Exposure to traffic-related air pollution and changes in exhaled nitric oxide and DNA methylation in arginase and nitric oxide synthase in children with asthma.

BACKGROUND: Traffic-related air pollution (TRAP) has been associated with increased risk of airway inflammation in children with asthma. While epigenetic changes could potentially modulate TRAP-induced inflammatory responses, few studies have assessed the temporal pattern of exposure to TRAP, epigenetic changes and inflammation in children with asthma. Our goal was to test the time-lag patterns of personal exposure to TRAP, airway inflammation (measured as fractional exhaled nitric oxide, FeNO), and DNA methylation in the promoter regions of genes involved in nitric oxide synthesis among children with asthma. METHODS: We measured personal exposure to black carbon (BC) and FeNO for up to 30 days in a panel of children with asthma. We collected 90 buccal cell samples for DNA methylation analysis from 18 children (5 per child). Methylation in promoter regions of nitric oxide synthase (NOS1, NOS2A, NOS3) and arginase (ARG1, ARG2) was assessed by bisulfite pyrosequencing. Linear-mixed effect models were used to test the associations of BC at different lag periods, percent DNA methylation at each site and FeNO level. RESULTS: Exposure to BC was positively associated with FeNO, and negatively associated with DNA methylation in NOS3. We found strongest association between FeNO and BC at lag 0-6 h while strongest associations between methylation at positions 1 and 2 in NOS3 and BC were at lag 13-24 h and lag 0-24 h, respectively. The strengths of associations were attenuated at longer lag periods. No significant associations between exposure to TRAP and methylation levels in other NOS and ARG isoforms were observed. CONCLUSIONS: Exposure to TRAP was associated with higher levels of FeNO and lower levels of DNA methylation in the promoter regions of the NOS3 gene, indicating that DNA methylation of the NOS3 gene could be an important epigenetic mechanism in physiological responses to TRAP in children with asthma.

Aided phytostabilisation reduces metal toxicity, improves soil fertility and enhances microbial activity in Cu-rich mine tailings.

(Aided) phytostabilisation has been proposed as a suitable technique to decrease the environmental risks associated with metal(loid)-enriched mine tailings. Field scale evaluations are needed for demonstrating their effectiveness in the medium- to long-term. A field trial was implemented in spring 2011 in Cu-rich mine tailings in the NW of Spain. The tailings were amended with composted municipal solid wastes and planted with Salix spp., Populus nigra L. or Agrostis capillaris L. cv. Highland. Plant growth, nutritive status and metal accumulation, and soil physico- and bio-chemical properties, were monitored over three years (four years for plant growth). The total bacterial community, α- and ß-Proteobacteria, Actinobacteria and Streptomycetaceae were studied by DGGE of 16s rDNA fragments. Compost amendment improved soil properties such as pH, CEC and fertility, and decreased soil Cu availability, leading to the establishment of a healthy vegetation cover. Both compost-amendment and plant root activity stimulated soil enzyme activities and induced important shifts in the bacterial community structure over time. The woody plant, S. viminalis, and the grassy species, A. capillaris, showed the best results in terms of plant growth and biomass production. The beneficial effects of the phytostabilisation process were maintained at least three years after treatment.

Traffic-related air pollution, chronic stress, and changes in exhaled nitric oxide and lung function among a panel of children with asthma living in an underresourced community.

We examined associations between short-term exposure to traffic-related air pollutants (TRAP) and airway inflammation and lung function in children with asthma, and whether these associations are modified by chronic psychological stress. Residents of underresourced port-adjacent communities in New Jersey were concerned about the cumulative impacts of exposure to TRAP, particularly diesel-engine truck emissions, and stress on exacerbation of asthma among children. Children with asthma aged 9-14 (n = 35) were recruited from non-smoking households. We measured each participant's (1) continuous personal exposure to black carbon (BC, a surrogate of TRAP) at 1-min intervals, (2) 24-h integrated personal exposure to nitrogen dioxide (NO2), (3) daily fractional exhaled nitric oxide (FeNO), and (4) lung function for up to 30 consecutive days. Personal BC was recorded by micro-aethalometers. We measured daily FeNO using the NIOX MINO, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) using Easy One Frontline spirometers. Chronic stress was measured with the UCLA Life Stress Interview for Children. The association was examined using linear mixed-effect models. In the fully adjusted model, an interquartile range (IQR) increase in BC at lag 0-6 h before the FeNO measurement was associated with 8 % (95 % CI: 3 % - 12 %) increase in FeNO, whereas an IQR increase in BC at lag 7-12 h and lag 0-24 h were associated with 6 % (95 % CI: 2 % - 11 %) and 7 % (2 % - 12 %) FeNO increases, respectively. There were no significant lung function changes per IQR increase in BC. No interactions were observed between chronic stress and BC on FeNO. Chronic stress was negatively associated with individual average FeNO levels. Our findings suggest that higher levels of BC exposure within the prior 24 h increased airway inflammation levels in children with asthma, with the strongest effect observed within the first 6 h.

