Neuronal vacuole formation in the rat posterior cingulate/retrosplenial cortex after treatment with the N-methyl-d-aspartate (NMDA) antagonist MK-801 (dizocilpine maleate)

Cytoplasmic vacuoles appear in neurons of the posterior cingulate/retrosplenial cortex (PC/RS) of rats after treatment with N-methyl-d-aspartate (NMDA) receptor antagonists. Prominent dilatation of mitochondria and endoplasmic reticulum has been described within 2 h; however, the ultrastructural features of vacuole formation are unknown. To investigate this, the present study examined the PC/RS cortex of male rats (age 60–70 days) at 15, 30, 45, 60, 90, and 120 min after subcutaneous treatment with 1 mg/kg of the noncompetitive NMDA antagonist MK-801 (dizocilpine maleate, 5-methyl-10, 11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine). Subtle mitochondrial dilatation was identified in a few neurons as early as 15 min postdose (MPD). By 30 MPD, dilatation was more pronounced in mitochondria and also involved the endoplasmic reticulum and perinuclear space. Ribosomal disaggregation and degranulation were also evident by 30 MPD. At all subsequent time points, dilatation of mitochondria and endoplasmic reticulum progressed in severity. Although the relative involvement of mitochondria and endoplasmic reticulum varied, glia were not involved. These ultrastructural data suggest that after treatment with MK-801, mitochondrial dilatation precedes involvement of endoplasmic reticulum in vacuolization of susceptible PC/RS cortical neurons. The early mitochondrial effects identified in this study suggest an initial metabolic insult that rapidly progresses to affect endoplasmic reticulum and ribosomes. This strengthens the relationship between the ability of certain NMDA antagonists to induce energy perturbations and neuronal vacuoles in the same region of the rat cerebral cortex.     

Cellular and molecular effects of trimethyltin and triethyltin: Relevance to organotin neurotoxicity

Many of the neurotoxic aspects of organotin exposure have been described. Organotin exposure culminates in its accumulation in the CNS and PNS. The clinical picture is dominated by neurological disturbances; yet, the primary basis for their neurotoxicity is unknown. Trimethyltin (TMT) is primarily a CNS neurotoxin affecting neurons within the hippocampal pyramidal band and the fascia dentata. Triethyltin (TET) is a neurotoxin that produces a pathological picture dominated by brain and spinal cord edema. The first part of this review summarizes the current understanding of the interaction of TMT and TET with biologically active sites in the induction of neurotoxicity. In the second part, several hypotheses for the differential neurotoxic effects of these organotins and their shortcomings are discussed.     

Differential generation of class I H-2D- versus H-2K-restricted cytotoxicity against a demyelinating virus following central nervous system infection

Despite the fact that both H-2K and D molecules are up-regulated in the central nervous system (CNS) following Theiler's murine encephalomyelitis virus (TMEV) infection, resistance in this virus model of multiple sclerosis maps exclusively to D. To address this paradox, we examined the ability of the K and D molecules to present viral antigens to cytotoxic T lymphocytes (CTL). Whereas no virus-specific CTL were detected in the CNS of susceptible B10.Q and B10.S mice 7 days post-infection, D-restricted CTL were identified readily in the CNS of resistant B10 animals. There was no evidence of K-restricted CTL in the CNS of B10 mice at day 7 post-infection. The presence of both K- and D-restricted virus-specific CTL in the spleen of immunized B10 mice demonstrates that the exclusive use of D molecules by CTL in the CNS of mice 7 days post-infection is not due to the inability of the K molecules to present viral peptides to lymphocytes. We conclude that the prominent role of the D locus in determining resistance or susceptibility to TMEV-induced demyelination is determined by factors governing the regulation of the immune response, and not by the presence or absence of CTL precursors capable of recognizing viral peptides presented by the K and D antigen-presenting molecules, or by differences in the ability of the K and D molecules to present viral peptides.     

