Biomedical subjects

S Pauli

Publications and source records attributed to S Pauli.

At least 19 recordsLinked to original sources

PubMed2003

Gene structure of human carbamylphosphate synthetase 1 and novel mutations in patients with neonatal onset.

Carbamylphosphate synthetase 1 (E.C. 6.3.4.16) deficiency is a rare autosomal recessive disorder of the urea cycle that can result in severe neonatal hyperammonemia. Since the genomic structure of the CPS1 gene was not yet elucidated, mutation detection was performed by analysis of transcripts in the past. Here, we present the entire DNA sequence of the human CPS1 gene including all exon-intron boundaries. Moreover, mutation analysis was performed in six patients leading to the detection of 9 novel mutations including the missense mutations c.2528T>C and c.2623A>G, the nonsense mutations c.712C>T and c.2115ins35bp, the splice site mutations c.1263+5G>C, c.3558+1G>C and c.4101+2T>C, and a small deletion c.3036_3038delGGT. The mutations c.2528T>C and c.2623A>G were identified on a double mutated allele. New data on the genomic structure of the CPS1 gene provided in this study are useful to characterize the heterogenous molecular basis of the disease in patients deficient for carbamylphosphate 1 deficiency.

Age of Onset↗

PubMed2003

Functional and immunophenotypic characteristics of isolated CD105(+) and fibroblast(+) stromal cells from AML: implications for their plasticity along endothelial lineage.

BACKGROUND: In vitro cultures of BM cells from newly diagnosed patients with AML displayed a defective BM stromal compartment, with a reduced number of fibroblast-colony-forming unit (CFU-F: 1 +/- 1.25 SD) and a decreased proliferative ability. The purposes of our study were: 1). to select BM mesenchymal stem cells (MSC) and BM-derived stromal cells (BMDSCs) from AML patients at diagnosis and from healthy subjects, using an immunomagnetic system and either anti-CD105 or anti-fibroblast MAbs; 2). to study the immunophenotypic and functional properties of freshly isolated and cultured mesenchymal cells; 3). to test the in vitro plasticity of the selected cells to differentiate towards an endothelial phenotype. METHODS: Fresh mononuclear cells obtained from BM of 20 patients newly diagnosed with AML and from eight healthy subjects were selected by using anti-fibroblast and anti-CD105 MAbs. Freshly isolated cells were analyzed, characterized by flow cytometry using a wide panel of MAbs and seeded in long-term culture medium to assess CFU-F formation. The level of confluence after 30 days and functional capacity in a long-term colony-forming cell culture (LTC-CFC) were tested. Furthermore, the cultured selected cell populations were assayed for their ability to differentiate into an endothelial-like cell phenotype with the addition of vascular endothelial growth factor (VEFG) and endothelial cell growth supplement (ECGS). RESULTS: In normal subjects the selection produced an increase of the CFU-F number of 2.6-fold with anti-fibroblast MAb and 2.7-fold with the anti-CD105 MAb. Anti-fibroblast and anti-CD105 MAb selection from AML BM cells resulted in a statistically significant greater count of CFU-F that was respectively 10.6-fold (P = 0.04) and 14.4-fold (P = 0.00001) higher in comparison with the unselected AML samples. Interestingly, in 80% of AML samples immunoselection was also able to restore the capacity of the CFU-F to proliferate and form confluent stromal layers. The isolation of those layers sustained the proliferation and differentiation of hematopoietic stem cells in the LTC-CFC. The phenotypic profile of cultured BMDSCs was different from that of the freshly isolated cells, and changed in relation to the culture conditions: CD105+ selected cells cultured with VEGF and ECGS expressed endothelial markers, a finding that suggests that this cell subpopulation may have the potential to differentiate toward an endothelial-like phenotype. DISCUSSION: We report that immunomagnetic selection represents a valid tool for the selection of BM mesenchymal cells in samples obtained from both healthy subjects and patients with AML. This technique was able to rescue two functional and immunophenotypic compartments related to two different selected populations. In particular, the CD105+ cells isolated in AML displayed, after stimulation with VEGF and ECGS, the ability to change towards an endothelial-like cell phenotype, thus revealing an unexpected plasticity. Both CD105+ and fibroblast+ cells once successfully isolated might represent sources of mesenchymal cells populations useful for in vitro investigations and, above all, as therapeutic devices.

Adult↗

PubMed2002

Structure of the human argininosuccinate synthetase gene and an improved system for molecular diagnostics in patients with classical and mild citrullinemia.

