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Biomedical subjects

J Nagel

Publications and source records attributed to J Nagel.

At least 19 recordsLinked to original sources
PubMed2006

The role of group I metabotropic glutamate receptors in schizophrenia.

It has been proposed that glutamatergic transmission, in particular NMDA receptor function, might be altered in schizophrenia. This hypothesis is mainly based on the observation that uncompetitive NMDA receptor antagonists, e.g. phencyclidine, evoke psychotic symptoms in healthy subjects, whereas agonists interacting at the glycine site of the NMDA receptor complex, e.g. glycine or D-serine, administered jointly with typical neuroleptics, can alleviate schizophrenic symptoms. The function of NMDA receptors may be modulated by group I mGluRs (mGluR1 and mGluR5), which have also been shown to be altered in schizophrenia. In rodents, mGluR5 antagonists, but not mGluR1 ones, potentiate the locomotor activity and the deficit of prepulse inhibition (PPI) induced by uncompetitive NMDA receptor antagonists. These antagonists (of either type) administered alone are not active in the above tests. Hence, antagonists of mGluR1 and mGluR5 may evoke different effects on the NMDA receptor antagonists-induced behavior and, possibly, on schizophrenic symptoms.

Animals↗
PubMed2004

Reverse microdialysis of a dopamine D2 receptor antagonist alters extracellular adenosine levels in the rat nucleus accumbens.

Recent evidence suggests that modulation of dopaminergic transmission alters striatal levels of extracellular adenosine. The present study used reverse microdialysis of the selective dopamine D(2) receptor antagonist raclopride to investigate whether a blockade of dopamine D(2) receptors modifies extracellular adenosine concentrations in the nucleus accumbens. Results reveal that perfusion of raclopride produced an increase of dialysate adenosine which was significant with a high (10 mM) and intermediate (1 mM) drug concentration, but not with lower drug concentrations (10 and 100 microM). Thus, the present study demonstrates that a selective blockade of dopamine D(2) receptors in the nucleus accumbens produced a pronounced increase of extracellular adenosine. The cellular mechanisms underlying this effect are yet unknown. It is suggested that the increase of extracellular adenosine might be related to a homeostatic modulatory mechanism proposed to be a key function of adenosine in response to neuronal metabolic challenges.

Adenosine↗
PubMed2004

Melanoma and nonmelanoma skin cancer in patients with multiple tumours--evidence for new syndromes in a population-based study.

BACKGROUND: The hypotheses that Swedish patients with four or more primary tumours [including at least one cutaneous malignant melanoma (CMM)] harbour an increased number of CDKN2A (formerly p16) germline mutations, and that this group of patients show a predisposition to other tumours, e.g. nonmelanoma skin cancer (NMSC), were studied descriptively. So far the mutation 113insArg explains all CDKN2A-associated CMM in ethnic Swedes. OBJECTIVES: All patients with four or more primary tumours, of which at least one was a CMM, from the Southern Swedish Regional Tumour Registry, between 1958 and 1999, were included in this study. METHODS: Forty-four patients were found and subdivided into three groups according to having multiple CMM (group A) or single CMM +/- NMSC (groups B and C). Screening for the presence of the Swedish founder mutation 113insArg in blood or in tissue blocks was performed. RESULTS: Patients in group A were younger at the time of the first CMM diagnosis than patients in group B and group C. The 113insArg mutation was found in four of 44 patients (9%), three with multiple CMM. In group C (n = 14) no founder mutation was evident, while in group B (n = 15) one mutation carrier was found. Nonmutation carriers with multiple CMM (group A) also had a predilection for meningiomas and neurinomas (four patients) or multiple NMSC (three patients). In group B CMM were especially associated with adenocarcinomas but in group C CMM were associated with multiple NMSC. CONCLUSION: The association between meningiomas and neurinomas (no acoustic neurinoma was seen) might indicate a new syndrome. Patients in groups B and C may harbour unknown genetic defects, which could interact with different environmental risk factors.