Decreased [H]hemicholinium binding to high-affinity choline uptake sites in aged rat brain

The binding of [³H]hemicholinium ([³H]HCh-3) to sodium-dependent high-affinity choline uptake sites provides a useful neuroanatomical and functional marker of the cholinergic system. We examined the autoradiographic distribution of [³H]HCh-3 binding sites in the forebrain of young (4–6 months) and old (32 months) rats. There was a widespread reduction of [³H]HCh-3 binding site density in the aged rat brain. This loss presented regional differences with maximal reduction in the medial and posterior striatum (55%) and in the dentate gyrus (47%), in limbic areas such as basolateral amygdala, tubercle olfactorium and piriform cortex the autoradiographic signal was about 25–30% lower. In aged hippocampus and cerebral cortex the density of [³H]HCh-3 binding sites was about 40% lower, the difference between young and senescent animals being less evident in the medial septum and basal nucleus. No significant alterations were observed in interpeduncular nucleus from old rats. These data are in agreement with the functional results obtained by measuring other cholinergic parameters in the aged rat and confirm the vulnerability of cholinergic system during aging     

Epidemiology and clinical manifestation of HIV infection in Northern Zaire

1275 patients were evaluated for HIV-1+2 seroprevalence and its association with clinical symptoms of HIV infection. Of 667 apparently healthy subjects, 8.2% had anti-HIV-1 antibodies. In 465 patients with clinical signs of AIDS, 39.4% were seropositive. 143 patients with miscellaneous symptoms had positive predictive values for HIV infection between 67% (vaginal ulcerations) and 20% (profound pyogenic abscesses). The WHO definition for AIDS had a specificity of 78.3%, a sensitivity of 72.2% and a predictive value of 61.6%.     

Brain-derived neurotrophic factor in cerebrospinal fluid of patients with chronic daily headache: relationship with nerve growth factor and glutamate levels

Little has been done to investigate the biochemical basis of chronic daily headache (CDH). Our group has recently demonstrated an increase in the cerebrospinal fluid (CSF) levels of nerve growth factor (NGF) in CDH patients, supporting the involvement of this growth factor in the abnormal processing of head pain in this pathological condition. Other members of the neurotrophin family, especially brain-derived neurotrophic factor (BDNF), have been hypothesized as being involved in the development of chronic head pain in patients affected by CDH, but so far no data are available on this subject. BDNF, NGF and glutamate levels were determined in the CSF of 25 patients affected by CDH with a previous history of migraine. These levels were compared with those of a group of 20 control subjects, for whom the CSF examination and other instrumental investigations excluded diseases of the central and peripheral nervous systems. Significantly higher levels of BDNF, NGF and glutamate were found in CDH patients compared with control subjects (p<0.0001, p<0.0002 and p<0.001, respectively). A significant positive correlation emerged between CSF values of BDNF and those of NGF (r=0.61, p<0.001) and glutamate (r=0.44, p<0.025) in CDH patients. No significant differences were detected in BDNF, NGF and glutamate levels between CDH patients with analgesic overuse and those without. These results support the involvement of BDNF in CDH through the potentiation of glutamatergic transmission involved in the processing of head pain. The significant correlation between BDNF and NGF levels suggests that NGF-mediated up-regulation of BDNF in central sites involved in long-term sensitization plays a key role in persistent head pain in CDH patients. Correspondence to P. Sarchielli     

Monitoring of central venous oxygen saturation versus mixed venous oxygen saturation in critically ill patients

