Biomedical subjects

J Hiltunen

Publications and source records attributed to J Hiltunen.

At least 19 recordsLinked to original sources

PubMed2006

Platelet function after single [153Sm]EDTMP therapy in prostate cancer.

AIM: Aim of the study was to assess whether [153Sm] EDTMP therapy at a low-dose is associated with platelet activation. METHODS: In 29 patients suffering from metastatic prostate cancer platelet count and various platelet function parameters have been monitored for 2 months after a single (the first) application of 1.1 GBq mCi [153Sm]EDTMP. RESULTS: After 3 days insignificant signs of platelet activation (increase in malondialdehyde, adenosine diphosphate-induced platelet aggregation, decreased platelet sensitivity) occur, normalizing rapidly. At the nadir of platelet count (3-4 weeks) platelet aggregation response in non-count adjusted samples is somewhat lower, while activity per cell (count adjusted samples) is unchanged. Platelet proteins do not change at all. Insignificant activation of platelet function at day 3 is interpreted as an indicator of mild oxidation injury, late aggregation response changes in non-adjusted samples seem only to reflect temporarily decreased number of circulating platelets. Samarium-153-EDTMP therapy at doses (1.1 GBq) used in the Vienna-protocol is not associated with a significantly altered functional behavior of platelets. CONCLUSIONS: We conclude that a single dose of 1.1 GBq 153Sm-EDTMP does not significantly affect in vivo and ex vivo platelet function.

Aged↗

PubMed2003

Semantic decision making in early probable AD: a PET activation study.

We studied the neural correlates of semantic decision making in early probable Alzheimer disease patients and age-matched controls by measuring changes in relative cerebral blood flow by PET (oxygen-15) while they performed a category-specific word-matching task with either animal or artefact names. In comparison to a baseline (matching words by physical identity), semantic decision making elicited increased blood flow in the left frontal lobe (BA 6, 11, 47) and in the contralateral cerebellum in the controls. The only category-specific difference in controls was activation of the left supplementary motor area (BA 6) when making decisions on artefacts. In contrast, the patients recruited more extensive brain regions, encompassing areas in the left frontal lobe (BA 44, 45, 47), right occipital cortex (BA 18), midbrain, and the cerebellum bilaterally. Behaviorally, the patients performed the tasks with equal success albeit more slowly. No animal-artefact differences emerged in the patients' activation patterns, indicating that their activation increases reflected a generalized, presumably compensatory reaction to higher task demands in the face of a progressive neurological disease.

Aged↗

PubMed2002

Activation of somatosensory cortical areas varies with attentional state: an fMRI study.

The differing roles of SI and SII areas in the somatosensory system have received relatively little interest in previous research. In the present study fMRI was applied to determine possible changes in activations of these areas as a function of attentional modulation (attending vs. not attending to the stimulation of a finger). The results showed that attention induced larger regional changes, mostly enlargements of activated areas, at SII than at SI. The number of instances where new, emerging activations, not present in the non-attend condition, were observed was larger at SII than at SI. These differential attentional effects indicate that SII areas may have a role in more complex tactile functions such as tactile working memory mechanisms.

Adult↗

PubMed2002

Speech sounds learned by sleeping newborns.

It is not yet clear whether humans are able to learn while they are sleeping. Here we show that full-term human newborns can be taught to discriminate between similar vowel sounds when they are fast asleep. It is possible that such sleep training soon after birth could find application in clinical or educational situations.

Humans↗

PubMed2002

Could automated template based quantification of benzodiazepine receptors in brain single photon emission tomography with 123I NNC 13-8241 be used to demonstrate neuronal damage in traumatic brain injury?

Automated methods are required for the analysis of brain single photon emission tomography images. We applied an automated method to assess the benzodiazepine receptor distribution in the brain. Images of 19 patients with mild traumatic brain injury who had received I NNC 13-8241 were compared with a mean brain template accumulated from 18 healthy volunteers. To obtain more information, we calculated the neuronal benzodiazepine receptor binding in the brain by using pre-defined anatomical regions and a voxel-by-voxel technique. The group of patients with mild traumatic brain injury differed significantly (P =0.015) from the group of healthy volunteers in the distribution of benzodiazepine receptors. This methodological work suggests that a reference based template and a three-dimensional brain model help in regional analysis and quantification and could be useful in demonstrating permanent neuronal damage after head injury.

