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Biomedical subjects

I Holopainen

Publications and source records attributed to I Holopainen.

At least 19 recordsLinked to original sources
PubMed2002

Focal and global cortical hypometabolism in patients with newly diagnosed infantile spasms.

OBJECTIVE: To evaluate the occurrence and prognostic importance of focal defects in cerebral cortical glucose metabolism in infants with newly diagnosed symptomatic and cryptogenic infantile spasms. PATIENTS AND METHODS: Ten children with symptomatic and seven with cryptogenic infantile spasms underwent MRI, video-EEG, and PET using fluorodeoxyglucose as a tracer within 2 weeks of diagnosis. PET was repeated at 1 year of age in 12 patients. RESULTS: Cortical hypometabolic foci were found in 13 children (77%) with newly diagnosed spasms (six cryptogenic and seven symptomatic). The hypometabolic foci disappeared in seven of nine reexamined at age 1. The occipital foci disappeared in all (n = 6). Focal findings on PET correlated well with focal findings on video-EEG. There was no difference in quantitative cortical or subcortical glucose metabolic rate at the onset of infantile spasms between children with cryptogenic and symptomatic etiology of spasms. The glucose metabolic rate at the onset of spasms or focal lesions in glucose metabolism did not have prognostic value for seizure outcome. CONCLUSIONS: Infantile spasms are often associated with transient cortical, especially occipital, hypometabolic foci that are not necessarily associated with structural lesions and do not indicate a poor prognosis.

Cerebral Cortex↗
PubMed2001

Cognitive functions of adolescent childhood cancer survivors assessed by event-related potentials.

BACKGROUND: Neurophysiological methods were applied to examine subtle central nervous system (CNS) adverse effects for adolescent childhood cancer survivors. We analyzed auditory event-related potentials (ERPs)-P300 and MMN/P3a complex-to find out whether there was impaired attention orientation in asymptomatic cancer survivors, and whether these ERP methods could be used as more objective tools in detecting those survivors who might need academic testing. Previous clinical studies of P300 have focused on leukemia survivors. MMN for cancer survivors has not been reported. PROCEDURE: The subjects were survivors of childhood leukemia (n=11) and solid tumors (n=8), as well as healthy controls (n=10). The mean age was 15.5 years for survivors and 15.9 years for controls. Pure sine-wave tones (500 and 553 Hz, 100 ms) were used as stimuli in an oddball paradigm. The ERPs to frequency change were measured. MMN recordings were performed in a passive non-attended situation where the subject was watching a voiceless video cartoon. P300 was produced thereafter, but in an active attend situation, by the same auditory oddball paradigm as MMN. RESULTS: A significant difference was detected between the groups for the latency of P300 at electrodes Cz (P = 0.03) and C4 (P = 0.05). The cancer survivors had prolonged P300 latencies as an indication of prolonged short-term memory processing. The area and latency parameters of MMN did not differ significantly between the study groups, but in cancer survivors, the area and the mean amplitude of the subsequent P3a wave were diminished. The results indicate that the discrimination process was not as easy for the survivors as for the controls. However, it seems that in cancer survivors the basic mechanism starting attention shift to novel stimuli is not impaired. CONCLUSIONS: These results indicate that it is important to carefully evaluate the proper methods for the teaching of children who are survivors of malignancies. The auditory information may not always lead to the best possible learning results.

Achievement↗
PubMed2001

Early and late mismatch negativity elicited by words and speech-like stimuli in children.

In auditory perception the brain's attentional and preattentional mechanisms select certain stimuli for preferential processing and filter out irrelevant input. This study investigated nonattentive auditory processing in children. Event-related potentials (ERPs) provide a means to study neural correlates related to language and speech-sound processing. Mismatch negativity (MMN) is an ERP wave that indicates attention-independent perceptual change detection. In this study cortical ERPs were elicited by complex tones, naturally spoken words, and pseudowords, with each stimulus type containing equal acoustical elements. Tones elicited a bifurcated mismatch negativity (MMN), with early MMN (peaking at 150-200 ms) being more dominant. On the other hand, words elicited a strong late MMN, peaking at about 400-450 ms after stimulus onset. The MMN wave form was significantly weaker for pseudowords than for words. The late MMN wave, especially for word differences, was found to reflect summating MMN generators and memory trace formation on gestalt bases. Results suggest that the auditory processing, even nonattended, is highly associated with the cognitive meaning of the stimuli.