Thalamocortical Projections Are Significantly Impaired in the R6/2 Mouse Model of Huntington's Disease.

As Huntington's disease (HD) progresses, there is a significant loss of neurons in the striatum in addition to a distinct thinning of the cerebral cortex. Despite an early presence of sensorimotor deficits in patients with HD, electrophysiological studies designed to assess the integrity of thalamocortical circuits are sparse. Using the R6/2 mouse model of HD, we provide evidence of reduced connectivity between thalamic cells and their targeted cortical regions. Whole-cell patch clamp recordings from ventral anterolateral nucleus (VAL; motor) and ventral posteromedial nucleus (VPM; somatosensory) thalamic neurons in ex vivo brain slices of R6/2 and wild-type (WT) mice revealed that cells in both thalamic nuclei of R6/2 mice exhibited significant differences in passive and active cell membrane properties (smaller cell membrane capacitances, faster decay time constants and increased input resistances) compared with WT cells. Although only cells in the VPM of symptomatic R6/2 mice had more depolarized resting membrane potentials compared with WTs, cells in both nuclei displayed increased excitability in symptomatic, but not presymptomatic, R6/2 mice. Optical activation of VAL and VPM terminals elicited smaller magnitude current responses in cortical pyramidal neurons (CPNs) in both motor cortex (M1CTX) and somatosensory barrel cortex (BCTX) of symptomatic R6/2 mice compared with CPNs in WT mice. Furthermore, we observed a decrease in the frequency of thalamocortical excitatory quantal events in R6/2 BCTX CPNs, with no genotype-dependent differences in AMPA:NMDA response amplitude ratios. These data suggest there is a decrease in the transmission of thalamocortical information that is likely because of impaired neurotransmitter release.

[Effectiveness of peri-articular infiltration with local anesthetic and adjuvants for post-surgical pain control in total knee replacement]. / Eficacia de la infiltración periarticular con anestésico local y adyuvantes para control del dolor postquirúrgico en la artroplastía total de rodilla.

INTRODUCTION: Total knee arthroplasty (TKA) is one of the most successful orthopedic treatments, however, it has been associated with severe postsurgical pain in 30-60% of patients. We propose that infiltration of the articular capsule of the knee during surgery will decrease postsurgical pain. MATERIAL AND METHODS: Experimental, randomized, double-blind study in patients undergoing unilateral TKA between April 2018 and January 2019. Patients were divided into two groups, the first infiltration with placebo and the second with anesthetic solution and adjuvants (fentanyl, epinephrine and ketorolac). Pain was measured with the visual analog scale (VAS) at 4, 6, 8, 12, 18, 24, 36 and 48 hours postsurgical, as well as the consumption of opioid analgesics and antiemetics. RESULTS: 20 patients in each group, with a follow-up of 4 weeks. There were no significant differences in demographic characteristics between the two groups. Better control of postsurgical pain was observed in the group that received infiltration with anesthetic and adjuvant, as well as a decrease in the consumption of opioid analgesics and antiemetics. There was no difference in bleeding or in the incidence of infections between the two groups. CONCLUSION: Peri-capsular infiltration is a safe and effective method, as part of multimodal analgesia in total knee arthroplasty, as it decreases postsurgical pain, opioid and antiemetic use and does not increase postsurgical bleeding.

