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Role of nucleosides and nucleotides in the immune system, gut reparation after injury, and brain function.

Emerging evidence indicates the importance of nucleosides and nucleotides in the maintenance of functions of the bone marrow hematopoietic cells, intestinal mucosa, and the brain, which have limited de novo synthesis of purine and pyrimidine bases. We have found that nucleosides and nucleotides stimulate hemopoieses and increase peripheral neutrophil counts in mice treated with cyclophosphoamide. Intraperitoneal administration of nucleosides and nucleotides decreased bacterial translocation, the number of colony-forming units, and increased survival against methicillin-resistant Staphylococcus aureus. In vitro immune studies in mice showed that nucleosides and nucleotides increase the delayed-type cutaneous hypersensitivity and the popliteal lymph node blastogenic response to antigens, allogens, and mitogens. Both intraperitoneal and oral administration of nucleosides and nucleotides reduced endotoxin-induced bacterial translocation and improved injury to the gut in protein-deficient mice. However, oral administration of nucleosides and nucleotides in experimental colitis resulted in a worsening of colitic conditions and increased interleukin-8 and tumor necrosis factor-alpha concentrations in inflamed colonic portions, indicating the pro-inflammatory activities of nucleosides and nucleotides. Memory-deficient senescence-accelerated mice and mice with dementia showed improved memory with dietary nucleosides and nucleotides supplementation. These results indicate that supplementation with nucleosides and nucleotides is beneficial to the functions of the system and the brain. However, beneficial effects to the gut appear to depend on the type of damage sustained by the gut.

Animals↗

Structural and functional brain imaging in Friedreich's ataxia.

BACKGROUND: Although the major neuropathologic changes in Friedreich's ataxia (FA) affect the spinal cord and peripheral nerves, we previously found abnormally increased glucose metabolism in the cerebral hemispheres in ambulatory patients and a return toward normal metabolism in nonambulatory patients. OBJECTIVE: To determine whether brain atrophy accompanies the decline in cerebral glucose metabolism in FA and whether the degree of atrophy and the extent of decline in cerebral glucose metabolism are related to clinical severity. DESIGN: Prospective series. SETTING: University referral center. PATIENTS: Twenty-two patients with FA and 26 patients with dizziness, headache, or minor acute head trauma, serving as control subjects, who underwent computed tomographic scans that were interpreted as normal. MEASURES: In patients with FA and control subjects, regional atrophy was assessed using subjective and objective measures on computed tomographic scans. In patients with FA, local cerebral glucose metabolism was measured with positron emission tomography, and clinical severity was assessed with a clinical rating scale. RESULTS: Atrophy in the cerebral hemispheres, cerebellum, and brain stem was significantly greater in patients with FA than in control subjects, and the degree of atrophy correlated with the clinical severity. Local cerebral metabolic rate for glucose declined significantly from the initially elevated levels in the thalamus, cerebellum, and brain stem in correlation with increasing clinical severity. CONCLUSIONS: The structure and function of wide-spread brain regions including the cerebral hemispheres are abnormal in FA, and these abnormalities correlate with the clinical severity.

Adult↗

Anatomical and functional brain imaging using high-resolution echo-planar spectroscopic imaging at 1.5 Tesla.

High-resolution echo-planar spectroscopic imaging (EPSI) of water resonance (i.e. without water suppression) is proposed for anatomic and functional imaging of the human brain at 1.5 T. Water spectra with a resolution of 2.6 Hz and a bandwidth of 333 Hz were obtained in small voxels (1.7 x 1.7 x 3 mm3) across a single slice. Although water spectra appeared Lorentzian in most of the voxels in the brain, non-Lorentzian broadening of the water resonance was observed in voxels containing blood vessels. In functional experiments with a motor task, robust activation in motor cortices was observed in high-resolution T2* maps generated from the EPSI data. Shift of the water resonance frequency occurred during neuronal activation in motor cortices. The activation areas appeared to be more localized after excluding the voxels in which the lineshape of the water resonance had elevated T2* and became more non-Lorentzian during the motor task. These preliminary results suggest that high-resolution EPSI is a promising tool to study susceptibility-related effects, such as BOLD contrast, for improved anatomical and functional imaging of the brain.

Adult↗

Function of metal-ion homeostasis in the cell division cycle, mitochondrial protein processing, sensitivity to mycobacterial infection and brain function.

