Neuropathological Diagnostic Criteria for Creutzfeldt-Jakob Disease (CJD) and Other Human Spongiform Encephalopathies (Prion Diseases)

Neuropathological diagnostic criteria for Creutzfeldt-Jakob disease (CJD) and other human transmissible spongiform encephalopathies (prion diseases) are proposed for the following disease entities: CJD - sporadic, iatrogenic (recognised risk) or familial (same disease in 1st degree relative): spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; or encephalopathy with prion protein (PrP) immuno-reactivity (plaque and/or diffuse synaptic and/or patchy/perivacuolar types). Gerstmann-Sträussler-Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia): encephalo(myelo)pathy with multicentric PrP plaques. Familial fatal insomnia (FFI) (in member of a family with PRNP178 mutation): thalamic degeneration, variable spongiform change in cerebrum. Kuru (in the Fore population). Without PrP data, the crucial feature is the spongiform change accompanied by neuronal loss and gliosis. This spongiform change is characterised by diffuse or focally clustered small round or oval vacuoles in the neuropil of the deep cortical layers, cerebellar cortex or subcortical grey matter, which might become confluent. Spongiform change should not be confused with non-specific spon-giosis. This includes status spongiosus (“spongiform state”), comprising irregular cavities in gliotic neuropil following extensive neuronal loss (including also lesions of “burnt-out” CJD), “spongy” changes in brain oedema and metabolic encephalopathies, and artefacts such as superficial cortical, perineuronal, or perivascular vacuolation; focal changes indistinguishable from spongiform change may occur in some cases of Alzheimer's and diffuse Lewy body diseases. Very rare cases might not be diagnosed by these criteria. Then confirmation must be sought by additional techniques such as PrP immunoblotting, preparations for electron microscopic examination of scrapie associated fibrils (SAF), molecular biologic studies, or experimental transmission.     

Neocortical and hippocampal EEG in normal and lateral hypothalamic-damaged rats

Cortical and hippocampal EEG were correlated with behavior in rats before and after bilateral hypothalamic (LH) damage. In Stage 1 of recovery (aphagia and adipsia), the neocortex showed continuous large amplitude slow activity. It did not desynchronize during spontaneous acts such as grooming as well as during tail pinch-induced struggling or orienting, even though a slow form of hippocampal theta accompanied these acts. However, during Stage 2 (anorexia), the neocortical EEG did desynchronize when such theta appeared. Therefore, as behavioral recovery progresses after LH damage, there appears to be a concomitant recovery of cortical participation in such behavior. Early in recovery, LH rats, unlike normals, showed slow (3–4.5 Hz) atropine-sensitive hippocampal theta during automatisms such as grooming as well as during immobility. Thus, LH damage, while temporarily abolishing fast. noncholinergic theta, appears to release slow cholinergic theta. Later in recovery, faster atropine-resistant (noncholinergic) theta becomes functional again.     

Differential activation of mouse hepatitis virus-specific CD4+ cytotoxic T cells is defined by peptide length.

In this study we have characterized the core epitope recognized by the MHV-A59-specific CD4+ cytotoxic T lymphocyte (CTL) clones HS1 and B6.1, derived from BALB/c and C57/BL6 mice, respectively. These CD4+ clones respond to the promiscuous peptide fragment S-329-343 of the glycoprotein S of MHV-A59. The results indicate that the core peptides of both clones overlap but are not identical. The core region of the HS1 clone is an 8-mer, and comprises the amino acid residues S-332-339, whereas the minimal epitope for clone B6.1 is a 9-mer and comprises the amino acid residues S-334-342. The peptide fragment S-329-343 activates all T-cell effector functions, including proliferation, cytokine secretion and cytolysis. However, in the present study we show that T-cell activation is not an all-or-none phenomenon, in which T-cell stimulation leads to activation of all T-cell effector functions. It appears that changes in the length of a peptide ligand can differentially activate the cytolytic machinery from proliferation and cytokine secretion. Furthermore, the results indicate that, in our case, modulation of the flanking residues of the core epitopes did not convert the cytokine profile of polarized T-helper type-1 (Th1) clones into a Th2-type pattern.     