Age Factors↗
PubMed1999

A new metabolite contributing to N-acetyl signal in 1H MRS of the brain in Salla disease.

OBJECTIVE: To determine whether N-acetylaspartate (NAA) is reduced in patients with Salla disease, a neurodegenerative disorder. BACKGROUND: 1H MRS allows the brain metabolism to be studied noninvasively in vivo. N-acetyl (NA) is composed primarily of NAA, which is regarded as a neuronal marker. The NA signal in 1H MRS is reduced in several neurodegenerative disorders. Increased NA signal has thus far only been found in Canavan's disease as a result of NAA accumulation in the brain tissue. In Salla disease, an autosomal recessive free sialic acid storage disorder, N-acetylneuraminic acid (NANA), accumulates in lysosomes of brain tissue. METHODS: The authors studied eight patients with Salla disease (age range, 6 to 44 years) and eight age-matched healthy volunteers using quantitative 1H MRS. The spectra were obtained from two selected 8-cm3 volumes of interest localized in the basal ganglia and in the parietal white matter using conventional 1.5-T MRI equipment. The spectral resonance lines of NA groups, creatine and phosphocreatine (Cr), and choline-containing compounds (Cho) were analyzed quantitatively. All MR images were evaluated to verify the state of myelination. RESULTS: 1H MRS from parietal white matter revealed 34% higher NA and 47% higher Cr concentrations, and a 35% lower Cho concentration in the patients with Salla disease compared with the age-matched control subjects. The patients had a 22% higher water content in their parietal white matter, whereas in the basal ganglia the water concentrations did not differ significantly. In the patients' basal ganglia the Cr concentration was 53% higher. CONCLUSIONS: NAA is considered to be a neuronal marker that, except for Canavan's disease, has been found or assumed to be either stable or reduced. However, in Salla disease the high NA signal may have a contribution from accumulated lysosomal NANA, which offsets the possible loss of NAA. The high Cr is in line with the increased glucose uptake found in our earlier 2-fluoro-2-deoxy-D-glucose-PET study, reflecting increased energy demand. It is worth noting that in a conventional 1H MRS ratio-based analysis these underlying abnormalities would have remained undetected. Our study thus emphasizes the importance of a quantitative assessment of metabolite concentrations in 1H MRS for detecting altered brain metabolism.

Adolescent↗
PubMed1999

Genotype and phenotype in patients with dihydropyrimidine dehydrogenase deficiency.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G-->A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered beta-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.

Animals↗
PubMed1999

Increased brain glucose utilization in Salla disease (free sialic acid storage disorder).

UNLABELLED: Salla disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed evidence of dysmyelination, but the biological mechanism of the brain dysfunction is unknown. METHODS: Nine patients with Salla disease (age 2.5 mo-42 y) presenting the disease in varying degrees of severity were studied by PET using 2-fluoro-2-deoxy-D-glucose (FDG) as a tracer. Local cerebral metabolic rates for glucose (LCMRGlc) in individual brain regions were compared with controls. RESULTS: The FDG PET results showed significantly increased LCMRGlc values in the frontal and sensorimotor cortex and especially in the basal ganglia of the patients. Cerebellar hypometabolism was present in all seven patients with marked ataxia, whereas the less severely affected patients without obvious ataxia had normal or even high glucose uptake in the cerebellum. CONCLUSION: The increased cerebral glucose utilization is a constant finding in Salla disease and may reflect the basic defect of the sialic acid metabolism in this disorder. The FDG PET findings in the cerebellum suggest a correlation between glucose uptake and the severity of the clinical symptoms.

