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Biomedical subjects

B Giometto

Publications and source records attributed to B Giometto.

At least 37 records · Page 2Linked to original sources
PubMed1999

Inhibition of sensory neuron apoptosis and prevention of loss by NT-3 administration following axotomy.

Following permanent transection of their peripheral axons, a proportion of adult rat dorsal root ganglion neurons undergo programmed cell death (apoptosis) over a period of months. The underlying causes of this neuron loss are unclear, but may involve the interruption of the supply of target-derived neurotrophic factors, the replacement of which could prevent this loss from occurring. To investigate whether the administration of neurotrophic factors can prevent the dorsal root ganglion neuron death in adults, a 1 mg/ml solution of ciliary neurotrophic factor or of NT-3 was applied via a silicon reservoir to the proximal stump after unilateral sciatic transection at mid-thigh level. The incidence of apoptotic neurons and neuronal loss in the L4 and L5 ganglia ipsilateral to sciatic nerve transection when compared with the contralateral ganglia was then measured 1 month later. This was assessed by examining serial sections of ganglia for neurons undergoing apoptosis and expressing the total counted as a percentage of the total number of neurons estimated using a stereological neuron counting technique. Our results show that NT-3 administration significantly reduced the incidence of apoptotic neurons and prevented neuron loss, while CNTF had no effect on either parameter.

Animals↗
PubMed1999

Detection and localisation of HIV-1 DNA and RNA in fixed adult AIDS brain by polymerase chain reaction/in situ hybridisation technique.

In the brain of patients with AIDS, HIV-1 is localised in a productive form in mononuclear cells. One issue that still needs clarification is whether HIV is localised in cells other than those of mononuclear lineage. Gene amplification by polymerase chain reaction/in situ hybridisation (PCR-IS) could shed light on it. In this study, formalin-fixed, paraffin-embedded brain tissue from ten adult AIDS sufferers was used. Five of them showed evidence of HIV encephalitis (HIVE), five did not show any abnormality. Nested PCR revealed HIV-1 DNA in all HIVE cases and in three of the group without HIVE. HIV-1 DNA and RNA were also detected in situ in seven cases (all seven were also HIV-1 DNA positive in tube). A higher signal was located in the white than in the grey matter. HIV-1 DNA was found in microglia, macrophages, perivascular cells, multinucleated gaint cells (MGC) and in CD68-negative cells. Some of them were identified as endothelial cells, astrocytes and oligodendrocytes. Reverse transcriptase-PCR-IS was positive in macrophages, MGC, endothelial and glial cells. These results confirm infection of endothelial cells and other glial cells and give clues about the route of entry of virus into the central nervous system and the pathogenesis of the disease. This study did not give any convincing evidence supporting an infection of neurons by HIV-1.

AIDS Dementia Complex↗
PubMed1999

Autosomal dominant myopathy with proximal weakness and early respiratory muscle involvement maps to chromosome 2q.

Two Swedish families with autosomal dominant myopathy, who also had proximal weakness, early respiratory failure, and characteristic cytoplasmic bodies in the affected muscle biopsies, were screened for linkage by means of the human genome screening set (Cooperative Human Linkage Center Human Screening Set/Weber version 6). Most chromosome regions were completely excluded by linkage analysis (LOD score <-2). Linkage to the chromosomal region 2q24-q31 was established. A maximum combined two-point LOD score of 4.87 at a recombination fraction of 0 was obtained with marker D2S1245. Haplotype analysis indicated that the gene responsible for the disease is likely to be located in the 17-cM region between markers D2S2384 and D2S364. The affected individuals from these two families share an identical haplotype, which suggests a common origin.

Chromosomes, Human, Pair 2↗
PubMed1999

Autoimmunity in paraneoplastic neurological syndromes.