INTRODUCCIÓN: La artroplastía total de rodilla (ATR) es uno de los tratamientos ortopédicos más exitosos; sin embargo, se ha asociado a dolor postquirúrgico intenso en 30-60% de los pacientes. Nosotros planteamos que la infiltración de la cápsula articular de la rodilla durante la cirugía disminuirá el dolor postquirúrgico. MATERIAL Y MÉTODOS: Estudio experimental, aleatorio, doble ciego, en pacientes sometidos a ATR unilateral entre Abril de 2018 a Enero de 2019. Los pacientes fueron divididos en dos grupos, el primero infiltración con placebo y el segundo con solución anestésica y adyuvantes (fentanilo, epinefrina y ketorolaco). Se cuantificó mediante escala visual análoga (EVA) del dolor a las cuatro, seis, ocho, 12, 18, 24, 36 y 48 horas postquirúrgicas, así como del consumo de analgésicos opioides y antieméticos. RESULTADOS: Veinte pacientes en cada grupo, con un seguimiento de cuatro semanas. No hubo diferencias significativas en las características demográficas entre ambos grupos. Se observó un mejor control del dolor postquirúrgico en el grupo que recibió infiltración con anestésico y adyuvante, además de una disminución en el consumo de analgésicos opioides y antieméticos. No hubo diferencia en sangrado ni en la incidencia de infecciones entre ambos grupos. CONCLUSIÓN: La infiltración pericapsular es un método seguro y eficaz, como parte de la analgesia multimodal en la artroplastía total de rodilla, ya que disminuye el dolor postquirúrgico, el consumo de opioides y antieméticos y no incrementa el sangrado postquirúrgico.

Behaviour of enzymatic activities and root elongation in Argiudoll soils from the Argentine Humid Pampa treated with biosolids.

The incorporation of biosolids to soil is a strategy aiming at the re-location of these materials in the environment with a useful end: soil fertilization. In this work, the response of two Argiudoll soils (one with more than 100 years of agriculture and the other, a virgin one) to biosolid incorporation was studied under laboratory conditions. To measure this response, soil enzymatic biodescriptors, such as dehydrogenase and urease activities, and tests related to plant physiology (the root elongation test) were employed. The addition of the biosolid to both soils had a stimulating effect though different on each soil according to the added dose. Adjustment of the regression line for dehydrogenase activity with root elongation was positive and statistically significant (p<0.001). Results suggest that biodescriptors employed were suitable for studying the impact of amended biosolids on different soils.

Prevalence of M. tuberculosis infection and tuberculosis disease among HIV-infected people in Spain.

OBJECTIVE: To study the prevalence of Mycobacterium tuberculosis infection (MTBI) and past/current tuberculosis (TB) among human immunodeficiency virus (HIV) infected persons in Spain. DESIGN: Longitudinal study conducted between 2000 and 2003 at 10 HIV hospital-based clinics. Data were drawn from clinical records. Associations were measured using odds ratios (ORs) and their 95% confidence intervals (95%CI). RESULTS: Of the 1242 persons who met the eligibility criteria, most were male (75%), aged <40 years (75%) and unemployed (40%). HIV infection occurred through intravenous drug use (53%), heterosexual sex (29%) and sex between men (16%). In the initial evaluation, 315 subjects had evidence of MTBI: 84 (6.8%) had a history of TB, 23 (1.8%) current TB and 208 (16.8%) latent tuberculosis infection (LTBI). MTBI was associated with male sex, age 30-49 years, contact with a TB case, homelessness, poor education, and negatively with CD4 <100 cells/mm(3). Among subjects with MTBI, past/current TB was associated with retirement/disability (OR 6, 95%CI 1.6-22.5), CD4 <200 cells/mm(3) (OR 9.7, 95%CI 3.8-24.6), viral load >55,000 copies (OR 5.3, 95%CI 1.4-20.0), and negatively, with skilled work (OR 0.4, 95%CI 0.1-1.0) or administrative/managerial/professional work (OR 0.05, 95%CI 0.01-0.4). CONCLUSION: Social context has an impact on the effectiveness of HIV and TB control programmes even in industrialised countries with free access to health care.

Modification of the degradative capacity of a soil artificially contaminated with diesel.

Samples of an Ah horizon from a Cambisol under oakwood vegetation were artificially contaminated with diesel (at doses of 20, 40, 80, 160 and 400 microl g(-1)) under laboratory conditions. The presence of the contaminant caused a decrease in the microbial biomass and in phosphomonoesterase, beta-glucosidase and particularly, urease activities. In contrast, the basal respiration and mineralization of nitrogen, specifically ammonification, both increased. The microorganisms that survived in the contaminated soil showed increased metabolic activity, as a result of their use of dead microorganisms as a substrate and of a lack of competition. Although the results indicate that the properties related to the degradative capacity of the soils varied differently in response to the contamination, the use of a biochemical quality index (including different biochemical properties), which was designed for estimating the degree of deterioration of the soil, revealed a clear decrease in the biochemical quality of the diesel-contaminated soils.