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia, an autosomal recessive inherited defect of the urea cycle. Most patients described so far have presented with the classical form of the disease. There are also patients with a mild form of citrullinemia in whom the exact molecular basis and clinical relevance are uncertain. Mutations in the human ASS gene have not yet been described in mildly affected or asymptomatic patients with citrullinemia. The genomic sequence of the human ASS gene is not precisely known making mutation analysis difficult. Here, the entire genomic DNA sequence and mutations in the ASS gene of patients with the classical and mild form of the disease are described. The mutations c.1168G-->A (G390R) and IVS13+5 G-->A and the novel mutation c.323G-->T (R108L) have been found to be associated with classical citrullinemia, whereas the novel mutations c.535T-->G (W179R), and c.1085G-->T (G362V) have been detected on alleles of the mildly affected patients. Thus, mutations found in the human ASS gene of asymptomatic children with biochemical abnormalities and in some cases enzymatically proven citrullinemia have allowed us to classify these cases as ASS-deficient patients. The elucidation of the structure of the human ASS gene has made possible the use of intronic primers for molecular analysis of patients with mild disease and the classical form, and provides another option for prenatal diagnostics in affected families with the severe type.

Amino Acid Sequence↗

PubMed2002

Osteomyelitis pubis versus osteitis pubis: a case presentation and review of the literature.

An athletic 23 year old man presented with suprapubic tenderness, fever, and raised inflammatory blood variables. A diagnostic laparoscopy was performed, with a presumed diagnosis of retrocaecal appendicitis, but no abnormalities were found, apart from free fluid in the pouch of Douglas. Imaging of the pubic area suggested bony infection and inflammation. Biopsy and culture confirmed the presence of Staphylococcus aureus, a very common pathogen. The final diagnosis was osteomyelitis pubis, an infectious disease, and osteitis pubis, an inflammatory disease.

Adult↗

PubMed2001

CD34(+) cell subsets and long-term culture colony-forming cells evaluated on both autologous and normal bone marrow stroma predict long-term hematopoietic engraftment in patients undergoing autologous peripheral blood stem cell transplantation.

OBJECTIVE: The aim of this study was to evaluate which CD34(+) cell subset contained in leukapheresis products could be regarded as the most predictive of long-term hematopoietic recovery after autologous peripheral blood stem cell transplantation (auto-PBSCT). MATERIALS AND METHODS: Based on data from 34 patients with hematologic malignancies, doses of CD34(+) cells and CD34(+) cell subsets, defined by the expression of HLA-DR, CD38, CD117 (c-kit/R), CD123 (alpha subunit of IL-3/R), CD133 (AC133), and CD90 (Thy-1) antigens, were correlated with the number of short-term (i.e., colony-forming cells [CFC]) and long-term culture CFC (LTC-CFC) (generated at week 5 of culture) and with the kinetics of hematopoietic engraftment following auto-PBSCT. The capacity of autologous stroma (AS), normal human bone marrow stroma, and M2-10B4 murine cell line to sustain CD34(+) cell growth was comparatively evaluated in the LTC assay. RESULTS: Our data demonstrated that some of the most primitive progenitor subsets (CD34(+)CD117(-)HLA-DR(-), and CD34(+)CD38(+)HLA-DR(-)) showed the strongest correlation with LTC-CFC numbers generated within the AS, whereas no significant correlation was noted using normal bone marrow stroma. Multivariate analysis showed that the only CD34 cell subset independently associated with long-term (3 to 6 months) platelet engraftment after auto-bone marrow transplantation was the CD34(+)CD117(-)HLA-DR(-) phenotype; long-term erythrocyte engraftment was correlated with CD34(+)CD38(+)HLA-DR(-) cell content. The latter further influenced platelet engraftment in the first 3 months after auto-PBSCT. The most predictive parameters for neutrophil engraftment were CD34(+)CD38(+)HLA-DR(-) cell subtype and the total LTC-CFC quantity infused. CONCLUSIONS: These data further support the hypothesis that the type of stromal feeders influences the frequency of LTC-CFC, possibly because they differ in their ability to interact with distinct subsets of hematopoietic stem cells. Furthermore, as the use of AS in LTC assay can mimic in vitro the human bone marrow microenvironment, it can be speculated that this culture system could be a useful means to study the kinetics of recovery of bone marrow stroma following chemotherapy and PBSCT. From these results, it can be concluded that some CD34(+) cell subsets appear to be more reliable predictors of long-term hematopoietic recovery rates than total CD34(+) cell quantity.