In patients with Paraneoplastic Neurological Disorders, the researcher detected several autoantibodies reacting with neuronal antigens and tumors; their characteristics supported the hypothesis that autoimmunity plays a part in these diseases and gave impetus to the study of these neurological disorders. The relationship between detection of anti-neuronal antibodies, clinical syndromes, and certain types of tumors suggested the utility of these antibodies as a new tool for clinical diagnosis, although their function in the pathogenesis of the various syndromes is still unclear. This paper intends to review the characteristics of the anti-neuronal antibodies so far identified, their correlation with clinical syndromes, and the function of antigens. In addition, the paper will offer some insights on the immunological mechanisms of neuronal damage and on treatment options.

Animals↗
PubMed1998

Autoimmunity in paraneoplastic neurological disorders.

Antibodies to neuronal antigens are found in a range of different neurological disorders, both central and peripheral, and often indicate the presence of particular underlying tumours. This conference and workshop was an opportunity to discuss the clinical associations of these antibodies, the relevance of new antibody specificities, and to establish protocols for their detection.

Antibodies↗
PubMed1997

Accumulation of beta-amyloid precursor protein in HIV encephalitis: relationship with neuropsychological abnormalities.

The pathogenesis of neuropsychological abnormalities in patients with human immunodeficiency virus type 1 (HIV-1) encephalitis is obscure because neurons are not the target of infection and severe neuronal loss occurs only late during the disease. Moreover, there is evidence indicating that HIV dementia is not a homogeneous entity and could partially reverse after treatment with zidovudine. The finding that impaired axonal flow, evidenced by beta-amyloid precursor protein immunoreactivity, could contribute to the neuropsychological deficits prompted the present study. Brains of patients with full-blown acquired immunodeficiency syndrome (AIDS) were studied and findings compared with those of normal and abnormal control subjects. The presence of HIV-1 DNA was investigated by nested polymerase chain reaction; axonal abnormalities were detected by beta-amyloid precursor protein, ubiquitin immunohistochemistry, and silver staining. Accumulation of beta-amyloid precursor protein was observed in all the HIV encephalitis brains studied; the appearance of the immunostaining varied from globular structures to bundles of parallel formations. In 2 AIDS brains without pathological abnormalities, only the latter pattern was detected. The brains with trauma were strongly reactive with beta-amyloid precursor protein antibody and the different reactivity within them correlated with posttrauma survival, only globular structures being detected in the older cases. No correlation was found between the different pattern of beta-amyloid precursor protein reactivity and dementia in AIDS patients. These results show that widespread axonal injury is a constant feature in AIDS brains and suggest that it could play a role in the pathogenesis of the neuropsychological abnormalities of these patients.

AIDS Dementia Complex↗
PubMed1997

Axotomy-induced apoptosis in adult rat primary sensory neurons.

Neuronal death following unilateral axotomy of a sensory nerve has long been inferred from neuronal counts of dorsal root ganglion neurons, using the contralateral ganglia as a control. The counting methods used usually involved the counting of neuronal nucleoli and made assumptions about them which could conceivably be flawed. Very few studies have used direct observations of dying or degenerating neurons to address questions concerning the duration of the period of neuronal death or the mechanisms involved in this process. Here we describe a morphological, morphometric and histochemical study into the nature and duration of sensory neuron death following transection and ligation of the sciatic nerve at mid-thigh level in the adult rat. We show that at least some of this neuronal loss occurs by apoptosis as defined by morphological criteria and in situ end-labelling of damaged DNA. Absolute numbers of apoptotic neurons were counted from serial paraffin sections of ganglia and estimates of neuronal numbers obtained by disector analysis at 1, 2, 3 and 6 months after axotomy. Using this approach we show that axotomy-induced apoptosis begins at around 1 week and continues up to at least 6 months after axotomy.

Animals↗
PubMed1997

Axonal damage revealed by accumulation of beta-APP in HIV-positive individuals without AIDS.

