoexpression of Toll-like receptors (TLR 2, TLR 4) in brains of young rats systemically exposed to Staphylococcus alpha-toxin or injured by neonatal hypoxia-ischaemia. The study was carried out on 6-week-old Wistar rats. A group of 6-week-old rats with severe brain injury caused by neonatal hypoxia-ischaemia was also studied separately. In all control rats, the immunoexpression of TLR 2 and TLR 4 was not detected. However, the expression of both TLRs was evident in all brains injured by HI or exposed to alpha-toxin. The immunoexpression was localised in the wall of the small brain vessels, cells of ependyma and leptomeninges. In such vessels the spectrum of ultrastructural lesions was found. The presence of TLR4 detected in the nerve cells of the subcortical gray matter of the brain is particularly of interest, but requires further studies. The presence of TLR 4 antigen in the nerve cells of the subcortical gray matter is particularly of interest. In conclusion, the results show that brain microvessels through TLRs may participate in the immune response of brain affected by bacterial infection as well as injured by non-infection insults.

An outline of the neuropathology of transmissible spongiform encephalopathies (prion diseases).

Abstract: We review here the basic neuropathology of transmissible spongiform encephalopathies (TSE) or prion diseases. The classic hallmark of TSE neuropathology is a combination (in different proportions in different diseases) of spongiform change, astrocytosis, neuronal loss and amyloid plaques. Immunohistochemically, accumulation of the abnormal isoform of prion protein (PrPSc or PrPd) is regarded as adiagnostic for TSE. We also review the peculiarities of kuru, variant Creutzfeldt-Jakob disease and Gerstmann-Straussler- -Scheinker disease.

Spongiform change--an electron microscopic view.

Abstract: The distribution of the somatostatin was studied by immunohistochemistry on serial sections of the 56 brain stems from subjects aged from 30 gestational weeks to 12 postnatal months, dying of both known and unknown causes. The unexplained deaths included 13 sudden intrauterine deaths, 4 sudden neonatal deaths and 24 sudden infant deaths. We observed intense somatostatin positivity in the cell bodies and fibres of many brainstem nuclei prevalently involved in the respiratory activity (parabrachial/Kolliker-Fuse complex, locus coeruleus, hypoglossus nucleus, dorsal vagus motor nucleus, tractus solitarii nucleus, ambiguus nucleus, and reticular formation) in stillbirths. Only in 8 foetuses with unexplained death the hypoglossus nucleus was somatostatin-negative. In the postnatal deaths, the immunopositivity was prevalently limited to the ventrolateral and ventral subnuclei of the tractus solitarii nucleus. In 13 sudden infant death victims and in one case of death due to pneumonia, somatostatin-positivity was also present in the hypoglossus nucleus. We concluded that: 1) the somatostatin is an important foetal breathing-inhibitor, but it becomes important for the physiological control of respiration immediately after delivery; 2) functional alterations of the hypoglossal nucleus can occur in both sudden perinatal and infant deaths and contribute to the induction of both fatal breathing movements in foetuses and abnormal ventilatory control in infants leading to irreversible apneic phenomena.

Bovine spongiform encephalopathy (BSE): the end of the beginning or the beginning of the end?