A novel Saccharomyces cerevisiae mutant, unable to grow in the presence of 12.5 mmol l-1 EGTA, was isolated. The phenotype of the mutant is caused by a single amino acid change (Gly149 to Arg) in the essential yeast cell division cycle gene CDC1. The mutant could be suppressed by overexpression of the SMF1 gene, which codes for a plasma membrane Mn2+ transporter. We observed that the yeast SMF1 gene shares homology with the mouse Nramp gene. Nramp (Bcg) was cloned as a gene responsible for mouse resistance to infection with mycobacteria and is identical with the Ity and the Lsh genes conferring resistance to infection by Salmonella typhimurium and Leishmania donovani, respectively. Although the cloning of Nramp identified the gene responsible for the resistance of mice to mycobacteria, its function is unknown. We propose that the mammalian protein, like the yeast transporter, is a Mn2+ and/or Zn2+ transporter. Following the phagocytosis of a parasite into the phagosome, the macrophage produces reactive oxygen and/or nitrogen intermediates that are toxic for the internalized bacteria. The survival of the pathogen during the burst of macrophage respiratory activity is thought to be partly mediated by microbial superoxide dismutase (SOD), which contains Mn2+ or Fe2+ in its active centre. Nramp may transport Mn2+ from the extracellular milieu into the cytoplasm of a macrophage and, after the generation of the phagosome, remove Mn2+ from the organelle. Thus, the Mn(2+)-depletion of the phagosome microenvironment by the Nramp gene product may be a rate-limiting step in the metalloenzyme's production by the engulfed bacteria. This limitation will restrict the mycobacterial ability to produce active enzymes such as SOD and prevent the propagation of the ingested microorganisms. Conversely, an increased concentration of Mn2+ in the phagosome caused by a defective Nramp transporter (Bcgs) may promote the growth of the mycobacteria and render the organism sensitive to the pathogen. We use a similar approach to identify, clone and study other metal-ion transporters.

Animals↗

Brain function in epilepsy: midbrain, medullary, and cerebellar interaction with the rostral forebrain.

Against the background previous findings in epileptic patients, in whom electroencephalographic recordings were obtained from numerous deep and surface brain sites during seizures, rhesus monkeys with electrodes implanted into specific brain sites were used to demonstrate anatomical connections by evoked potential techniques and to serve as models of experimental epilepsy. In the animals, many monosynaptic connections were revealed between forebrain sites consistently involved in seizures in patients and more caudal brain sites subserving functions of sensory perception, eye movement, synaptic chemical transmission, and motor coordination. Further, the participation of these interrelated sites during seizures was demonstrated. The findings provide an anatomical-physiological explanation for many of the clinical phenomena observed in epileptic patients and a rationale for the use of cerebellar stimulation as a treatment.

Animals↗

Functional brain imaging and the neuropathology of schizophrenia.

We know much more about the anatomy of the frontal lobes than we do about their functions or how these functions go wrong in schizophrenia. Key areas for brain imaging research that will increase our understanding of frontal function concern (1) long-range functional connectivity and the mechanisms by which one brain region modulates activity in another and (2) the mechanisms underlying specific signs and symptoms associated with schizophrenia.

Brain↗

Brain function and writing with the unaccustomed left hand.

Twenty right-handed subjects were asked to handprint a passage containing all the letters of the alphabet once with each hand. The purpose was to describe the changes a document examiner can expect to find in handprinting done with the unaccustomed left hand and to offer a hypothesis as to why these changes occur. It was found that many of the writers displayed persistent differences between their right- and left-hand writings. It is suggested that these differences were due to both a lack of manual dexterity when writing with the unaccustomed left hand and to the fact that different neurophysiological processes are involved.

Brain↗

Functional brain imaging of symptoms and cognition in schizophrenia.

The advent of functional magnetic resonance imaging and positron emission tomography has provided novel insights into the neural correlates of cognitive function and psychopathological symptoms. In patients with mental disorders, cognitive and emotional processes are disrupted. In this chapter, we review the basic methodological and conceptual principles for neuroimaging studies in these patients. By taking schizophrenia as an example, we outline the cerebral processes involved in the symptoms of this disorder, such as auditory hallucinations and formal thought disorder. We also characterize the neural networks involved in their emotional and cognitive dysfunction.

Brain↗

Functional brain imaging using fMRI and optical topography in infancy.