The presence of neuropsychological disturbances in HIV-positive, pre-symptomatic individuals is a controversial issue. Neuroimaging studies have not shown brain atrophy or hyperintensity in the white matter, whereas proton magnetic resonance spectroscopy has revealed some abnormality of cerebral biochemistry. Using an antibody to beta-amyloid precursor protein (beta-APP), we previously demonstrated frequent and widespread axonal changes in the brains of AIDS patients. In this study, we extended the use of beta-APP to asymptomatic patients in order to establish a possible morphological correlation with neuropsychological disorders. Brain samples from 29 patients were examined. Results showed bundles of beta-APP-positive axons in 8/29 cases (27%). The changes, seen in both superficial and deep white matter, were either focal or diffuse, could not be visualized by silver or ubiquitin stains, and did not coexist with any change in distribution or morphology of astrocytes and microglial cells. We conclude that in HIV-positive asymptomatic individuals, axonal changes: (a) may be related to the state of immune activation with consequent presence of toxic substances, including cytokines, observed in these patients; (b) may represent mild changes that could undergo repair, unless other pathological events, such as the supervening of the AIDS stage and the specific encephalitis, make them permanent.

Amyloid beta-Protein Precursor↗
PubMed1997

Sub-acute cerebellar degeneration with anti-Yo autoantibodies: immunohistochemical analysis of the immune reaction in the central nervous system.

We report the pathological findings of a woman with a sub-acute cerebellar syndrome who had undergone surgery 3 years before for endometrial carcinoma. Both serum and cerebrospinal fluid contained high titres of autoantibodies against the cytoplasm of Purkinje cells that recognized a band of 62 kDa on immunoblotting of neuronal extracted proteins (pattern anti-Yo). No tumour was found despite a full range of gynaecological investigations; the neoplastic marker CA125 was slightly elevated and oligoclonal bands were detected in the cerebrospinal fluid. The patient died from acute myocardial infarction 4 months after developing this syndrome. At autopsy, no macroscopic evidence of tumour was obtained and the brain showed no abnormalities. On microscopic examination of the central nervous system diffuse degeneration of Purkinje cells could be seen throughout the cerebellum. Immunohistochemical analysis showed a CD8 lymphocyte infiltration in the cerebellum and cerebral cortex and diffuse microglial activation throughout the brain. These cells expressed high levels of MHC-II antigens on their cell membranes. The serum autoantibodies reacted with the cytoplasm of the remaining Purkinje cells. The short interval between the onset of symptoms and death of the patient could explain the difference between our findings and those reported in the literature in which no inflammatory infiltrates were detected. The immunohistochemical findings as well as the inflammatory cerebrospinal fluid profile seen in our case seem to support the concept that in paraneoplastic cerebellar degeneration with anti-Yo antibodies, an immune mediated mechanism is responsible for the damage to the cerebellum.

Aged↗
PubMed1997

Folliculo-stellate cells of human pituitary adenomas: immunohistochemical study of the monocyte/macrophage phenotype expression.

Folliculo-stellate cells (FS) represent a small percentage of anterior pituitary elements of still undetermined embryological origin. They are sparse among endocrine pituitary cells and are characterized by the lack of secretory granules and by the presence of few branching processes inserted between hormone-secreting cells. Although FS cell role is still under discussion, recent reports showed that they produce monocyte-derived cytokines able to influence the hormone production and modulate the immunoendocrine connections. In this study we applied three monocyte-macrophage markers (HAM56, KP1, HLA-DR) to 15 pituitary adenomas in order to ascertain whether FS cells belong to the macrophage lineage. In this case FS cells could be considered the resident macrophages of the pituitary. FS cells were identified according to the reactivity to S-100, GFAP and vimentin. We confirm that S-100 represents the most useful marker for these cells that were detected scattered between tumor cells in more than half of the adenomas. GFAP stained only a percentage of FS cells, while vimentin recognized in addition to stellate cells endothelia, perivascular and infiltrating macrophages. We were unable to detect the expression of the macrophage markers on S-100 and GFAP reactive cells. Indeed, HAM56, KP1 and HLA-DR-positive cells were mostly round, small size and located in the perivascular and septal positions where FS cells were never detected. Lack of expression of monocyte-macrophage lineage markers by FS cells in pituitary adenomas suggests their preferential neuroectodermal origin. However, further studies on normal human pituitary will be needed before ruling out a possible role for FS cells as resident pituitary macrophages.