Herion addicts infected by HBV and HIV have a low prevalence of HBV DNA in peripheral blood mononuclear cells

Several reports show that the prevalence of HBV (hepatitis B virus) carriers in HIV (human immunodeficiency virus) infected populations is significantly higher than in HIV seronegative individuals, independent of the risk group for HIV, that is, homosexuals or drug abusers. In this context, evaluation of the simultaneous presence of HBV and HIV in PBMCs (peripheral blood monuclear cells) is of particular interest for at least 2 reasons: 1) the possible reciprocal influence of the 2 viruses when they infect the same cell; 2) the possibility that HIV-iduced hematological disorders could indirectly influence the settling of HBV in blood cell populations. We report data on the frequency of PCR positivity for HBV DNA in PBMCs from 62 HIV infected patients, rigorously selected by risk group, that is, intravenous use of heroin for at least 3 years and syringe promiscuity. Sixtyseven HIV negative individuals who never used any drug formed the control group. The analysis of the cases positive for HBV DNA in PBMCs showed that 1) the overall prevalence of PCR positivity found in HIV infected patients was significantly lower than that registered in the control group; 2) PCR positivity among the subjects who were HBsAg negative and anti-HBV positive was extremely low in the HIV infected patients (3.7%) but quite frequent in the HIV negative subjects (37.0%). The results support the hypothesis that, unlike the HIV negative individuals, our HIV infected patients exhibited HBV DNA in PBMCS almost exclusively when they presented with active HBV replication.     

A microiontophoretic study of the action of kainic acid and putative neurotransmitters in the rat mesencephalic trigeminal nucleus

The ‘excitotoxic’ hypothesis proposes that neurotoxic amino acids exert their effect through neuronal excitation (Olney, Ho &;Rhee, 1971).Colonnier, Steriade &;Landry (1979) have found that trigeminal mesencephalic neurons in the cat are resistant to the neurotoxic effect of kainic acid. In the present study it was found that the same neurons in the rat also resist the cytotoxic action of this amino acid. In addition, kainic acid, applied iontophoretically onto these neurons failed to alter their firing frequency. The resistance of these neurons to both neurotoxic and excitatory actions of kainic acid is consistent with the ‘excitotoxic’ hypothesis.Other putative neurotransmitters were applied by microiontophoresis on these neurons and none were found to alter their rate of discharge. Procaine however applied with relatively low ejecting currents consistently reduced their firing rates. The failure of the putative neurotransmitters tested to influence the rate of discharge of the trigeminal mesencephalic neurons suggests that the chemical synapses present on these neurons in the rat (Hinrichsen &;Larramendi, 1970) utilize another neurotransmitter from those tested. Alternatively the synapses might have a role other than the direct regulation of the firing frequency of these primary afferent neurons.     

Surface properties and cell response of low metal ion release Ti-6Al-7Nb alloy after multi-step chemical and thermal treatments

Ti-6Al-7Nb samples treated by innovative multi-step chemical and thermal processes were characterized in order to evaluate their surface properties and cell interaction. The main object was to asses if the treatments were effective in order to obtain a surface presenting at the same time bone-like apatite induction ability, low metal ion release, good cell response and high protein binding. The morphology, crystallographic structure, porosity and wettability of the treated materials were investigated, as well as their interaction with simulated body fluid during soaking for different times. Cytotoxicity, protein adsorption tests and in vitro fibroblast and osteoblast-like cell cultures were also performed.     