Adult↗

PubMed2001

Angiogenesis in multiple myeloma: correlation between in vitro endothelial colonies growth (CFU-En) and clinical-biological features.

Mouse models and studies performed on fixed bone marrow (BM) specimens obtained from patients with multiple myeloma (MM) suggest that plasma cell growth is dependent on endothelial cell (EC) proliferation within the BM microenvironment. In order to assess whether EC overgrowth in MM reflects a spontaneous in vitro angiogenesis, BM mononucleated cells from 13 untreated (UT) MM, 20 treated (11 with melphalan and nine with DAV schedule) MM, eight patients with monoclonal gammopathy of uncertain significance (MGUS) and eight controls were seeded in an unselective medium to assess EC proliferation. Furthermore, the influence of IL6 on the EC growth was investigated. Endothelial colonies (CFU-En) appeared as small clusters, formed by at least 100 slightly elongated and sometimes bi-nucleated cells expressing factor VIII, CD31 and CD105 (endoglin). The CFU-En mean number/10(6) BM mononucleated cells in untreated MM samples (2.07 s.d. +/- 1.3) was significantly higher than in normal BM (0.28 +/- 0.48), while no difference was seen between normal BM and MGUS (0.28 +/- 0.54). Interestingly, the mean number of CFU-En in the DAV group (1.88 +/- 1.6) did not differ from the UT, while it was found to be lower in the melphalan group (0.31 +/- 0.63). The addition of anti-IL6 monoclonal antibody induced a reduction of both the plasma cells in the supernatant and the CFU-En number. This study describes a rapid and feasible assay providing support for the association between EC and plasma cells further suggesting that the in vitro angiogenesis process may parallel that observed in vivo.

Adult↗

PubMed2001

Induction of topoisomerase II activity after ErbB2 activation is associated with a differential response to breast cancer chemotherapy.

ErbB2 (HER-2) gene amplification and overexpression have been shown to predict a better outcome with doxorubicin-based chemotherapy as opposed to alkylator-based chemotherapy in early stage breast cancer. To understand the mechanism of differential response to these two regimens, we have evaluated the effect of signaling through the ErbB2 receptor on downstream enzymes that may affect drug response, using two different models. The first system employs breast cancer cells that have high levels of endogenous ErbB2 by gene amplification (BT-474 and SKBR3 cells). The second system allows us to isolate the effect of ErbB2 receptor-mediated intracellular signaling using an epidermal growth factor receptor-ErbB2 chimeric receptor activated by epidermal growth factor. Our experiments show that the cytotoxicity of doxorubicin is inhibited in ErbB2+ breast cancer cells by the anti-ErbB2 antibody, Herceptin. This is accompanied by a decrease in topoisomerase (topo) IIalpha protein and activity, suggesting that this is the mechanism of change in doxorubicin response. In addition, a 10-100-fold (1-2 log) decrease in the LD(50) of doxorubicin is seen after ErbB2 activation using the chimeric receptor model. Furthermore, we see a 100-fold decrease in the LD(50) of etoposide, another topo II inhibitor. This increase in doxorubicin sensitivity is associated with a 4.5-fold increase in the amount of topo IIalpha protein and an increase in topo II activity as measured by DNA decatenating and unknotting activities, as well as cleavable complex formation. In contradistinction to doxorubicin, we have observed an increased resistance to cyclophosphamide chemotherapy after chimeric receptor activation. We propose that the differential benefit seen with doxorubicin- versus alkylator-based chemotherapy in ErbB2+ breast cancer is due, in some cases, to ErbB2-mediated topo IIalpha activation. These data also suggest hypotheses for the optimal sequencing of Herceptin and chemotherapy agents in ErbB2+ breast cancer.

3T3 Cells↗

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

Stapled versus hand-sewn vascular anastomoses. An experimental study in the rabbit.