Abstract: Bovine spongiform encephalopathy (BSE) is a zoonosis being the origin of variant Creutzfeldt-Jakob disease and an important cattle disease in its own right. This association has driven both the research into the disease and extensive epidemiological investigations of practical value. Not only has the occurrence of BSE has a serious effect on animal health and public health, it has also seriously interrupted trade in cattle and cattle products from affected countries. Since 2001, several additional European countries, Japan, Israel and Canada have reported BSE in native-born stock and this has led to a concern about the BSE status of countries that have imported cattle and cattle products from any affected country. A single case recently reported in the USA was in a cow imported from Canada, thus extending the risk of BSE occurrence into the North American continent as a whole. Extensive feed and offal bans have protected the food and feed chains in all countries with BSE, even though initially they tended to be leaky. Application of newly-developed, approved ‘Rapid’ tests for misfolded PrP in central nervous tissue of targeted, high-risk animals and slaughter cattle now provides the tools whereby the real incidence of the disease (and to a degree, infection) can be determined in an active surveillance programme. ’Rapid’ testing also enables the progress of epidemics to be monitored in response to applied measures. In the EU, over 10 million cattle are tested annually. Analysis of the extensive data shows that it is the beginning of the end of the BSE epidemic in the UK; most European countries, Israel and Japan are close behind. The epidemic in North America (two cases to date) is at the beginning. Significant measures had already been adopted there to reduce the risk from recycling of infection via feed but it remains to be seen if they are watertight. Advice has been given to ensure that public health is protected and to monitor the epidemic by strategic use of approved ‘Rapid’ tests to determine that the epidemic is in fact trivial as believed, or otherwise to identify weaknesses in measures that can be corrected. It is imperative that all countries conduct risk assessments for BSE, follow the OIE recommendations and do not unreasonably disrupt international trade. There is a responsibility for all countries with BSE to ensure that infection is not exported to any country, particularly through live cattle and especially via meat-and-bone-meal, which is the acknowledged vehicle of transmission. There is also a responsibility placed upon all countries to protect, not only their cattle populations, but also their human populations from exposure to this economically important fatal disease. If all the advice is taken and measures enforced there is a prospect that BSE can be eliminated from countries and regions as a prelude to eradication from the world.

Review: pathology of variant Creutzfeldt-Jakob disease.

Abstract: Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease that results from exposure to the bovine spongiform encephalopathy (BSE) agent, probably by the oral route. The pathological features of vCJD are unique, with extensive involvement of lymphoid tissues in addition to the central nervous system. This article reviews the histopathology and biochemistry of vCJD, emphasising diagnostic features and indicating several areas of active research. The widespread distribution of infectivity in lymphoid tissues in vCJD has lead to concerns over the possibility of iatrogenic disease transmission by contaminate surgical instruments, or by blood transfusion. vCJD has so far only occurred in individuals within a genetic subset defined by the natural polymorphism at codon 129 in the prion protein gene. It remains uncertain if this disease will occur in other genetic subgroups within the population. Continuing surveillance of vCJD in the UK and other countries in which BSE has been identified will be necessary for future estimations of disease numbers worldwide.

Alzheimer lesions after ischemia-reperfusion brain injury.

Abstract: For now the best-established and accepted theory in Alzheimer’s disease (AD) etiology by most scientists is the "amyloid theory", as the main molecular factor of neurodegeneration in AD. We critically review these observations and highlight inconsistencies between the predictions of the "amyloid hypothesis" and the published data. The research of neurobiology of AD, now more than ever, needs an infusion of new concepts. Handful researchers now recognize brain ischemia as a prominent feature in AD and a potential target for therapy aimed at treatment and prevention of disease. The "ischemia-reperfusion theory" was primarily aimed at stimulating study and redirecting the focus of investigations towards ischemic cellular mechanisms of AD. To accommodate the recent progress of study in AD there is a need to synthesize all the divergent pieces of data into a coherent story. This review provides a synopsis of current information about ischemic cellular and molecular mediators involved in Alzheimer’s neuropathology as well as interactions between these mediators that influence pathology. In this paper, current knowledge on the close relation between vascular disease factors and Alzheimer’s type dementia will be reviewed. We will summarize the data with a special focus on Alzheimer lesions in experimental brain ischemia. Taken all together, evidence presented in this review suggests a scheme for Alzheimer’s pathogenesis with ischemia playing a crucial role in influencing and linking β-amyloid deposition to neuronal damage and clinical disease.

Gerstmann-Sträussler-Scheinker disease. I. Human diseases.