Adenoma↗
PubMed1996

HIV-1 DNA in brains in AIDS and pre-AIDS: correlation with the stage of disease.

Seventeen asymptomatic individuals positive for human immunodeficiency virus type 1 (HIV-1) and 16 patients with acquired immunodeficiency syndrome (AIDS), all with polymerase chain reaction evidence of HIV-1 DNA, were selected for quantitative analysis to correlate the levels of HIV-1 DNA in brain tissue with the stage of infection. The AIDS patients either were clinically asymptomatic or presented various abnormalities. Neuropathological lesions were assessed by morphological and immunohistochemical methods. To determine the level of HIV-1 DNA, semiquantitative nested polymerase chain reaction was applied using a digoxigenin-labeled primer and chemiluminescence. Serial dilutions of standard HIV DNA were run in parallel with brain DNA samples. Among the 16 AIDS brains studied, 9 showed changes characteristic of HIV encephalitis/leukoencephalopathy while 1 showed focal pontine leukoencephalopathy and 6 showed no obvious neuropathological lesions. Abnormalities in pre-AIDS individuals included meningitis, microgliosis, and astrogliosis. Copy numbers of HIV-1 DNA in the brains of AIDS patients were higher than those in asymptomatic individuals (median, 135 vs 45 copies/150,000 cells). However, there was some degree of overlapping between the two groups, with some AIDS patients showing low figures while 3 asymptomatic individuals had high copy numbers. This suggests that the use of HIV-1 DNA load in the central nervous system as an indicator of progression of the disease should be restricted to large series and not single patients.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Immune infiltrates and cytokines in gliomas.

Frozen sections of 21 gliomas were analysed to characterize inflammatory infiltrating cells, HLA-DR antigen expression and cytokine secretion. Mononuclear cells infiltrating the tumours were mostly macrophages, which were detected in 100% of cases, and expressed HLA-DR antigens. Lymphocytes were less frequently seen and expressed the CD8 phenotype. Interleukin-1 beta (IL-1 beta) and Interleukin-6 (IL-6), two cytokines mainly produced by activated cells of the macrophage lineage, were demonstrated especially in neoplastic astrocytes. IL-1 beta immunoreactivity was detected in all tumours, and was prevalent in more anaplastic gliomas; IL-6 was found in anaplastic gliomas and in glioblastomas. IL-1 receptors were expressed by both infiltrating macrophages and neoplastic astrocytes in the gliomas analysed. These findings suggest that cytokine production in gliomas seems not related to immune reactions against the tumour and their synthesis by anaplastic astrocytes could follow an unregulated activation of many metabolic processes after neoplastic transformation.

Astrocytes↗
PubMed1996

Programmed cell death in brains of HIV-1-positive AIDS and pre-AIDS patients.

Neuropathological studies have revealed that the brains of HIV-1-infected AIDS patients show the typical encephalitis and, in addition, neuronal loss. More recently, this neuronal cell loss has been thought to take place via programmed cell death (apoptosis) which has been demonstrated by an in situ end labelling (ISEL) technique. In this study 54 brains of HIV-1-positive patients were investigated by the ISEL technique to investigate whether apoptosis is also present in the brains of patients at the asymptomatic stage. Of these, 10 patients suffered from HIV encephalitis (HIVE), 8 had AIDS without neuropathological disorders and 36 were HIV-1-positive pre-AIDS patients. Apoptotic cells were detected in 6 of the 10 HIVE, 1 of the 8 AIDS without central nervous system (CNS) disease and 4 of the 36 asymptomatic individuals. A difference seen between the AIDS and pre-AIDS cases was that, in the latter, apoptotic cells were found in the white matter in all 4 cases, while only 2 of these 4 showed apoptotic neurons. The presence of apoptotic cells in a number, albeit small, of brains of HIV-1-positive pre-AIDS individuals, combined with abnormalities described previously in the same group of patients gives further support to the opinion that brain damage already occurs during the early stages of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Investigation on the expression of major histocompatibility complex class II and cytokines and detection of HIV-1 DNA within brains of asymptomatic and symptomatic HIV-1-positive patients.