Eficacia de la infiltración periarticular con anestésico local y adyuvantes para control del dolor postquirúrgico en la artroplastía total de rodilla / Effectiveness of peri-articular infiltration with local anesthetic and adjuvants for post-surgical pain control in total knee replacement

Resumen: Introducción: La artroplastía total de rodilla (ATR) es uno de los tratamientos ortopédicos más exitosos; sin embargo, se ha asociado a dolor postquirúrgico intenso en 30-60% de los pacientes. Nosotros planteamos que la infiltración de la cápsula articular de la rodilla durante la cirugía disminuirá el dolor postquirúrgico. Material y métodos: Estudio experimental, aleatorio, doble ciego, en pacientes sometidos a ATR unilateral entre Abril de 2018 a Enero de 2019. Los pacientes fueron divididos en dos grupos, el primero infiltración con placebo y el segundo con solución anestésica y adyuvantes (fentanilo, epinefrina y ketorolaco). Se cuantificó mediante escala visual análoga (EVA) del dolor a las cuatro, seis, ocho, 12, 18, 24, 36 y 48 horas postquirúrgicas, así como del consumo de analgésicos opioides y antieméticos. Resultados: Veinte pacientes en cada grupo, con un seguimiento de cuatro semanas. No hubo diferencias significativas en las características demográficas entre ambos grupos. Se observó un mejor control del dolor postquirúrgico en el grupo que recibió infiltración con anestésico y adyuvante, además de una disminución en el consumo de analgésicos opioides y antieméticos. No hubo diferencia en sangrado ni en la incidencia de infecciones entre ambos grupos. Conclusión: La infiltración pericapsular es un método seguro y eficaz, como parte de la analgesia multimodal en la artroplastía total de rodilla, ya que disminuye el dolor postquirúrgico, el consumo de opioides y antieméticos y no incrementa el sangrado postquirúrgico.

Abstract: Introduction: Total knee arthroplasty (TKA) is one of the most successful orthopedic treatments, however, it has been associated with severe postsurgical pain in 30-60% of patients. We propose that infiltration of the articular capsule of the knee during surgery will decrease postsurgical pain. Material and methods: Experimental, randomized, double-blind study in patients undergoing unilateral TKA between April 2018 and January 2019. Patients were divided into two groups, the first infiltration with placebo and the second with anesthetic solution and adjuvants (fentanyl, epinephrine and ketorolac). Pain was measured with the visual analog scale (VAS) at 4, 6, 8, 12, 18, 24, 36 and 48 hours postsurgical, as well as the consumption of opioid analgesics and antiemetics. Results: 20 patients in each group, with a follow-up of 4 weeks. There were no significant differences in demographic characteristics between the two groups. Better control of postsurgical pain was observed in the group that received infiltration with anesthetic and adjuvant, as well as a decrease in the consumption of opioid analgesics and antiemetics. There was no difference in bleeding or in the incidence of infections between the two groups. Conclusion: Peri-capsular infiltration is a safe and effective method, as part of multimodal analgesia in total knee arthroplasty, as it decreases postsurgical pain, opioid and antiemetic use and does not increase postsurgical bleeding.

Dopamine D4 receptor-deficient mice display cortical hyperexcitability.

The dopamine D(4) receptor (D(4)R) is predominantly expressed in the frontal cortex (FC), a brain region that receives dense input from midbrain dopamine (DA) neurons and is associated with cognitive and emotional processes. However, the physiological significance of this dopamine receptor subtype has been difficult to explore because of the slow development of D(4)R agonists and antagonists the selectivity and efficacy of which have been rigorously demonstrated in vivo. We have attempted to overcome this limitation by taking a multidimensional approach to the characterization of mice completely deficient in this receptor subtype. Electrophysiological current and voltage-clamp recordings were performed in cortical pyramidal neurons from wild-type and D(4)R-deficient mice. The frequency of spontaneous synaptic activity and the frequency and duration of paroxysmal discharges induced by epileptogenic agents were increased in mutant mice. Enhanced synaptic activity was also observed in brain slices of wild-type mice incubated in the presence of the selective D(4)R antagonist PNU-101387G. Consistent with greater electrophysiological activity, nerve terminal glutamate density associated with asymmetrical synaptic contacts within layer VI of the motor cortex was reduced in mutant neurons. Taken together, these results suggest that the D(4)R can function as an inhibitory modulator of glutamate activity in the FC.