Abstract: Gerstmann-Straussler-Scheinker disease (GSS) is a slowly progressive hereditary autosomal dominant disease (OMIM: 137440) and the first human transmissible spongiform encephalopathy (TSE) in which a mutation in a gene encoding for prion protein (PrP) was discovered. Its true prevalence is difficult to estimate but figures within the range of 1-10/100,000,000 are quoted. GSS is defined as a neurodegenerative disease "in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multi-centric PrP plaques". In this review, we summarise data on all the families with GSS. The hallmark of the GSS neuropathology is the multi-centric plaque but the pattern varies between families. In the second part of this review the experimental data using experimental models of GSS in transgenic mice are summarised as well as structural biology of mutated PrP in GSS.

Contribution of neuropathology to the understanding of human prion disease.

Abstract: Neuropathology is an important tool for definitive diagnosis of sporadic, genetic, and acquired prion disease. Classical neuropathological hallmark is the highly disease-specific spongiform change accompanied by neuronal loss, astro- and microgliosis. Spongiform change of the neuropil consists of either microcystic or confluent vacuoles and varies greatly within the same brain. In addition, the most important aspect of confirmatory diagnosis is the demonstration of disease-associated prion protein (PrPd) by immunohistochemistry or Western blotting. Different PrPd immunostaining patterns include patchy/perivacuolar surrounding spongiform change, diffuse/synaptic, perineuronal, or plaque type. The latter includes unicentric kurutype plaques or multicentric plaques as in the peculiar genetic prion disorder, Gerstmann-Straussler-Scheinker disease. PrPd immunostaining patterns correlate well with phenotypes defined by the polymorphic codon 129 and the type of protease resistant PrPd seen on Western blots. PrPd immunoreactivity in the cerebellum may be highly informative about disease subtypes. Although the central nervous system is the major site of PrPd accumulation, it may also be observed in peripheral nerves as adaxonal deposits; in skeletal muscle as granular immunoreactivity in particular in abundance in a unique instance of concomitant Creutzfeldt-Jakob disease and inclusion body myositis; as well as associated with dendritic cells and macrophages in vessel walls. A subset of inhibitory GABAergic neurons is selectively affected in experimental and human prion disease. The central pathogenetic cascade includes oxidative stress and apoptosis. Deposition of terminal complement components on neurons accompanies tissue damage.

Amyloid plaques in transmissible spongiform encephalopathies (prion diseases).

Abstract: Amyloid plaques are encountered in all cases of kuru and Gerstmann-Straussler-Scheinker disease (GSS) and in some 10-15% of sporadic Creutzfeldt-Jakob disease (sCJD) cases. In variant Creutzfeldt-Jakob (vCJD) the particular type of plaque known as "florid" or "daisy" plaque exists in 100% of cases. By electron microscopy several types of amyloid plaque were delineated, corresponding to those seen by PrP immunohistochemistry. Unicentric "kuru" plaques consisted of stellate arrangements (stars or cores) of amyloid bundles emanating from a dense interwoven centre. A proportion of kuru plaques formed very dense stars, reminiscent of sea urchins in shape. Others presented a looser pattern. Amyloid stars were enveloped by astrocytic processes. High-power electron micrographs revealed that amyloid bundles were concealed within grooves of obscure cellular origin. Interestingly, basement membranes lined with electron-dense material were observed at the periphery of many amyloid plaques of GSS. Dystrophic neurites were seen only rarely. Microglial cells formed a significant part of the amyloid plaques. Occasionally clusters composed of several kuru plaques were found. These were intermediate forms to multi-centric plaques, which consisted of several merging stellate cores. Smaller amyloid deposits surrounded larger cores. In contrast to the kuru plaques, associated with a limited number of dystrophic neurites (DN), numerous such structures were seen at the periphery. The DN were filled with abnormal organelles such as electron-dense bodies, multi-vesicular bodies and multilamellar bodies and thus were indistinguishable from those seen in scrapie and CJD or Alzheimer's disease, except that they did not contain paired helical filaments (PHF). Instead, piled neurofilaments were often detected in the centres of DN. Similar DN were observed but these were not associated with any plaques. The last and, by the same token, the rarest type of plaque was the purely neuritic plaque. These consisted of large areas filled with DN of different sizes and shapes (sometimes bizarre) but not amyloid bundles. Analogously to the kuru and multi-centric plaques, astrocytic processes were observed at the periphery. By means of light microscopy and semi-thin (1 microm) sections discrete PrP-immunopositive plaques were observed (data not shown), in the subependymal region but not in the deep brain neuroparenchyma, in both 263K and 22C-H scrapie-infected hamster brains. These plaques were not discernible by routine haematoxylin and eosin staining. Ultrastructurally, plaques were recognised as areas of low electron density containing haphazardly-oriented fibrils which, when immunogold techniques were applied, were heavily decorated with PrP-conjugated gold particles.