Among the various mechanisms proposed to explain the pathogenesis of cerebral lesions in human immunodeficiency virus (HIV)-induced encephalitis, a cytokine-mediated action has found most favour. Indeed, elevated expression of cytokines such as interleukin (IL)-1 and tumor necrosis factor-alpha (TNF-alpha), thought to be neurotoxic, has been found in AIDS patients. As a previous study had demonstrated the presence of HIV proviral DNA in brain tissue of a number of HIV-positive non-AIDS patients, we undertook this present investigation using morphological, immunohistochemistry (IHC) and polymerase chain reaction (PCR) methods to detect the expression of major histocompatibility complex (MHC) class II molecules, the presence of HIV-1 proviral DNA and of the cytokines TNF-alpha, IL-1 alpha, IL-4 and IL-6 in brains of the same group of individuals. The study included brains of 36 asymptomatic HIV-1 positive patients and the results were compared with those of AIDS patients either affected by HIV encephalitis (n = 8) or exempt from any neuropathological changes (n = 10) as well as of normal controls (n = 5). Results show that: HIV proviral DNA could be detected by PCR in 17 out of the 36 brains from HIV-positive pre-AIDS cases; most (15 of 17) of PCR-positive brains showed minimal to severe expression of MHC class II antigen; and cytokines could be detected predominantly within white matter even at this early stage. The data demonstrated that the state of immune activation described in AIDS is already present at the pre-AIDS stage and suggest that the presence of cytokines may already trigger the cascade of events leading to brain damage.

AIDS Dementia Complex↗
PubMed1996

Detection of paraneoplastic anti-neuronal autoantibodies on paraffin-embedded tissues.

Anti-neuron-specific autoantibodies are widely recognised as useful, though non-specific, diagnostic markers of paraneoplastic neurological disorders. However, controversies on the best way to detect these autoantibodies have recently arisen, and the use of different procedures for their detection by different laboratories has made results difficult to compare. The aim of this study was to adapt the existing immunohistochemical techniques used for the detection of anit-neuron autoantibodies to improve their visualisation and to facilitate a wide application of these procedures. Sera and cerebrospinal fluid (CSF) were obtained from 15 patients known to carry paraneoplastic anti-neuronal autoantibodies; in addition, one serum with "atypical" anti-neuron autoantibody and 18 control sera were studied. Paraformaldehyde-fixed, paraffin-embedded rat nervous tissue and formalin-fixed, paraffin-embedded human nervous tissue treated in a microwave oven were used as substrate; the reactions were developed by immunoperoxidase methods. At the dilutions used for diagnostic purposes, all the sera and CSFs showed staining whose intensity and specificity was comparable to that obtained using frozen tissue; the end-point dilutions were, however, reduced. The atypical pattern of staining of one serum was confirmed and better emphasised using these procedures; all control sera and CSFs were negative. The morphology was improved by the use of paraffin-embedded tissues; moreover, the results obtained are permanent because of peroxidase staining, which makes it possible to use them as standards for further investigations and for comparison between different laboratories. The convenience of using paraffin-embedded material could facilitate a wide application of these procedures in clinical neurology.

Animals↗
PubMed1996

Anti-gabaergic neuron autoantibodies in a patient with stiff-man syndrome and ataxia.

We describe a patient with autoimmune insulin-dependent diabetes whose original symptoms of trunk stiffness and rigidity of the abdomen were followed three years later by a pancerebellar syndrome. An autoantibody (autoAb) against GABAergic neurons was found in the patient's serum and cerebrospinal fluid (CSF); on Western blot, this autoAb recognized a 64-kDa antigen of cerebellar protein. The detection of this antibody in a case with ataxia suggests that a spectrum of different neurological diseases may be observed in patients harbouring anti-GABAergic neuron autoAb and supports the concept that factors other than autoAb contribute to the clinical presentation of these disorders.

Animals↗