Changes in cortical and striatal neurons predict behavioral and electrophysiological abnormalities in a transgenic murine model of Huntington's disease.

Neurons in Huntington's disease exhibit selective morphological and subcellular alterations in the striatum and cortex. The link between these neuronal changes and behavioral abnormalities is unclear. We investigated relationships between essential neuronal changes that predict motor impairment and possible involvement of the corticostriatal pathway in developing behavioral phenotypes. We therefore generated heterozygote mice expressing the N-terminal one-third of huntingtin with normal (CT18) or expanded (HD46, HD100) glutamine repeats. The HD mice exhibited motor deficits between 3 and 10 months. The age of onset depended on an expanded polyglutamine length; phenotype severity correlated with increasing age. Neuronal changes in the striatum (nuclear inclusions) preceded the onset of phenotype, whereas cortical changes, especially the accumulation of huntingtin in the nucleus and cytoplasm and the appearance of dysmorphic dendrites, predicted the onset and severity of behavioral deficits. Striatal neurons in the HD mice displayed altered responses to cortical stimulation and to activation by the excitotoxic agent NMDA. Application of NMDA increased intracellular Ca(2+) levels in HD100 neurons compared with wild-type neurons. Results suggest that motor deficits in Huntington's disease arise from cumulative morphological and physiological changes in neurons that impair corticostriatal circuitry.

Q fever mimicking herpetic encephalitis.

We describe a patient with temporal lobe encephalitis associated with primary Coxiella burnetii infection who presented with CT and MRI findings suggestive of herpes simplex encephalitis and an initial improvement during treatment with acyclovir. Q fever should be considered in the differential diagnosis of patients whose manifestations suggest herpes encephalitis.

Aging reduces neostriatal responsiveness to N-methyl-D-aspartate and dopamine: an in vitro electrophysiological study.

Excitatory amino acids and dopamine interact to control information flow in the neostriatum. The present study was designed to examine some of the age-induced alterations in the interaction of these two neurotransmitter systems. First, responsiveness of neostriatal neurons to glutamate and N-methyl-D-aspartate was compared in neurons from young and in aged animals. N-Methyl-D-aspartate function was chosen for emphasis because declines in cognitive processes during aging are thought to involve changes in this excitatory amino acid receptor. Second, the age-related changes in dopamine's ability to modulate responses mediated by excitatory amino acid receptors was examined. Specifically, the ability of dopamine to differentially modulate responses induced by N-methyl-D-aspartate and glutamate was assessed. There is considerable evidence for alterations in dopamine receptors and behavioral responses to dopamine in aged animals. It thus becomes important to determine how these alterations are reflected at an electrophysiological level. The responses to application of excitatory amino acid agonists and dopamine as well as changes in synaptic responses mediated by activation of N-methyl-D-aspartate receptors were assessed in 69 neurons obtained from young Fischer 344 rats (3-5 months) and young cats (3-4 years) and 69 neurons obtained from aged Fischer 344 rats (24-26 months) and aged cats (10-16 years) using an in vitro slice preparation. The results indicated that populations of aged neurons from both rats and cats displayed qualitative and quantitative alterations in responses to iontophoretic application of excitatory amino acid receptor agonists. These alterations included lack of response, unusual responses consisting of depolarizations without action potentials or combinations of prepotentials and full amplitude action potentials. Threshold currents for induction of responses were also significantly elevated in neurons from aged animals. Synaptic response components mediated by activation of N-methyl-D-aspartate receptors in aged rats were reduced as well. Exposure to Mg(2+)-free artificial cerebrospinal fluid resulted in marked increases in the size of responses evoked by local stimulation in young neurons from rats. These increases, which are mediated by activation of N-methyl-D-aspartate receptors, were significantly attenuated in aged neurons. The ability of dopamine to modulate responses mediated by activation of excitatory amino acid receptors was reduced in cells from both aged rats and cats. Subpopulations of cells were either unresponsive to dopamine or required higher iontophoretic current intensities to modulate excitatory amino acid-induced responses. The present findings further document age-induced changes in neostriatal electrophysiology indicating that interactions between excitatory amino acids and dopamine appear to be compromised during aging. They emphasize alterations in N-methyl-D-aspartate receptor function and suggest further than the ability of neostriatal neurons to integrate information is altered during aging. The present findings are supported by data from the literature indicating decreases in N-methyl-D-aspartate receptor function during aging. Furthermore, the decreases in excitatory amino acid function during aging suggest that therapeutic interventions designed to prevent or retard the deleterious effects of age in the neostriatum might be directed toward enhancing excitatory amino acid receptor function.