Adolescent↗

PubMed2001

Measurement of the striatal dopamine transporter density and heterogeneity in type 1 alcoholics using human whole hemisphere autoradiography.

Dopaminergic mechanisms are involved in the positive reinforcing and addicting effects of alcohol. Positron emission tomography (PET) and single photon emission tomography (SPET) studies have indicated alterations in striatal dopamine transporters (DAT) and in presynaptic dopamine (DA) function in alcoholics, although also contradictory results have been reported. Normal variations in blood flow, metabolism, and receptor densities are apparently important to brain function. Such variations are known to decrease during pathophysiological processes, such as epilepsy, whereas normal receptor distributions are broadly heterogenous. We evaluated the densities and heterogeneities of striatal DAT in 8 adult-onset, Cloninger type I alcoholics and 10 controls using [125I]N-(3-iodoprop-2E-enyl)-2beta-carbomethoxy-3beta- (4'-methylphenyl)nortropane ([125I]PE2I) as a ligand for human postmortem whole hemisphere autoradiography, which provided high resolution images of the brain when compared with in vivo PET and SPET. The mean density and heterogeneity of DAT were markedly lower in the alcoholics. A significant linear correlation existed between DAT density and heterogeneity, as well as between DAT densities in the nucleus accumbens and in the dorsal striatum (caudate and putamen) in alcoholics, but not consistently in controls. The observed low DAT density and heterogeneity in the dorsal striatum suggest that type 1 alcoholics may have a dysfunctional DA system. These data indicate that human whole hemisphere autoradiography with the analysis of binding heterogeneity may be a relevant tool to measure pathological processes in the brain.

Alcoholism↗

PubMed2001

SPET imaging of central muscarinic acetylcholine receptors with iodine-123 labelled E-IQNP and Z-IQNP.

1-Azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (IQNP) is a muscarinic acetylcholine receptor (mAChR) antagonist and the racemic ligand contains eight stereoisomers. In a single-photon emission tomography (SPET) study in monkeys we recently confirmed that [123I]E-(R,R)-IQNP ([123I]E-IQNP) is a radioligand with modest selectivity for the M1 and M4 subtypes, whereas [123I]Z-(R,R)-IQNP ([123I]Z-IQNP) is non-subtype selective. In the present SPET study, E- and Z-IQNP were examined in human subjects. SPET examination was performed on three male subjects after i.v. injection of [123I]E-IQNP and in another three after i.v. injection of [123I]Z-IQNP. The binding potential (BP) for [123I]E-IQNP was calculated using several quantitative approaches with the cerebellum as a reference region. High-performance liquid chromatography was used to measure radioligand metabolism in plasma. Following [123I]E-IQNP, the radioactivity was high in the neocortex and striatum, intermediate in the thalamus and low in the pons and cerebellum, which is consistent with the rank order for the regional density of M1 and M4 subtypes in vitro. For all regions, peak equilibrium was identified within the 48-h data acquisition. The simplified reference tissue approach using SPET data from 0 to 48 h was the most reliable in this limited series of subjects. Following injection of [123I]Z-IQNP, radioactivity was high in the neocortex and striatum, intermediate in the thalamus and pons and low in the cerebellum, which is in agreement with the density of M1, M2 and M4 subtypes as measured in vitro. Quantitative analyses provided indirect support for specific M2 binding of Z-IQNP in the cerebellum. The high selectivity of [123I]E-IQNP for M1 and M4 receptors allowed the use of cerebellum as a reference region devoid of specific binding, and may be advantageous for applied clinical studies of M1 and M4 receptors binding in man. [123I]Z-IQNP has potential for exploration of M2 receptor binding in the cerebellum.

Adult↗

PubMed2001

Technetium-99m labelling of glycosylated somatostatin-14.