Astrocytes in transmissible spongiform encephalopathies (prion diseases).

Abstract: Astrocytosis is one of the hallmarks of neuropathology of transmissible spongiform encephalopathies (TSEs) or prion diseases. In this review, we summarize data on astrocytic reaction, including naturally occurring or experimentally induced TSEs. A particular form of astrocytic reaction is known as gliocytosis and it is typical for experimental scrapie in mouse or in hamsters. Also, astrocytes participate in the formation of amyloid plaques. An interesting interaction between astrocytes and oligodendrocytes is discussed in detail as well as a particular form of astrocytic reaction in panencephalopathic form of TSEs.

Peripheral nerve tumours--diagnostic and therapeutical basics.

Abstract: In this review of international literature, we have described recent opinions on diagnostics and therapy of peripheral nerve tumours We have emphasised the use of differential diagnostics on certain stages of therapeutic procedures The importance of proper surgical technique choice and its influence on final results have been especially underlined Other important factors influencing final therapeutical results have also been considered and discussed

Adrenal Schwannoma. Report of two cases.

Abstract: Adrenal tumours are frequently incidental discoveries, and their therapy is a subject of controversial discussions. Herein we describe two cases of adrenal schwannoma discovered during autopsy. The accidental observation of two benign schwannomas of the adrenal gland on asymptomatic patients led to the hypothesis that the real frequency of this type of lesion was underestimated. Furthermore, the adrenal origin of the superior retro-peritoneum schwannomas represents a diagnostic hypothesis to be considered when the original structure of the neoplasia can't be established.

Molecular approaches to mechanisms of prion diseases.

Abstract: Prion diseases such as scrapie in sheep, bovine spongiform encephalopathy in cattle, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease and fatal familial insomnia in man are neurodegenerative disorders. In humans, the diseases can be sporadic, inherited, or acquired by infection. The underlying pathogenic event in prion diseases is a conformational modification of the cellular isoform prion protein (PrP(C)) to the pathogenic isoform (PrP(SC)) that accumulates in the central nervous system. However, in humans, in some inherited cases the pathological PrP is not PrP(Sc), but a transmembrane form of prion protein, (Ctm)PrP. Prion protein is encoded by the cellular gene, PRNP, which has been mapped to human chromosome 20p21. Familial prion diseases are thought to result from a change in structure of the prion protein produced by the mutated PRNP gene. Furthermore, polymorphic codon 129 of the PRNP gene encodes either methionine or valine and appears to influence the susceptibility of patients to iatrogenic and sporadic CJD as well as the neuropathological phenotype in these forms of CJD. Polymorphisms in the promoter region of PRNP gene or disturbances in prion protein metabolism, such as incorrect activity of cellular chaperones or proteasomes are considered as susceptibility factors in human prion diseases.

Ultrastructural evaluation of activated forms of microglia in human brain in selected neurological diseases (SSPE, Wilson's disease and Alzheimer's disease).