Age-induced changes in electrophysiological responses of neostriatal neurons recorded in vitro.

The present studies were undertaken to determine whether the major electrophysiological characteristics of neostriatal neurons are altered during aging. The passive and active membrane properties of 130 neostriatal neurons obtained from young (three to five months, N = 65) and aged (24-26 months, N = 65) Fischer 344 rats were compared using an in vitro slice preparation. The results indicated that in a population of aged neostriatal neurons the majority of the electrophysiological changes that occurred resulted in decreases in cellular excitability. These changes included increased threshold to induce action potentials by intracellular current injection and decreased negativity of membrane potentials at which such action potentials were induced. In addition, there were increases in the amplitude of the action potential afterhyperpolarization and increases in the frequency of occurrence of accommodation when trains of action potentials were induced. These two latter effects can limit the frequency of action potential generation. The thresholds to elicit synaptically evoked depolarizing responses and action potentials were increased. The results also indicated that a number of basic electrophysiological parameters were unchanged by the aging process. These included action potential amplitude, rise time and duration, resting membrane potential, input resistance and time constant. Although thresholds for the induction of synaptic and action potentials by extracellular stimulation were increased, the latency, amplitude and duration of the evoked depolarization remained unchanged. These findings suggest that the ability of neostriatal neurons to integrate spatiotemporal inputs must be severely compromised in this population of aged cells. Furthermore, the present findings, when compared with age-induced electrophysiological alterations in neurons in other brain areas, indicate that age may differentially alter electrophysiological properties of neurons in separate nuclei. Profiles of age-related changes in neurophysiological properties of neurons provide important information that can be related to the contributions of individual neural areas to the behavioral effects of aging.

Neurophysiological, pharmacological and morphological properties of human caudate neurons recorded in vitro.

Tissue samples from the caudate nucleus were obtained from eight children (eight to 172 months of age) who underwent hemispherectomies for the relief of intractable seizures. Neurophysiological, pharmacological and morphological properties of caudate neurons were characterized by intracellular recordings in an in vitro slice preparation. These properties were compared with those of tissue obtained from animal studies. Electrophysiological properties of human caudate neurons that were similar to those of cat caudate and rat neostriatal cells included resting membrane potential, input resistance, action potential rise time, fall time, duration and action potential afterhyperpolarization amplitude, as well as the general characteristics of locally evoked synaptic responses. Properties that were different included action potential amplitudes and time-constants. Human caudate neurons also displayed responses similar to those of cat caudate or rat neostriatal cells to manipulation of excitatory amino acid receptor systems and to dopamine application. Kynurenic acid, a broad-spectrum excitatory amino acid receptor antagonist, decreased the amplitude of evoked synaptic responses, indicating that they were partially mediated by excitatory amino acids. In Mg2+ free Ringer's solution, the amplitudes and durations of postsynaptic responses were increased and bursts of action potentials were induced. These effects were mediated by activation of N-methyl-D-aspartate receptors since they were blocked by 2-amino-5-phosphonovalerate, a specific N-methyl-D-aspartate-receptor antagonist. Iontophoretic application of N-methyl-D-aspartate also induced membrane oscillations and bursts in almost all caudate neurons. Dopamine decreased the amplitude of postsynaptic responses, an effect antagonized by domperidone, a selective D2 dopamine receptor antagonist. Developmentally, the greatest change was an increase in action potential amplitude, although input resistance decreased and action potential afterhyperpolarization amplitude increased. Postsynaptic responses were similar across age. All but one of the caudate neurons identified by intracellular injection of biocytin or Lucifer Yellow were medium-sized spiny cells. These experiments show that human caudate neurons display a number of electrophysiological properties similar to rat neostriatal or cat caudate neurons recorded in brain slices. Furthermore, few electrophysiological parameters changed significantly over the age period examined suggesting that the human caudate at eight months displays many of the neuronal functions of the more mature caudate nucleus.