Continous monitoring of mixed venous (SvO₂) and central venous (ScO₂) oxygen saturation was compared in 7 critically-ill patients (Apache II score: 19±2.1) to determine whether or not information derived from ScO₂ were reliable in clinical practice. Patients were catheterized with both a pulmonary artery (PA) and a central venous (CV) catheter, each of them mounted with fiberoptic sensors (Opticath PA Catheter P7110 and Opticath CV Catheter U440, Abbott). A total of 580 comparative measurements were obtained during periods without and with therapeutic interventions (drug-titration, bronchial suction, use of PEEP, changes in FiO₂...). The systematic error between the 2 measurement techniques was 0.6% and 0.3% in periods with and without therapeutic interventions, respectively. The variability between the 2 techniques was 10% for both periods. Differences between the values were 5% in 49% of values during periods of stability and in 50% of values during periods with therapeutic interventions. There were poor correlations between the values during periods without (r=0.48) and with therapeutic interventions (r=0.62). Better, but still less than ideal, correlations were obtained with changes in SvO₂ and ScO₂ during periods without (r=0.70) and with therapeutic interventions (r=0.77). Although there is a need to develop a simple technique to monitor mixed venous oxygen saturation, the present study indicates that ScO₂ monitoring was not reliable in the study patients.     

Modulation of cutaneous reflexes in arm muscles during walking: further evidence of similar control mechanisms for rhythmic human arm and leg movements

Stimulation of cutaneous nerves innervating the hand evokes prominent reflexes in many arm muscles during arm cycling. We hypothesized that the mechanisms controlling reflex modulation during the rhythmic arm swing of walking would be similar to that documented during arm cycling. Thus, we expected cutaneous reflexes to be modulated by position in the walking cycle (phase dependence) and be different when walking compared to contraction while standing (task dependence). Subjects performed static postures similar to those occurring during walking and also walked on a treadmill while the superficial radial nerve was electrically stimulated pseudorandomly throughout the step cycle. EMG was recorded bilaterally from upper limb muscles and kinematic recordings were obtained from the elbow and shoulder joints. Step cycle information was obtained from force-sensing insoles. Analysis was conducted after averaging contingent upon the occurrence of stimulation in the step cycle. Phase-dependent modulation of cutaneous reflexes at early (~50–80 ms) and middle (~80–120 ms) latencies was observed. Coordinated bilateral reflexes were seen in posterior deltoid and triceps brachii muscles. Task dependency was seen in that reflex amplitude was only correlated with background EMG during static contraction (75% of comparisons for both early and middle latency reflexes). During walking, no significant relationship between reflex amplitude and background EMG level was found. The results show that cutaneous reflex modulation during rhythmic upper limb movement is similar to that seen during arm cycling and to that observed in leg muscles during locomotion. These results add to the evidence that, during cyclical movements of the arms and legs, similar neural mechanisms observed only during movement (e.g. central pattern generators) control reflex output. Electronic Publication     

Benzylamine oxidase in normal and atherosclerotic human aortae

Assays of serum benzylamine oxidase (BzAO) have led some workers to postulate a relationship between elevated BzAO activity and diseases characterized by proliferating connective tissue. The present study was designed to determine whether BzAO activity of a cellular tissue is also affected. BzAO was assayed in homogenates of normal and atherosclerotic human aortae. Characterization done in normal aortae showed that BzAO is not a classical monoamine, diamine, polyamine, or lysyl oxidase, nor is it a ceruloplasmin. The enzyme is heat stable at 60 degrees C and is associated primarily with the microsomal fraction on density centrifugation. Compared with phenylethylamines and indoleamines, benzylamine is the best substrate. BzAO is sensitive to inhibition by hydrazines and chymotrypsin but not trypsin, and is insensitive to Triton X-100 and sulfhydryl-group blockade. BzAO activity of atherosclerotic plaque (expressed per gram wet weight or per milligram protein) was decreased markedly compared to that in adjacent, nonplaque regions and in normal aortae. However, on a per milligram DNA basis, the BzAO activity of plaque did not differ from that of nonplaque tissue. We conclude that there is a decreased cell population density in plaque, a contention supported by kinetic analysis. Plaque BzAO showed a decreased Vmax with no change in the Km of benzylamine compared with nonplaque tissue. Thus, if a relationship exists between BzAO activity and proliferating connective tissue, it is not apparent at the level of the cellular enzyme in atherosclerotic aortae of man.