OBJECTIVE: Narrowing of vascular anastomoses is a frequently encountered surgical problem, with intimal hyperplasia being one of its most important causes. The aim of the present study was to compare in a rabbit model 'manual' (hand-sewn) with 'stapled' anastomoses (using a staple device) with respect to occurrence and severity of intimal hyperplasia. MATERIALS AND METHODS: Twenty-four male rabbits (mean weight 2,849 g) were randomly allocated to one of two groups (n = 12). An end-to-end anastomosis of the left femoral artery was performed in all animals under general anesthesia. The anastomosis was hand sewn in group 1, while a vascular closure stapler (VCS) was used in group 2. Both anastomotic time and total operation time were recorded. After 28 days, the rabbits were sacrificed. The femoral artery of operated and nonoperated sides were removed and prepared for anatomopathological examination. The I/M ratio (= difference between tunica intima and tunica media) was determined on hematoxylin-eosin stained slides. All results were analyzed using Student's t test. RESULTS: Mean anastomotic times were 25 +/- 7 min for the 'manual' group and 17 +/- 9 min for the 'stapled' group (p = 0.02). There was no significant difference in the total operation time (55 +/- 15 vs. 41 +/- 18 min, p = 0.057). All animals survived the anastomosis procedure. In the group of 'manual' anastomosis, morbidity was significantly higher. At the moment of sacrifice, all anastomoses were patent. There was no difference in the I/M ratio between the groups. CONCLUSIONS: The use of VCS is a promising alternative to hand-sewn anastomoses. It takes less time to perform a stapled anastomosis, the technique has a shorter learning period and morbidity seems to be lower when vascular anastomoses are applied with the VCS in this rabbit model.

Anastomosis, Surgical↗

PubMed2000

Lamellar bone formation in an atherosclerotic plaque of the carotid artery, with a review of histogenesis--a case report.

Longer existing atherosclerotic lesions may contain calcifications; lamellar bone rarely develops within them. A 59-year-old man was referred with a progressive stroke. A high-grade stenosis of the left common carotid artery, formed by an ulcerating atherosclerotic plaque with a free-floating thrombus, was detected on angiography. An urgent endarterectomy was performed. Surprisingly this plaque contained pieces of lamellar bone, proved by histologic examination.

Angiography↗

PubMed1998

Tumour necrosis factor-alpha and interleukin-2 differentially affect hippocampal serotonergic neurotransmission, behavioural activity, body temperature and hypothalamic-pituitary-adrenocortical axis activity in the rat.

Intraperitoneal endotoxin injection and central administration of interleukin (IL)-1beta profoundly activate hippocampal serotonergic neurotransmission. This study was designed to investigate, using in vivo microdialysis, the effects of another endotoxin-induced proinflammatory cytokine, tumour necrosis factor-alpha, and the effects of the non-inflammatory cytokine, IL-2, on hippocampal extracellular levels of serotonin. To compare the effects of these cytokines on neurotransmission with the effects on physiological parameters and behaviour, hypothalamic-pituitary-adrenocortical (HPA) axis activity, body temperature and behavioural activity were monitored as well. Time-dependent changes in serotonergic neurotransmission and HPA axis activity were determined by measuring serotonin, its metabolite 5-hydroxyindoleacetic acid and free corticosterone in dialysates. Total behavioural activity was scored by assessing the time during which rats were active. Core body temperature was measured by biotelemetry. Intracerebroventricular injection of 50 or 100 ng recombinant murine tumour necrosis factor-alpha exerted no effect on hippocampal serotonergic neurotransmission, and induced no signs of sickness behaviour. However, these doses produced a dose-dependent increase in body temperature and free corticosterone levels. In contrast, intracerebroventricular administration of 500 ng, but not of 50 ng, recombinant human IL-2 produced a marked increase in hippocampal extracellular concentrations of serotonin and 5-hydroxyindoleacetic acid, accompanied by a pronounced behavioural inhibition and other signs of sickness. Moreover, both doses of IL-2 caused a dose-dependent increase in body temperature and free corticosterone levels. Interestingly, intracerebroventricular pretreatment with the IL-1 receptor antagonist showed that the effects of IL-2 on hippocampal serotonin were completely dependent on endogenous brain IL-1. However, IL-1 seemed to play only a minor role in the IL-2-induced increase in free corticosterone. Taken together, the results show that cytokines produce partially overlapping brain-mediated responses, but are selectively effective in stimulating hippocampal serotonergic neurotransmission and inducing sickness behaviour. Moreover, we postulate that activation of hippocampal serotonin release is instrumental in the full development of behavioural inhibition.

Animals↗

PubMed1998

Comparison between plain and gentamicin containing collagen sponges in infected peritoneal cavity in rats.