Abstract: Activated forms of microglia were ultrastructurally evaluated in three neurological diseases of different aetiology (subacute sclerosing panencephalitis--SSPE, Wilson's disease and Alzheimer's disease). The occurrence of activated rod, ramified and amoeboid microglia was found in the investigated diseases. The widest ultrastructural variability of microglia was in SSPE, including the presence of mitotic chromosomes or centrioles in its cytoplasm, which indicates microglia proliferation. In the nuclei of activated microglia, some nuclear bodies with different structures were frequently seen, whereas lamellar structures (similar to developing Birbeck's bodies--pathognomonic to Langerhans-type dendritic cells) were observed in the cytoplasm. The activated forms of microglia with apoptotic features were found only in SSPE cases. Some apoptotic nuclei were filled with nucleocapsids of measles virus. In Alzheimer's disease, activated microglia was most frequently bound to senile plaques. Ramified microglia was in contact with amyloid fibrils, which penetrated its cytoplasm and reached the nuclear membrane and channels of rough endoplasmic reticulum, or was situated among dystrophic neurites. Rod microglia was found predominantly at the edge of senile plaques. In Wilson's disease, the ultrastructure of activated microglia showed mostly indirect forms between rod, ramified and amoeboid microglia. The microglia ultrastructure suggests that its morphological form may express functional involvement in the pathogenesis of a given disease entity.

Variant Creutzfeldt-Jakob disease.

Abstract: Current evidence indicates that variant Creutzfeldt-Jakob disease is caused by the transmission of bovine spongiform encephalopathy to humans. The clinical and investigative features of variant CJD are relatively distinct from sporadic CJD and the neuropathological appearances are novel. The number of cases of vCJD in the UK may have peaked, but the total future number of cases of vCJD is uncertain and the possibility of secondary iatrogenic transmission via blood transfusion has recently been identified.

Kuru: a half-opened window onto the landscape of neurodegenerative diseases.

Abstract: Kuru, the first human neurodegenerative disease classified as a transmissible spongiform encephalopathy (TSE), prion disease or, in the past, as a slow unconventional virus disease, was first reported to Western medicine in 1957 by Gajdusek and Zigas. A complete bibliography of kuru through 1975 has been published by Alpers et al. The solution of the kuru riddle opened a novel field of biomedical sciences and initiated more than a quarter of century of research that has already resulted in two Nobel prizes (to D. Carleton Gajdusek in 1976 and to Stanley B. Prusiner in 1997) and was linked to a third (to Kurt Wuthrich who determined the structure of the prion protein). Kuru research has impacted the concepts of nucleation-polymerization "protein cancers", and "conformational disorders". This paper is dedicated to Dr. Carleton Gajdusek on the occasion of his 80th birthday. "Kuru" in the Fore (Fig. 1) language means to shiver from fever or cold. The Fore used the noun of the kuru-verb to describe the always fatal disease which decimated their children and adult women but rarely men. It has been and still is restricted to natives of the Fore linguistic group at Papua New Guinea's Eastern Highlands and those neighboring linguistic groups which exchange women with Fore people (Auiana, Awa, Usurufa, Kanite, Keiagana, late, Kamano, Kimi; Fig. 2). Neighboring groups into which kuru-affected people did not settle through marriage or adoption, such as the Anga (Kukukuku), and remote lagaria, Kamano and Auiana people, were not affected. It seems that Kuru first appeared at or shortly after the turn of XX century in Uwami village of Keiagana people and spread to the Awande in the North Fore where the Uwami had social contacts. Within 20 years it had spread further into the Kasokana (in 1922 according to Lindebaum) and Miarasa villages of North Fore, and a decade later had reached the South Fore at the Wanikanto and Kamira villages. Kuru became endemic in all villages that it entered and became hyperendemic in the South Fore region. All native informants stressed the relatively recent origin of kuru. Interestingly enough, when kuru first appeared, it was considered poetically by Fore as similar to "the swaying of casuarinas tree" and kuru was labeled cassowary disease to stress the similarity between cassowary quills and "waving casuarinas fronds". Gajdusek first learned about kuru from Dr. Roy Scragg, director of Public Health in Port Mosby, who had already read a report sent by Dr. Vin Zigas to Dr. John Gunter in 1956. In March 1957, Gajdusek joined Zigas, who at that time was a medical patrol officer in Kainantu, Eastern Highland District of the Territory of Papua New Guinea.