Adolescent↗
PubMed1995

Endogenous gamma-L-glutamylglutamate is a partial agonist at the N-methyl-D-aspartate receptors in cultured cerebellar granule cells.

gamma-L-Glutamylglutamate (LGG), an endogenous constituent of the brain, reduced the glutamate-evoked increase in intracellular Ca2+ in cultured cerebellar granule cells. The extent and properties of this inhibition were different at different Mg2+ concentrations. The intracellular Ca2+ response to NMDA was slightly enhanced by 0.1 mM LGG in normal (1.3 mM) Mg2+ medium, but in Mg(2+)-free medium LGG was stimulatory at low (0.1-1 microM) NMDA and inhibitory at high (0.1-1 mM) NMDA concentrations. In the absence of Mg2+, LGG alone increased cytosolic free Ca2+ and depolarized the cells. These effects were potentiated by glycine and blocked by extracellular Mg2+, 2-amino-5-phosphonopentanoate (APV), 7-chlorokynurenate, 3-amino-1-hydroxypyrrolidin-2-one (HA-966) and 5,7-dinitroquinoxaline-2,3-dione (MNQX). The results indicate that LGG is a partial NMDA agonist. On the other hand, the non-NMDA antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 6,7-dinitroquinoxaline-2,3-dione (DNQX) also inhibited the effects of LGG. This indicates an involvement of non-NMDA receptors in the actions of LGG. The consequent depolarization may also contribute to the activation of NMDA receptor-governed ionophores.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Practical issues in the clinical application of mismatch negativity.

The mismatch negativity (MMN) recordings provide an objective measure of the preattentive, automatic auditory discrimination function. This article deals with issues central to the recording of the MMN and the interpretation of the results for clinical and electrodiagnostic purposes. The methods of acquiring as pure an MMN response as possible, i.e., one not contaminated by auditory cortical responses reflecting other functions, are discussed first. Second, other technical questions associated with the recording are reported on, e.g., what MMN parameters should be recorded and how, what is the smallest recordable MMN response, and what is the repeatability of the MMN recordings. Then, the effect of various physiological factors on the MMN (age, alertness, gender, topographic distribution of the MMN) is considered. The correlation between auditory discrimination performance and the MMN amplitude, observed in normal population, is dealt with. Finally, there is a short concluding overview on clinical findings of MMN recordings and discussion on their electrodiagnostic applications.

Amplifiers, Electronic↗
PubMed1994

Pharmacological characterization of glutamate binding sites in cultured cerebellar granule cells and cortical astrocytes.

Membranes prepared from cerebellar granule cells and cortical astrocytes exhibited specific, saturable binding of L-[3H]glutamate. The apparent binding constant KD was 135 nM and 393 nM and the maximal binding capacity Bmax 42 and 34 mumol/kg in granule cells and astrocytes, respectively. In granule cells the binding was strongly inhibited by the glutamate receptor agonists kainate, quisqualate, N-methyl-D-aspartate (NMDA), L-homocysteate and ibotenate, and the antagonist DL-5-aminophosphonovalerate. In astrocytes, only quisqualate among these was effective. L-Aspartate, L-cysteate, L-cysteinesulphinate and gamma-D-glutamylglycine were inhibitors in both cell types. The binding was totally displaced in both cell types by L-cysteinesulphinate with IC50 in the micromolar range. In astrocytes the binding was also totally displaced by quisqualate, but in granule cells only partially by NMDA, kainate and quisqualate in turn. It is concluded from the relative potencies of agonists and antagonists in [3H]glutamate binding that cerebellar granule cells express the NMDA, kainate and quisqualate types of the glutamate receptor, while only the quisqualate-sensitive binding seems to be present in cortical astrocytes.

Animals↗
PubMed1994

Ring chromosome 20 mosaicism in a girl with complex partial seizures.

The authors report an 11-year-old girl with epilepsy, poor school-performance and minor behavioural disorders. The epilepsy is characterized by complex partial seizures, sometimes progressing secondarily into generalized tonic-clonic seizures, and is poorly controlled by medical treatment. Chromosomal analysis revealed a ring chromosome 20 mosaicism. The affected patient shows signs of ring chromosome 20 syndrome, characterized in the present case by poor school-performance, behavioural disorders and epilepsy.