We performed functional magnetic resonance imaging and optical topography over the visual cortex of subjects during sedation with pentobarbital, and 8-Hz flickering light was intermittently projected onto their eyelids. Two age groups were analyzed: infants <60 days old and those >60 days old (corrected for gestational age at birth). The stimulus-related signal change was positive in the lateral geniculate nucleus regardless of the infant's age, but it reversed in the primary visual cortex from positive in the infants less than 60 days old to negative in the infants more than 60 days old (Experiment 1). We also investigated spontaneous changes in the cerebral oxygenation state of neonates and infants aged 1 month during quiet sleeping by using a form of multi-channel near-infrared spectroscopy: non-invasive optical topography. Spatially synchronized oscillations of changes in the concentration of oxy-hemoglobin (oxy-Hb) and deoxy-Hb were observed throughout the occipital cortex in neonates but not in the infants aged 1 month. Time series analysis based on the theory of non-linear oscillations showed that the mean periods of the oscillation for each infant ranged from 11 to 18s. The phase lag of oxy-Hb relative to deoxy-Hb was stable at about 3 pi/4 in neonates but in the infant aged 1 month, time lag was unstable. These findings may be due to rapid synaptogenesis in early life.

Journal Article↗

Cytochromes P450 in brain: function and significance.

The presence and activity of cytochromes P450 in brain regions and various brain cells have been extended and advanced over the last five years covered by this review. Using in situ hybridization and immunohistochemical techniques, many cytochrome P450 enzymes have been demonstrated to be present in brain and to have a regional rather than universal distribution. Many of these various cytochromes P450 have been shown to catalyze the metabolism of neurosteroids as well as other biologically significant compounds in brain. In addition, many cytochrome P450 enzymes have been implicated in the metabolism of psychoactive drugs such as neuroleptics and antidepressants. The regulation of cytochrome P450 expression has been studied at greater detail, the regulation of aromatase being a prominent example during the last five years.

Animals↗

Imaging brain function in animals to understand drugs of abuse and potential pharmacotherapies.

Brain imaging studies can be used to enhance current understanding of how CNS drugs act. Because the brain is in reality a collection of independent, albeit interconnected, neural organs, identification of sites of brain action are critical to an appraisal of how each drug exerts its different behavioral and physiological effects. For new drugs not yet tested in humans, identification of which neuronal structures are affected by a drug can give clues as to what to expect from the drug if it is eventually exposed to clinical testing. Receptor binding autoradiography, more than any other technique, pinpoints the distribution of those sites at which a given drug acts. When combined with 2-DG autoradiography, the intensity and direction of the action at each of these sites, as well as the impact of these actions on additional sites, can be appreciated. In addition to identification of sites of drug action, brain imaging studies can be used to identify classes of drug action, interactions between drugs, and, perhaps more than any other technique, enhance the appreciation of the similarities and differences between the effects in animals and those in humans. When applied to drugs of abuse, brain imaging studies can be used to help identify key physiological events underlying drug reinforcement as well as those important for various physiological effects of each drug. Armed with such information, brain imaging techniques can play a unique role as one component of an effort to discover pharmacotherapies for drug abuse.

Animals↗

Imaging techniques in the analysis of brain function and behaviour.

Techniques such as positron-emission tomography, single-photon-emission computed tomography, functional magnetic-resonance imaging and magnetoencephalography permit the observation of biological processes in the brain in a noninvasive manner. They have yielded new insights into the biological interrelations of sensory, motor and cognitive functions, as well as into brain diseases. Combined use of these techniques may provide more information than just the sum of its constituents, and this may narrow the gap between the biological data provided by these techniques and the mental models described by clinicians, mathematicians, psychologists and philosophers.

Brain↗

Functional brain imaging using a blood oxygenation sensitive steady state.

Blood oxygenation level dependent (BOLD) functional MRI (fMRI) is an important method for functional neuroimaging that is sensitive to changes in blood oxygenation related to brain activation. While BOLD imaging has good spatial coverage and resolution relative to other neuroimaging methods (such as positron emission tomography (PET)), it has significant limitations relative to other MRI techniques, including poor spatial resolution, low signal levels, limited contrast, and image artifacts. These limitations derive from the coupling of BOLD functional contrast to sources of image degradation. This work presents an alternative method for fMRI that may over-come these limitations by establishing a blood oxygenation sensitive steady-state (BOSS) that inverts the signal from deoxygenated blood relative to the water signal. BOSS fMRI allows the imaging parameters to be optimized independently of the functional contrast, resulting in fewer image artifacts and higher signal-to-noise ratio (SNR). In addition, BOSS fMRI has greater functional contrast than BOLD. BOSS fMRI requires careful shimming and multiple acquisitions to obtain a precise alignment of the magnetization to the SSFP frequency response.