Intracellular neurophysiological analysis reveals alterations in excitation in striatal neurons in aged rats.

Intracellular recordings were used to characterize the physiological changes underlying decreases in excitation observed in striatal neurons during the aging process. Rats were divided into 3 age groups: young (3-5 months), middle-aged (10-12 months) and aged (greater than 24 months). All experiments were performed in urethane-anesthetized rats. Recordings were obtained from 33 neurons in young, 17 in middle-aged and 20 in aged rats. When identified by intracellular injections of Lucifer yellow all recorded neurons were medium-sized spiny cells. Resting membrane potentials were at least -40 mV and action potentials greater than 35 mV. Postsynaptic responses were evoked by stimulation of frontal cortex. In all recorded neurons, regardless of age, excitatory postsynaptic potentials (EPSPs) could be evoked. However, the threshold currents for eliciting both EPSPs and synaptically driven action potentials were significantly higher in neurons obtained from aged rats than those recorded in the other two groups. Other changes in excitation in aged striatal neurons consisted of absence of spontaneously occurring EPSPs, higher current to induce firing by intracellular injections of depolarizing current and an inability of orthodromically induced action potentials to follow paired stimulation pulses to the cortex at short interpulse intervals. These data were interpreted to indicate that a combination of changes in synaptic connectivity and in membrane properties underlie the decreases in excitation. Together with our previous findings obtained from aged cats these results indicate that decreased neuronal excitability is a major effect of aging in the striatum.

Basal forebrain neurons have axon collaterals that project to widely divergent cortical areas in the cat.

Basal forebrain neurons with axon collaterals that project to widely divergent cortical areas were identified using retrograde transport of two labels. A proportion of neurons in the basal forebrain have axon collaterals that project to both anterior (precruciate gyrus) and posterior (marginal and suprasylvian gyri) cortical areas or to medial (precruciate gyrus) and lateral (ectosylvian and anterior suprasylvian gyri) cortical areas. These branched fibers originate from cells located predominantly in the basal nucleus of Meynert. The existence of such neurons suggests that individual basal forebrain cells are capable of influencing widespread neocortical zones in the cat.

Norepinephrine modulates excitatory amino acid-induced responses in developing human and adult rat cerebral cortex.

These experiments were designed to assess the ability of norepinephrine and its beta-receptor agonist, isoproterenol, to modulate responses induced by activation of excitatory amino acid receptors in brain slices obtained from developing human cortex or adult rat cortex. Human cortical slices were obtained from children undergoing surgery for intractable epilepsy (9 months to 10 yr of age). For comparison, slices were also obtained from rats (2-3 months of age). Iontophoretic application of glutamate, N-methyl-D-aspartate or alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) produced excitatory responses consisting of membrane depolarizations accompanied by action potentials. Iontophoretic or bath application of norepinephrine or isoproterenol enhanced responses evoked by glutamate or N-methyl-D-aspartate. Depolarizations occurred with shorter latencies and their amplitudes increased. Action potential frequency was also increased and responses were of longer duration. In contrast, norepinephrine or isoproterenol had no effect on responses induced by AMPA. The enhancement of responses induced by N-methyl-D-aspartate or glutamate was antagonized by the beta-adrenergic receptor antagonist propranolol. Similar findings were obtained from neurons in humans or rats. These results suggest that norepinephrine, possibly via beta-receptors, potentiates responses mediated by glutamate and N-methyl-D-aspartate receptors without affecting those mediated by AMPA receptors. These effects were observed at all ages studied, indicating that the ability of norepinephrine to modulate excitatory neuronal transmission is well developed in human cortex by 9 months of age.

The kinetics and displacement of [11C]flunitrazepam in the brain of the living baboon.

The distribution and kinetics of [11C]flunitrazepam in the brain were studied by positron emission tomography in the living baboon. Flunitrazepam was labelled on the methyl group with the 20 min positron emitter carbon 11. Fifteen to 25 mCi corresponding to 15-30 nmol were injected i.v. and sequential tomographic pictures of the brain were obtained. In some experiments, therapeutic doses of various benzodiazepines were injected i.v. subsequently in order to study the displacement of the radioactive ligand from brain structures. Lorazepam was shown to displace [11C]flunitrazepam from brain tissue, although other benzodiazepines (chlordiazepoxide, Ro 116896 and Ro 116893) led to a redistribution of the radioactive ligand in the body accompanied by an increase of brain radioactivity.