Child↗
PubMed1993

A specific antisense oligodeoxynucleotide to mRNAs encoding receptors with seven transmembrane spanning regions decreases muscarinic m2 and gamma-aminobutyric acidB receptors in rat cerebellar granule cells.

Many receptors that inhibit adenylyl cyclase belong to a common superfamily of receptors that couple to guanine nucleotide binding proteins. These receptors are thought to span the membrane seven times and to have a highly homologous amino acid sequence (LACADL) in the second membrane spanning region. The antisense oligodeoxynucleotide seven-transmembrane spanning receptor (7TMR), a 15-mer that binds to mRNA encoding this amino acid sequence, was added to cerebellar granule neuron cultures to decrease receptors of this superfamily. Intact antisense 7TMR was found to enter neurons. This 4- to 6-day treatment with antisense oligonucleotide decreased the total number of muscarinic receptor binding sites by about 40% and completely eliminated muscarinic m2 receptors that inhibit cyclic AMP formation. Antisense 7TMR treatment at 25 microM prevented the gamma-aminobutyric acid (GABA)B-mediated inhibition of cyclic AMP formation by about 40%. The treatment was effective in decreasing GABAA receptors only when the antisense oligonucleotide was given 1 day after plating the cells, and the receptor response assay was performed 6 days later. The half-maximal concentration of antisense 7TMR was approximately 5 microM in blocking GABAB receptors. Antisense 7TMR appeared to be specific because another antisense oligodeoxynucleotide sequence (15-mer) having four mismatches with 7TMR had no effect on either muscarinic m2 or GABAB receptor-mediated responses and did not affect the total number of muscarinic binding sites. These results are consistent with the view that antisense oligonucleotides decrease proteins in which the nucleotide sequence is known such as the muscaranic m2 receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Muscarinic m2 receptors in cerebellar granule cell cultures from rat: mechanism of short-term desensitization.

Cerebellar granule cell cultures of rat express only muscarinic m2 and m3 receptor subtypes and exhibit the pharmacological profile of muscarinic m2 receptors that couple to guanine nucleotide binding proteins to inhibit adenylyl cyclase. In vivo pretreatment with muscarinic agonists desensitizes the muscarinic m2 receptor with 50% complete desensitization within 15 to 20 min. After a 1-hr pretreatment with a maximal concentration of carbachol (short-term desensitization), m2 receptor responsiveness reappeared after a 1-hr treatment of cultures with atropine. However, after a 6-hr pretreatment with carbachol (long-term desensitization), m2 receptor responsiveness did not reappear after 1-hr treatment with atropine. Short-term desensitization was homologous for the m2 receptor because treatment of cultures with carbachol did not alter gamma-aminobutyric acidB receptor-mediated inhibition of adenylyl cyclase. Muscarinic m2 receptor desensitization was not mimicked by the addition of analogs of cyclic AMP, cyclic GMP or diacylglycerol to the cultures. The agonist-induced desensitization was not blocked by a cyclic AMP analog, 8-(4-chlorophenylthio)-cyclic AMP. Pretreatment with antisense oligodeoxynucleotides against the mRNA-encoding beta adrenergic receptor kinase attenuated the desensitization by carbachol (100 microM, 1 hr) of m2 receptors. Irreversible labeling of muscarinic m2 and m3 receptors with [3H]propylbenzilycholine mustard followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis produced a loss of the muscarinic m2 receptor (66-kDa protein), but not the muscarinic m3 receptor (92-kDa protein). We suspect that the short-term desensitization results from the phosphorylation of the muscarinic m2 receptor followed by loss of receptor from the plasma membrane.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Proposed antagonists at GABAB receptors that inhibit adenylyl cyclase in cerebellar granule cell cultures of rat.