This study presents a technetium-99m labelling method based on organometallic chemistry. It describes the simple mixing of a 99mTc(I)-carbonyl compound [99mTc(OH2)3(CO)3]+ with a histidine-tagged somatostatin-dextran (SMS-Dx-His) conjugate. Somatostatin and histidine was coupled to periodate activated dextran. The linkage was stabilised by reductive amination. The conjugate was then radiolabelled with 99mTc by using the 99mTc(CO)3 core. The labelling efficiency was 65-80% and the radiochemical purity > 95%. In the in vitro cysteine challenge, the result showed that 25% of the radiolabel was released after 1 h incubation at 37 degrees C (cysteine-conjugate at 1000:1 molar ratio). The radiolabelled SMS-Dx-His showed similar HPLC profile as the unlabelled conjugate. This labelling method, employing non reducing conditions, is useful for the labelling of peptides containing disulphide bonds. It should be possible to be used also for labelling with rhenium-188 for therapeutic applications.

Chromatography, High Pressure Liquid↗

PubMed2001

Dopamine D(2)/D(3)-receptor and transporter densities in nucleus accumbens and amygdala of type 1 and 2 alcoholics.

Alcohol acts through mechanisms involving the brain neurotransmitter dopamine (DA) with the nucleus accumbens as the key zone for mediating these effects. We evaluated the densities of DA D(2)/D(3) receptors and transporters in the nucleus accumbens and amygdala of post-mortem human brains by using [(125)l]epidepride and [(125)I]PE2I as radioligands in whole hemispheric autoradiography of Cloninger type 1 and 2 alcoholics and healthy controls. When compared with controls, the mean binding of [(125)I]epidepride to DA D(2)/D(3) receptors was 20% lower in the nucleus accumbens and 41% lower in the amygdala, and [(125)I]PE2I binding to DA transporters in the nucleus accumbens was 39% lower in type 1 alcoholics. These data indicate that dopaminergic functions in these limbic areas may be impaired among type 1 alcoholics, due to the substantially lower number of receptor sites. Our results suggest that such a reduction may result in the chronic overuse of alcohol as an attempt to stimulate DA function.

Adult↗

PubMed2001

Biodistribution, blood half-life, and receptor binding of a somatostatin-dextran conjugate.

Derivatives of somatostatin (sms) are attracting increasing interest as part of the treatment of several cancer diseases expressing sms receptors (srs). Radiolabeled sms analogs can additionally be used for systemic radiotherapy and for diagnostic investigations. Glycosylated sms-14 (sms-dextran70) was characterized regarding in vitro srs binding, biodistribution, and blood half-life in mice. Rat brain cortex membranes (expressing srs 2) were used for the srs binding study. Tyr3-Octreotide was used as positive control. The binding data were analyzed by competition curve analysis. In the biodistribution study, the Bolton-Hunter reagent was used for the radioiodination of sms-dextran70. Organs and blood were collected at different time-points and the percentage of the injected dose per gram of tissue (%ID/g) was calculated. The conjugate was administered subcutaneously (sc). The sms-dextran70 showed high srs binding affinity (i.e., in the same nanomolar range as the reference ligand Tyr3-octreotide (IC50 approximately 2.5 nM). The blood half-life was approx 27 h after reaching maximum blood concentration 24 h postinjection. Because of the molecular weight of the conjugate (i.e., approx 75,000) being above the kidney threshold for dextran (i.e., 50,000), the digestion and excretion is assumed to be mainly through the hepatobiliary system. Increased uptake was seen in the adrenals, which are receptor-positive organs. Some accumulation was seen in the stomach, indicating certain deiodination of the conjugate label. The sms-dextran70 showed promising properties and its clinical relevance is currently being evaluated in clinical phase I-II studies.

Animals↗

PubMed2000

fMRI activations of SI and SII cortices during tactile stimulation depend on attention.

Somatosensory cortical areas are widely studied with new functional imaging techniques, but usually with poor control over the attentional state of subjects. We applied fMRI to determine possible changes in activations of these areas due to modulations of attention. Attention induced large regional changes, mostly enlargements of activated areas, and more of those at SII than at SI. The number of instances where activation was only seen in attend conditions was also larger at SII than at SI. These results show the importance of controlling the attentional state of the subjects in imaging studies, and give evidence of the different roles of SI and SII cortices in the somatosensory system.

Adult↗

PubMed2000

Z-IQNP: a potential radioligand for SPECT imaging of muscarinic acetylcholine receptors in Alzheimer's disease.