Tubulovesicular structures--the ultrastructural hallmark for transmissible spongiform encephalopathies or prion diseases.

Abstract: Tubulovesicular structures (particles - TVS) are the only ultrastructural marker for all transmissible spongiform encephalopathies (TSEs) or prion disease as seen by thin section electron microscopy. The latter is stressed as opposed to negative-staining techniques. TVS are spheres or short rods of approximately 27-35 nm in diameter. What is particularly interesting, this size of TVS is also the size of filter cut-off as judged from ultrafiltration studies and the size of the smallest infectious unit as recently estaimated. TVS have been found in all naturally occurring and experimentally induced TSEs, including variant Creutzfeldt- -Jakob disease and human familial TSEs - fatal familial insomnia and Gerstmann-Straussler-Scheinker disease. In longitudinal studies, the number of neuronal processes containing TVS correlates roughly with the incubation period and with infectivity. Hence, they are readily found in hamsters infected with the 263K strain of scrapie but it is very difficult to find them in human TSEs where titre is lower. The composition of TVS is unknown but they are not composed of PrP. Their consistent presence in all TSEs suggests the role at least of TSE pathogenesis.

New therapeutic approaches in Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects a large proportion of the elderly population. It causes a progressive decline in memory and other cognitive functions. There is no effective treatment of AD despite the great effort in trying to find one. Herein new therapeutic approaches including those closely targeting the pathogenesis of the disease have been discussed. Potential disease modifying treatments that are being considered as future treatment of AD include avaccination, secretase inhibitors, cholesterol lowering drugs, metal chelators and anti- inflammatory agents. According to Evidence Based Dementia Practice, only inhibitors of acetylcholinesterase (AChE) are approved in mild and moderate stages of AD treatment. From the end of 2003, FDA also approved memantine for much severer phases of AD. When all the presented possibilities are taken into account, the most important target for scientists and physicians is not only to find ways for causative cure of AD, but also to be ready for that moment. There is a great need for finding routine biomarkers and sensitive enough clinical tests for diagnosis of AD in which the lasting pathological process does not destroy too many neurones.

Ultrastructure of the central nervous system: the basics.

Abstract: Since the articles in this supplement describe ultrastructural changes in diseases of the nervous system, for better understanding of these papers dealing with pathology of the this system, basic elements of the ultrastructure of the central nervous system are presented in this survey. Description of the fine structure of cells and fibres of the central nervous system presented below is based on classical textbooks as well as on the authors' personal experience. The details of ultrastructure of nerve cells (their nucleus and cytoplasm, including cell organelles: abundant granular endoplasmic reticulum, prominent Golgi apparatus, mitochondria, lysosomes, as well as other cell components including: neurofilaments, lipid droplets, multivesicular bodies, lipid droplets, lipofuscin granules, and in some cells melanin granules, and also cell processes), the interneuronal chemical synapses (specialized site of interneuronal communication) as well as all types of neuroglial cells (a class of non-neuronal supporting cells): astrocytes (fibrous and protoplasmic), oligodendrocytes, and microglia neuroglial cells are described.

Association of influenza incidence with multiple sclerosis onset.

Abstract: The aim of this study was to investigate the environmental factors influencing the tangible changes in the incidence of multiple sclerosis (MS) over a period of the past 30 years in the town Gniezno, Poland. We analysed many environmental factors to which the whole population was exposed in the respective period. The following factors were considered: viral infections (influenza, measles, varicella, rubella, mumps), atmospheric air pollution and climate conditions. A positive correlation has been found between the incidence of influenza and the incidence of MS in the same year (r = 0.37; p = 0.04) as well as with the MS incidence assessed after 5 years (r = 0.64; p = 0.0005). No significant correlation has been found between the incidence of MS and other investigated environmental factors. These results support the hypothesis that influenza infection could precipitate MS onset.