Peptide-based approaches to treat asthma, arthritis, other autoimmune diseases and pathologies of the central nervous system

In this review we focus on peptide- and peptidomimetic-based approaches that target autoimmune diseases and some pathologies of the central nervous system. Special attention is given to asthma, allergic rhinitis, osteoarthritis, and Alzheimer's disease, but other related pathologies are also reviewed, although to a lesser degree. Among others, drugs like Diacerhein and its active form Rhein, Pralnacasan, Anakinra (Kineret), Omalizumab, an antibody "BION-1", directed against the common beta-chain of cytokine receptors, are described below as well as attempts to target beta-amyloid peptide aggregation. Parts of the review are also dedicated to targeting of pathologic conditions in the brain and in other tissues with peptides as well as methods to deliver larger molecules through the "blood--brain barrier" by exploring receptor-mediated transport, or elsewhere in the body by using peptides as carriers through cellular membranes. In addition to highlighting current developments in the field, we also propose, for future drug targets, the components of the inflammasome protein complex, which is believed to initiate the activation of caspase- 1 dependent signaling events, as well as other pathways that signal inflammation. Thus we discuss the possibility of targeting inflammasome components for negative or positive modulation of an inflammatory response.     

Risk factors for antibiotic-resistant Escherichia coli isolated from hospitalized patients with urinary tract infections: a prospective study

From November 1998 to February 1999 we prospectively evaluated the prevalence of resistance to penicillins, cephalosporins, carbapenem, quinolones, aminoglycosides, and trimethoprim-sulfamethoxazole (SXT) in 320 Escherichia coli isolates isolated from hospitalized patients with acute urinary tract infections (UTIs). We also studied for these strains risk factors for resistance to amoxicillin-clavulanic acid (AMC), fluoroquinolones (FQs), and SXT. Resistance rates were consistent with those from major recent studies reported in the literature. Multivariate analyses selected the following factors as being significantly associated with E. coli resistance: (i) for resistance to AMC, prior (1 year) UTI (odds ratio [OR] = 2.71, P = 0.006), prior (1 year) urinary catheter (OR = 2.98, P = 0.0025), and prior (6 months) antibiotic exposure (OR = 2.68, P = 0.005); (ii) for resistance to FQs male sex (OR = 3.87, P = 0.03), with a trend toward significance for age >65 years (OR = 7.67, P = 0.06) and prior (1 year) UTI (OR = 2.98, P = 0.07); and (iii) for resistance to SXT, male sex (OR = 1.91, P = 0.046), hospitalization in an intermediate-term-care unit (OR = 2.18, P = 0.008), and prior (1 year) UTI (OR = 2.03, P = 0.03). Ours results suggest that prior UTI is a common risk factor for resistance to the different antibiotics tested. Although few studies on risk factors for E. coli resistance to antibiotics have been published, careful interpretation of their findings, taking into consideration the population, infection site, and period studied, should contribute to the formulation of a better strategy that can be used to overcome antibiotic resistance.     

Viral load,CD4 percentage,and delayed-type hypersensitivity in subjects receiving the HIY-1 Immunogen and antiviral drug therapy

Two trials of subjects inoculated with the inactivated, gp120-depleted HIV-1 Immunogen are reported. In one study, in which 19 subjects received ZDV and 8 subjects received ddI, treatment with the HIV-1 Immunogen did not affect the pharmacokinetic parameters of the antiviral drugs. In another study, 65 subjects who were previously immunized with the HIV-1 Immunogen over a mean period of 4.0 years (range, 1.2–5.4 years) received inoculations at 0 and 6 months. At some point during this 48-week study, 72% of the subjects (47/65) were receiving antiviral drug therapy. The HIV-1 DNA load in CD4 cells and CD4 percentage were found to be stable over the 48-week period. Delayed-type hypersensitivity to HIV-1 antigens increased after two inoculations with the HIV-1 Immunogen. In these two trials, no serious treatment-related adverse events were documented in the subjects. The two studies presented herein are the first to suggest that an immune-based therapy such as the HIV-1 Immunogen can be combined safely with antiviral drugs, supporting further study to evaluate the clinical utility of this approach.