RATIONALE: The density of the M2 subtype of muscarinic acetylcholine receptors (mAChR) has been shown to be reduced in the brain of patients with Alzheimer's disease (AD). It is therefore of interest to develop a brain imaging method for diagnostic purposes. Z-(R,R)-1-azabicyclo[2.2.2]oct-3-yl alpha-hydroxy-alpha-(1-iodo1-propen-3-yl)-alpha-phenylacetat e (Z-IQNP) is a muscarinic antagonist with high affinity for the M2 subtype. OBJECTIVE: The pharmacological characteristics and topographic distribution of radiolabelled Z-IQNP as a radioligand for the M2 mAChR subtype were examined in vitro and in vivo. METHODS: Z-IQNP was labelled with 1251 and 123I. Autoradiography was performed on whole-hemisphere cryosections from human post mortem brains. SPECT was performed in a cynomolgus monkey. RESULTS: Autoradiography showed binding of [125I]Z-IQNP in all brain regions, which was inhibited by the non-selective muscarinic antagonist scopolamine. The addition of BIBN 99, a compound with high affinity for the M2 subtype, inhibited [125I]Z-IQNP binding particularly in the cerebellum, which has a high density of the M2 subtype. SPECT demonstrated high uptake of [123I]Z-IQNP in all brain regions. The binding was markedly reduced in all brain regions after pretreatment with the non-selective muscarinic antagonist dexetimide and also the M1 antagonist biperiden. Dexetimide markedly inhibited [123I]Z-IQNP binding in the cerebellum, which is consistent with a high density of M2-receptors in this region. The sigma receptor binding compound DuP 734 had no effect on Z-IQNP binding either in vitro or in vivo. CONCLUSIONS: This study indicates that radiolabelled Z-IQNP has high specificity for mAChR with higher affinity for the M2 than the M1 subtype and negligible affinity for sigma recognition sites both in vitro and in vivo. [123I]Z-IQNP should be useful for future SPECT studies in AD for examination of the density of M2 receptors particularly in the cerebellum.

Alzheimer Disease↗

PubMed2000

Metabolism of [123I]epidepride may affect brain dopamine D2 receptor imaging with single-photon emission tomography.

Iodine-123 labelled epidepride is a novel radiopharmaceutical for the study of cerebral dopamine D2 receptors using single-photon emission tomography (SPET). A lipophilic labelled metabolite of [123I]epidepride which may enter the brain and hamper the quantitation of receptors has been observed in human plasma. In the present study, gradient high-performance liquid chromatography (HPLC) was used to investigate the plasma concentration of the lipophilic labelled metabolite and its correlation to SPET imaging of striatal dopamine D2 receptors. A linear regression fit showed a negative correlation between the amount of the lipophilic labelled metabolite and the striatum to cerebellum ratio (n=16, R=-0.58, P<0.02), suggesting that plasma metabolite analysis is essential when imaging dopamine D2 receptors with SPET using [123I]epidepride.

Adult↗

PubMed2000

In vivo detection of vascular adhesion protein-1 in experimental inflammation.

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation.

Amine Oxidase (Copper-Containing)↗

PubMed2000

IBIS data library: clinical description of the Finnish database. Improved Monitoring for Brain Dysfunction during Intensive Care and Surgery.

Improved monitoring of brain function in intensive care and surgery is a project aiming to develop methods of biosignal processing and interpretation, in order to characterise critical events during anaesthesia and cardiac surgery, effect of anaesthesia regimen, neurophysiological findings of different sedation levels, arousal from post-anaesthesia sedation, post-cardiopulmonary bypass brain dysfunction and early brain dysfunction in patients with multiple organ failure. A data library was collected in the three participating hospitals. This is a description of the data library from the University Hospital of Kuopio, Finland, which includes data from 40 patients after cardiac surgery and from seven patients with multiple organ dysfunction. This project demonstrates that active neuromonitoring can be performed in the intensive care unit without interference with the normal treatment and care. The presented database may serve other scientific workers as a reference for a typical spectrum of perioperative data with respect to severity of disease, length of cardiopulmonary bypass, postoperative levels of sedation and length of hospital stay in cardiac surgery patients, and for types of diseases and outcome in patients with multiple organ dysfunction.