Transgenic models of amyotrophic lateral sclerosis.

Abstract: Amyotrophic lateral sclerosis (ALS), the most frequent paralytic disease of adults, is untreatable and invariably fatal. Up to 20% of ALS cases are inherited (familial, fALS) and associated with mutations, usually of the superoxide dismutase type 1 (SOD-1) gene. This paper shortly reviews the background for and the use of rodent transgenic models of ALS. Silencing the SOD-1 gene does not produce paralytic phenotype, but transgenic rodents expressing human mutated (hm) SOD-1 atop their own enzyme develop relatively selective and fatal degeneration of motoneurons. Many essential neuropathological and biochemical features of the paralytic disease in hmSOD-1 transgenic mice and rats are similar to human fALS, and these animals are currently considered a model of the human disease. Two types of hypotheses put forward to explain pathomechanism of motoneuron degeneration in hmSOD-1 transgenics (hence also in human ALS) are the "gain of function" hypotheses which assume that the mutated enzyme displays new toxic catalytic properties, and the "gain of interaction" hypotheses which assume that the mutated protein molecules are toxic because they became misfolded and undergo oligomerization. Transgenic animal models of ALS are used for preclinical assessments of new therapeutic approaches ranging from mono- and polipharmacotherapy to gene therapy and stem cell therapy.

Long-term effect of IFN-beta 1a therapy on CCL2 (MCP-1) chemokine in patients with multiple sclerosis.

Abstract: Chemokines play an important role in pathogenesis of multiple sclerosis (MS), mediating migration of leukocytes into the central nervous system. CCL2 (MCP-1) chemokine is expressed in astrocytes in MS lesions. The aim of the study was to evaluate the effect of a two-year treatment with IFN-beta 1a on serum CCL2 level in MS patients. CCL2 concentration in sera of 18 relapsing-remitting MS (RR-MS) patients, and of 16 healthy controls was measured by ELISA. MS patients were treated with interferon-beta 1a (Avonex) in a dose of 30 μg i.m. once weekly. Significantly lower serum CCL2 level was found in MS patients in comparison with results of the control group. CCL2 concentration increased significantly after one year of therapy with IFN-beta, and remained high after the two-year treatment. The therapy of relapsing-remitting MS patients with interferon beta 1a is associated with a significant increase in CCL2 serum concentration.

Genetic aspects of amyloid beta-protein fibrillogenesis in Alzheimer's disease.

Abstract: Although deposition of aggregated amyloid beta-protein (Abeta) in human brain is a fundamental pathological event in the development of Alzheimer's disease (AD), our knowledge of the molecular mechanisms underlying the initiation of Abeta fibril formation remains still very incomplete. Recent data indicate that genetic factors have a direct effect on Abeta fibrillogenesis. Most of pathogenic mutations identified in genes responsible for familial AD (FAD) affect activities of alpha-, beta, and gamma-secretases during amyloid precursor protein (APP) processing leading to a significant increase in the Abeta42/Abeta40 concentration ratio. The enhanced anabolism of Abeta may lead to its deposition. Recently, it was shown that the two main alloforms of Abeta have distinct biological activity and behaviour at the earliest stage of assembly. In vitro studies showed that Abeta42 monomers, but not Abeta40, form initial and minimal structures (pentamer/hexamer units called paranuclei), which can oligomerise to larger forms. This finding may explain the particularly strong association of Abeta42 with AD. We have reviewed molecular effects of APP and Presenilin mutations responsible for FAD in both Abeta metabolism and formation of Abeta fibril.

Peripheral nerve tumours in own material.