OBJECTIVE: To study the usefulness of gentamicin-containing sponges in the infected peritoneal cavity in rats. DESIGN: Controlled study. MATERIAL: 83 Male Wistar rats, 36 of which were treated by plain sponge, 36 by gentamicin-impregnated sponge, and 11 acted as controls. INTERVENTIONS: A standard model of intraperitoneal infection was developed by making a 1 cm long incision in the caecum. MAIN OUTCOME MEASURES: Postoperative mortality, macroscopic and microscopic features of infection, and bacterial concentrations in the abdomen on days 3, 6, and 9. RESULTS: In the respective groups 2, 3 and 2 animals died during operation and 4/34 (11%), 3/33 (9%); and 0/9 died before day 3. There were appreciable reductions in the number of animals with features of infection after 3 days but these were not significant at 6 or 9 days. CONCLUSION: Gentamicin-containing collagen sponges placed on a septic focus in the abdomen reduce local infection for at least 3 days.

Animals↗

PubMed1998

Brain distortions in patients with primarily generalized tonic-clonic seizures.

PURPOSE: A precondition for the diagnosis of primarily generalized epilepsy with tonic-clonic seizures (GTCS) is absence of brain pathology. This definition, based on normal findings on computed tomography (CT) and magnetic resonance imaging (MRI) is challenged however, by observation of microscopic migrational disturbances in patients with GTCS. In the present study, we examined whether hitherto undiscovered gross manifestations of the reported migrational disturbances may be detected by analysis of CT and MRI scans with a computerized anatomic brain atlas. METHODS: The atlas program permitted group comparisons of size, intrinsic proportion, and shape of the brain. Healthy men (n = 20), patients with partial seizures (n = 8), secondarily generalized partial seizures (n = 8), and patients with GTCS (n = 10) were studied. The contours of the brain of the computerized atlas were first transformed and adjusted to the contours, central structures, and ventricles of each subject's MRI scans. During this process, the specific parameters for the shape, size, and proportion of the brain were determined, resulting in a set of values for each subject. These values were then applied for comparisons between the four investigated groups. RESULTS: In relation to the controls, patients with GTCS had brains significantly flattened in the craniocaudal direction (p = 0.002), with a disproportionally small caudal part. The anterior portion of their brain was also, relatively elongated as compared with the posterior portion (p = 0.04). Similar systematic abnormalities were not observed in patients with partial epilepsy. CONCLUSIONS: The observed deformations are compatible with previously reported findings of Purkinje cell degeneration and frontal lobe microdysgenesis in GTCS. The study suggests a new approach to identify effects of morphologic abnormalities in the brain when results of conventional structural neuroimaging are normal.

Adult↗

PubMed1998

Chylothorax complicating left lower sleeve lobectomy.

Postoperative chylothorax is an infrequent but potential life-threatening complication and has most often been described following oesophageal resection. Its incidence after pulmonary resection is low, but has increased to 0.3-0.5%, probably due to more extensive types of resections and radical lymph node dissections. We report a case of chylothorax after a left sleeve lobectomy for a primary bronchogenic carcinoma, that was treated conservatively with chest tube drainage and a diet of medium chain triglycerides. Five additional case reports in English and French literature confirmed chylothorax after bronchoplastic procedures to be extremely rare. More frequent use of bronchial sleeve resection as alternative to pneumonectomy to save functional lung tissue, can increase the incidence of chylothorax after bronchoplastic procedures.

Aged↗

PubMed1997

Three-dimensional visualization and quantification of the benzodiazepine receptor population within a living human brain using PET and MRI.

Positron emission tomography (PET) in combination with receptor-selective high-affinity radioligands allows the characterization of neuroreceptor distributions in the living human brain. Thus far, the visualization and quantification of receptors with PET have been limited to series of two-dimensional (2D) image planes of the anatomic receptor distribution. The development of high-resolution PET has increased the number of planes to approximately 50, supplying an excessive amount of image information from a single experiment. The inherent limitations of 2D techniques make them insufficient to apprehend and efficiently analyze this cumbersome amount of data. In the present communication we describe procedures to visualize and quantify in three dimensions (3D) the total image information from the compound set of 47 2D planes of a PET experiment using commercially available software. Three-dimensional computer graphic and volume rendering techniques were used to analyze and display the results. For the experimental application the benzodiazepine (BZ) antagonist [11C]flumazenil was used as radioligand to visualize the BZ receptor (BZR) population in the brain of a healthy human subject. Three-dimensional images of the radioligand binding receptor population were displayed with regard to volume and form in relation to the corresponding anatomic structures in the brain reconstructed from MR images. The volume-rendering technique allowed the inspection of PET signals representing BZR populations in the interior of the hemisphere as viewed from the medial projection. Thresholding and seeding techniques were used to define volumes and quantities. Using the PET data and volume rendering, the total amount of cerebral BZRs (NCerebrum) and the apparent volume they take into account (V(BZR, Cerebrum)app) could he calculated for the first time using an automated procedure. The cerebrum of the healthy subject contained 17.6 nmol of BZRs in a volume of approximately 1.25 L. The principles and application of the technical development described offer new dimensions to clinical neuroscience and should be practically useful for automated quantitative determination of neuroreceptor number in brain regions of patients with neuropsychiatric disorders and in relation to drug treatment.