Adult↗

PubMed2000

Radiolabeling of dextran with rhenium-188.

This study describes a method for the radiolabeling of dextran with rhenium-188 (188Re). In nuclear oncology 188Re is very useful for therapeutic applications. Its nuclear characteristics allow radiotherapy and in situ monitoring of tumor uptake as well as dosimetry calculations. Consequently new compounds with this radiolabel are of general interest. Dextran was oxidized with sodium periodate yielding reactive aldehyde groups and subsequently reacted with cysteine. The linkage was stabilized by reducing the Schiff bases with sodium cyanoborohydride. The conjugate was then radiolabeled with 188Re by using 188Re-gluconate as the transchelator, labeling the free thiols. Synthesis and radiolabeling were done in the absence of oxygen. The labeling efficiency was 60-70% and the radiochemical purity > 95%. The in vitro stability study, using "cysteine challenge" demonstrated that 50% of the radiolabel was transcomplexed to the 100 mM cysteine solution (after 1 h incubation at 37 degrees C). However, at physiologic conditions and presence of an antioxidant good stability was achieved. The 188Re labeled dextran presented in this study provides a template with therapeutic and diagnostic potential in nuclear oncology, either alone for local treatment or as a backbone in a tumor specific conjugate for systemic treatment.

Dextrans↗

PubMed1999

Dopamine transporter and D2-receptor density in late-onset alcoholism.

RATIONALE: Late onset type 1 alcoholism has been suggested to be associated with an underlying dopaminergic defect. Therefore, it is relevant to study both postsynaptic D2-receptor and presynaptic dopamine transporter (DAT) densities among alcoholics. OBJECTIVE: We investigated DAT densities, along with striatal and extrastriatal dopamine D2-receptor densities, in nine nonviolent late-onset male alcoholics, who had no major mental disorder nor antisocial personality disorder (ASPD), and nine healthy controls. METHODS: [123I]PE2I and [123I]epidepride were used in SPECT imaging. RESULTS: DAT occupancy ratios (striatum/cerebellum) were significantly lower among alcoholics than in controls. Extrastriatal D2-receptor occupancy ratios (temporal pole/cerebellum) were not significantly different between the groups. CONCLUSIONS: Striatal presynaptic DAT densities are decreased among type 1 alcoholics, and this finding is not associated with recent alcohol abuse.

Adult↗

PubMed1999

Iodine-123 labelled Z-(R,R)-IQNP: a potential radioligand for visualization of M(1 )and M(2) muscarinic acetylcholine receptors in Alzheimer's disease.

Z-(R)-1-Azabicyclo[2.2.2]oct-3-yl (R)-alpha-hydroxy-alpha-(1-iodo-1-propen-3-yl)-alpha-phenylacetate (Z-IQNP) has high affinity to the M(1 )and M(2) muscarinic acetylcholine receptor (mAChR) subtypes according to previous in vitro and in vivo studies in rats. In the present study iodine-123 labelled Z-IQNP was prepared for in vivo single-photon emission tomography (SPET) studies in cynomolgus monkeys. SPET studies with Z-[(123)I]IQNP demonstrated high accumulation in monkey brain (>5% of injected dose at 70 min p.i.) and marked accumulation in brain regions such as the thalamus, the neocortex, the striatum and the cerebellum. Pretreatment with the non-selective mAChR antagonist scopolamine (0.2 mg/kg) inhibited Z-[(123)I]IQNP binding in all these regions. The percentage of unchanged Z-[(123)I]IQNP measured in plasma was less than 10% at 10 min after injection, which may be due to rapid hydrolysis, as has been demonstrated previously with the E-isomer of IQNP. Z-[(123)I]IQNP showed higher uptake in M(2)-rich regions, compared with previously obtained results with E-[(123)I]IQNP. In conclusion, the radioactivity distribution from Z-[(123)I]IQNP in monkey brain indicates that Z-[(123)I]IQNP binds to the M(1)- and M(2)-rich areas and provides a high signal for specific binding, and is thus a potential ligand for mAChR imaging with SPET.

Alzheimer Disease↗