Abstract: Peripheral nerve tumours are rather rare soft tissue tumours In the present article, results of surgical treatment of the peripheral nerve tumours have been presented Clinical material consisted of 34 patients (16 females aged 19-55 years and 18 males aged 17- 75 years) The following surgical procedures were performed: excision of the tumour without damaging the structure of fascicles - 6 cases; excision of the tumour with transsection of 1-2 fascicles - 6 cases; excision of the tumour with transsection of many fascicles - 1 case; excision of the tumour with microsurgical reconstruction of part of the nerve - 6 cases; excision of the tumour without reconstruction of any part of the nerve - 4 cases; arm amputation in 1/3 proximal - 1 case; and evacuation of the intraneural cyst with wall excision - 2 cases The pre- and postoperative motor and sensory deficit have been evaluated Three point scale of deficit intensity from + to +++ has been established Peripheral nerve tumours were mainly benign and malignant neoplasm was only found in 2 cases There were no new neurological deficits after surgical treatment The surgical treatment results depended on the histopathological pattern, size and localisation of tumours and the choice of the optimal operative technique

Aneurysmal bone cyst of skull and vertebrae in children. Analysis of own material and review of the literature.

Abstract: Aneurysmal bone cyst (ABC) is a benign, expansive, osteolytic lesion, consisting of blood-filled cysts, capable both of rapid enlargement and spontaneous resolution. Asymptomatic cases have been reported too. The aim of this paper was to analyse the outcomes of surgical treatment of ABC in children and a review of pertinent literature. We adopted the method of retrospective analysis of medical documentation of 10 patients with ABC. These were patients at the Department of Neurosurgery of the Children's Memorial Health Institute (Warsaw, Poland) from 1980 to 2002. There were 2 cases of cranial lesions and 8 cases of vertebral lesions. All the patients underwent surgical treatment only. Total lesionectomy was obtained in 7 cases, subtotal--in 3 cases. With the mean follow-up time of 5.1 years, good outcome (no neurological deficits) was noticed in 5 cases, moderate disability in the form of paraparesis--in 4 cases and full paraplegia--in 1 case. The following perioperative complications were noticed: transient paraplegia (1 case) and recurrence of ABC requiring reoperation (1 case). Among the 8 patients with vertebral lesions, progressive scoliosis requiring instrumental stabilization of the spine was noticed in 5 cases (4 vertebral body lesions and 1 laminar lesion). Primaiy infiltration of vertebral body by an ABC may lead to subsequent progressive scoliosis, which requires instrumental stabilization of spine. This demands careful planning and development of a comprehensive treatment program. ABC in children is a predominantly aggressive lesion, but even subtotal excision does not entrain a recurrence. Localization of lesion at the D3-5 levels is associated with an increased risk of postoperative neurological deterioration. Patients should be treated surgically before the development of severe deficits, which later may prove irreversible.

Multiple brain metastases from malignant peripheral nerve sheath tumour (MPNST).

Abstract: Malignant peripheral nerve sheath tumours (MPNSTs) are rare soft tissue neoplasms arising from elements of the nerve sheath that often occur in the context of neurofibromatosis (NF) type 1. Their poor prognosis results from high local recurrence rate and distant dissemination. Nevertheless, the brain metastases are exceptional. We are presenting an unusual case of intrathoracic MPNST in a 33-year-old man with a five-year clinical course characterised by multiple times local recurrences of primary tumour and multiple remote metastases into the brain structures, thyroid and suprarenal gland. Moreover, the cerebellar metastasis regrew in spite of its total excision. Histologically, brain metastatic tumours were composed of spindle cells closely arranged in interlacing and woven fascicles. This highly cellular nerve tissue exhibited an advanced nuclear hyperchromasia and a high mitotic activity. The tumour exhibited rich delicate reticulin network. The schwannian nature of brain metastases has been confirmed by immunohistochemical findings showing S-100 protein and GFAP expression and ultrastructural evidences of the pericellular basal lamina.