Adult↗

PubMed1997

Bromine-76 and carbon-11 labelled NNC 13-8199, metabolically stable benzodiazepine receptor agonists as radioligands for positron emission tomography.

NNC 13-8241 has recently been labelled with iodine-123 and developed as a metabolically stable benzodiazepine receptor ligand for single-photon emission computed tomography (SPECT) in monkeys and man. NNC 13-8199 is a bromo-analogue of NNC 13-8241. This partial agonist binds selectively and with subnanomolar affinity to the benzodiazepine receptors. We prepared 76Br labelled NNC 13-8199 from the trimethyltin precursor by the chloramine-T method. Carbon-11 labelled NNC 13-8199 was synthesised by N-alkylation of the nitrogen of the amide group with [11C]methyl iodide. Positron emission tomography (PET) examination with the two radioligands in monkeys demonstrated a high uptake of radioactivity in the occipital, temporal and frontal cortex. In the study with [76Br]NNC 13-8199, the monkey brain uptake continued to increase until the time of displacement with flumazenil at 215 min after injection. For both radioligands the radioactivity in the cortical brain regions was markedly reduced after displacement with flumazenil. More than 98% of the radioactivity in monkey plasma represented unchanged radioligand 40 min after injection. The low degree of metabolism indicates that NNC 13-8199 is metabolically much more stable than hitherto developed PET radioligands for imaging of benzodiazepine receptors in the primate brain. [76Br]NNC 13-8199 has potential as a radioligand in human PET studies using models where a slow metabolism is an advantage.

Animals↗

PubMed1997

PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington's disease.

PET and: markers for the pre- and postsynaptic neurons were used to study the dopamine system in vivo in Huntington's disease. The radioligands used were [11C]SCH 23390 for D1-receptors, [11C]raclopride for D2-receptors and [11C]beta-CIT for dopamine transporters. Five patients with Huntington's disease and five matched controls were recruited. Brain anatomy was examined by MRI. The findings in patients were as follows. Postsynaptic D1- and D2-receptor densities were similarly reduced in the striatum. A reduction in D1-receptor density was shown in the temporal cortex; it draws attention to the cortical degeneration in relation to the cognitive deficits observed in Huntington's disease. The reduction of D1- and D2-receptor binding potentials in the striatum correlated significantly with increasing duration of illness. The correlation between the duration of illness and decline of D1- and D2-receptors make these receptors valuable as quantitative markers for the Huntington's disease degenerative process. Besides postsynaptic changes, a significant 50% decrease of [11C]beta-CIT binding to the dopamine transporter was found in the striatum. A reduced striatal blood flow in Huntington's disease cannot be excluded and could account for a small part of the decrease in [11C]beta-CIT binding. We suggest that the finding reflects a loss of presynaptic terminals or a reduced expression of dopamine transporter in the nigrostriatal dopaminergic system in Huntington's disease.

Adult↗

PubMed1996

Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride.

Epidepride is a benzamide with high affinity for central D2- and D3-dopamine receptors. The anatomical distribution of [125I]epidepride binding was examined by autoradiography, using postmortem human whole-hemisphere cryosections. The density of [125I]epidepride binding sites was high in caudate nucleus and putamen. [125I]epidepride also labeled receptors in extrastriatal region such as in the pallidum, some thalamic nuclei, the neocortex, and the substantia nigra. The neocortical binding was heterogeneously distributed. In most cortical regions, binding sites were located in superficial layers (I-II). However, in basal levels of the occipital cortex, [125I]epidepride binding was located in a deeper layer, probably corresponding to layer V. Competition studies indicated that most of the [125I]epidepride binding represented predominantly D2-dopamine receptors, in striatal as well as in extrastriatal regions. The presence of extrastriatal D2-dopamine receptor populations is of particular interest for research on schizophrenia and antipsychotic drug action.

Aged↗