Artifacts↗

Functional brain mapping in freely moving rats during treadmill walking.

A dilemma in functional neuroimaging is that immobilization of the subject, necessary to avoid movement artifact, extinguishes all but the simplest behaviors. Recently, we developed an implantable microbolus infusion pump (MIP) that allows bolus injection of radiotracers by remote activation in freely moving, nontethered animals. The MIP is examined as a tool for brain mapping in rats during a locomotor task. Cerebral blood flow-related tissue radioactivity (CBF-TR) was measured using [14C]-iodoantipyrine with an indicator-fractionation method, followed by autoradiography. Rats exposed to walking on a treadmill, compared to quiescent controls, showed increases in CBF-TR in motor circuits (primary motor cortex, dorsolateral striatum, ventrolateral thalamus, midline cerebellum, copula pyramis, paramedian lobule), in primary somatosensory cortex mapping the forelimbs, hindlimbs and trunk, as well as in secondary visual cortex. These results support the use of implantable pumps as adjunct tools for functional neuroimaging of behaviors that cannot be elicited in restrained or tethered animals.

Animals↗

Functional brain activation during arithmetic processing in females with fragile X Syndrome is related to FMR1 protein expression.

Arithmetic processing deficits in persons with fragile X Syndrome (fraX), the most common heritable cause of mental retardation, are well known. In this study, we characterize the neural underpinnings of these performance deficits using functional MRI. Given that a single gene defect (FMR1) is known to be responsible for this disorder, we also assess whether brain activation in arithmetic processing areas is related to amount of FMR1 protein expression (FMRP). Subjects included 16 females with fraX, and 16 female age-matched controls. Subjects viewed arithmetic equations with two (1 + 3 = 4) or three (2 + 3 - 1 = 5) operands, and were asked to judge whether the results were correct or not. Subjects with fraX showed significant impairment in behavioral performance on the 3-operand but not the 2-operand arithmetic equations. Significant brain activation was observed bilaterally in the prefrontal and parietal cortices for unaffected subjects, and bilateral prefrontal and left angular gyrus for subjects with fraX, for both trial types. Subjects with fraX exhibited less overall activation than did unaffected subjects in both types of trials; and, unlike the unaffected group, did not show increased extent of activation in association with greater task difficulty. During the 3-operand trials, activation in bilateral prefrontal and motor/premotor, and left supramarginal and angular gyri were positively correlated with FMRP, suggesting that decreased FMR1 protein expression underlies deficits in math performance in persons with fraX. More broadly, this investigation demonstrates a unique bridging of cognitive and molecular neuroscience and represents a useful approach for the study of brain development and function.

Adolescent↗

Functional brain imaging of episodic and semantic memory with positron emission tomography.

Human memory is composed of several independent but interacting systems. These include a system for remembering general knowledge, semantic memory, and a system for recollection of personal events, episodic memory. The results of positron emission tomography (PET) studies of regional cerebral blood flow indicate that networks of distributed brain regions subserve episodic and semantic memory. Some networks seem to be generally engaged in memory processes whereas the involvement of others is specific to factors such as the type of information to be remembered or the level of retrieval success. The PET findings help to understand memory dysfunction (a) by showing that multiple brain regions are involved in different memory processes and (b) by sharpening the interpretation of the functional role of different brain regions.

Brain↗

Transient crossed aphasia evidenced by functional brain imagery.

Crossed aphasia refers to language deficits induced by unilateral right hemisphere injuries in right-handed people who had no previous history of brain damage. One of the intriguing questions concerning crossed aphasia is the atypical language representation in the brain. In this respect, fMRI is a valuable tool for understanding the neural basis of crossed aphasia. Here, we used neuropsychological and fMRI language tasks in a right-handed subject who presented a crossed aphasia due to a right frontal meningioma. fMRI maps from two language tasks showed bilateral patterns of activation. In the light of previous studies reporting much frequent bilateral than exclusive right hemisphere representations, we hypothesise that some crossed aphasia cases could occur in subjects with bilateral language representation.

Aphasia↗