The effects of various proposed GABAB receptor antagonists on baclofen-mediated inhibition of adenylyl cyclase were studied in cultured cerebellar granule cells from rat. (+/-)-Baclofen maximally inhibited adenylyl cyclase by approximately 60% of the basal enzyme activity with an EC50 value of 10 microM. 3-Aminopropane sulfonic acid (3-APS) and 5-aminovaleric acid (5-AVA) produced similar responses to that seen with (+/-)-baclofen. Saclofen reversed the action of (+/-)-baclofen, 50 microM, with a half maximal inhibitory concentration (IC50) of about 1.0 mM. The most effective antagonist in blocking the action of (+/-)-baclofen was 3-aminopropyl-diethoxy-methyl-phosphonic acid (CGP 35,348). In the presence of (+/-)-baclofen, 50 microM, the IC50 for CGP 35,348 was 290 microM and its inhibitory constant (KA) was 180 microM. The agonist-like actions of 3-APS and 5-AVA were antagonized by CGP 35,348 suggesting that 3-APS and 5-AVA may act as weak agonists at the GABAB receptor that inhibits adenylyl cyclase. All antagonists tested, except the new compound CGP 35,348, have very low potencies at GABAB receptors that inhibit adenylyl cyclase, though these compounds have been quite effective at other GABAB receptor-mediated events. Thus, the GABAB receptor which inhibits adenylyl cyclase differs pharmacologically from other reported GABAB receptor/effector systems and supports the existence of multiple receptor subtypes.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Effect of magnesium on calcium influx activated by glutamate and its agonists in cultured cerebellar granule cells.

The effects of Mg2+ on the glutamate-, kainate-, N-methyl-D-aspartate- and quisqualate-induced influx of 45Ca2+ were studied in cultured cerebellar granule cells. The N-methyl-D-aspartate- and quisqualate-evoked influx was totally and the kainate- and glutamate-evoked influx partially blocked in 1.3 mM extracellular Mg2+. The increase in influx induced by kainate, quisqualate and glutamate was maximal at 0.1 mM Mg2+, whereas N-methyl-D-aspartate was most effective in totally Mg(2+)-free media. D-2-Amino-5-phosphonovalerate blocked partially and phencyclidine completely the enhancement of Ca2+ influx by 1 mM quisqualate in 0.1-mM Mg2+ medium. The effect of 10 microM quisqualate was also significantly inhibited by antagonists specific for different glutamate receptor subtypes, including N-methyl-D-aspartate, (RS) alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate and metabotropic receptors. This evidences a heterogeneous action of quisqualate, mediated by different glutamate receptor subtypes in 0.1 mM Mg2+ medium. The efficacy of quisqualate in inducing influx of Ca2+ and the selectivity of antagonists for different receptors are also modified by extracellular Mg2+.

2-Amino-5-phosphonovalerate↗
PubMed1992

Role of central GABAB receptors in physiology and pathology.

There are two major classes of gamma-aminobutyric acid (GABA)-sensitive receptors: GABAA and GABAB. The GABAA receptor, the better known of the two GABA receptors, is a heterooligomeric complex that forms a chloride channel. Multiple subtypes of the GABAA receptor result from the composition of different subunits. In contrast to the GABAA receptor, the GABAB receptor protein has not been isolated and purified to homogeneity. Various effector systems, however, have been identified for the GABAB receptor using a limited GABAB-specific pharmacologic reportoire. In almost all cases, activated GABAB receptors employ a guanosine triphosphate-binding protein to transduce a signal intracellularly. There may be multiple subtypes of the GABAB receptor. Because the responses elicited by activation of GABAB receptors are small in terms of their intensity and are considered to be modulatory, the role these receptors play in the central nervous system (CNS) may not be very obvious. However, it is our view that in a finely tuned instrument such as the brain, treatment with neuromodulators (drugs that produce slight changes in brain neurochemistry) may be safer than most current drugs. Moreover, neuromodulators may have far greater potential as pharmacotherapeutic agents for CNS disorders. Thus, in this article, we will review the pharmacologic characteristics of the GABAB receptor, known physiologic roles that this receptor plays in the CNS, and the importance of this receptor in certain disease states.

Animals↗