Adenocarcinoma↗
PubMed2003

Defective mismatch-repair in patients with multiple primary tumours including colorectal cancer.

Individuals with an inherited predisposition to cancer development are at an increased risk of developing multiple tumours. Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common hereditary cancer syndromes and is estimated to account for approximately 2% of colorectal cancers. However, HNPCC individuals are at an increased risk of developing other tumour types such as cancers of the endometrium, urothelium and small intestine. We have utilised a population-based regional cancer registry to identify all patients with double primary colorectal cancers and at least one additional malignancy and characterised the tumour spectrum in this patient group. We subsequently selected those 47 individuals who had developed at least four malignancies, including two colorectal cancers, for studies of the tumour characteristics associated with HNPCC. In total, these individuals developed 209 tumours, 156 of which were successfully retrieved. Microsatellite instability (MSI), a phenomenon caused by defective mismatch-repair (MMR), was identified in 63/154 (41%) evaluable tumours with a MSI-high pattern in 59 and a MSI-low pattern in four tumours. All tumours were immunohistochemically stained for the MMR proteins MLH1 and MSH2, with loss of expression in 55/63 (87%) MSI tumours and in 2/89 (2%) microsatellite stable (MSS) tumours. This loss affected MLH1 in 24 tumours and MSH2 in 33 tumours. A concordant loss of expression for the same MMR protein in several tumours from the same individual, a pattern that strongly suggests an underlying germline MMR gene mutation, was found in 17/45 (38%) patients and affected MLH1 in 8 patients and MSH2 in 9 patients. We conclude that the development of multiple primary tumours, including synchronous or metachronous colorectal cancers, is associated with an increased frequency of MSI and loss of immunohistochemical expression of MLH1 and MSH2.

Adult↗
PubMed2002

Effects of salient environmental stimuli on extracellular adenosine levels in the rat nucleus accumbens measured by in vivo microdialysis.

In the nucleus accumbens (NAc), the neuromodulator adenosine plays a major role in control of behaviour. The NAc subserves behaviour governed by salient stimuli in the environment, however, it is unknown whether such stimuli and the behavioural effects elicited are associated with changes in NAc extracellular adenosine levels. In order to further characterise the neuromodulatory actions of adenosine, the present study investigated for the first time the effects of four prototypical stimuli known to involve NAc processing on extracellular levels of adenosine in the NAc. Using in vivo microdialysis, the following stimuli were examined: (1) an appetitive, unfamiliar stimulus (palatable food), (2) an appetitive, familiar stimulus (standard laboratory food), (3) an aversive stimulus (handling) and (4) a novelty stimulus (cage change). Results revealed that neither of these stimuli significantly changed extracellular adenosine levels in the NAc. These findings demonstrate that NAc extracellular adenosine is not responsive to a number of prototypical salient stimuli in the environment. Thus the data provide no clues to suggest that transient changes of extracellular adenosine in the NAc modulate behavioural responses governed by these stimuli.

Adenosine↗
PubMed2001

[Illustration of elasticity differences using MR-elastography].

Differences of elasticity in tissue phantoms with inclusions of different elasticity were mapped by means of MR elastography (MRE). This new magnetic resonance imaging technique is based on the phase shift of the MR signal by switching a motion sensitizing magnetic field gradient simultaneously with the coupling of a shear wave. Wave patterns showing snapshots of the shear wave that propagates through the investigated substance were depicted in tomographic phase images. It was investigated wether a visualization of differences in elasticity of soft tissues was possible on the basis of differences in the wavelength. For this purpose, tissue phantoms with cylindrical inclusions were produced from agar gels, with agar concentrations between 1.0 and 1.5%. The diameters of the inclusions were of the order of a few centimetres. For diameters as small as 4 cm, there were still distinct differences in the wavelength between the matrix and the inclusion. The results of our study suggest that this technique has the potential for future application as an additional imaging method for tumor detection.

Agar↗
PubMed2001

Catalepsy induced by a blockade of dopamine D1 or D2 receptors was reversed by a concomitant blockade of adenosine A(2A) receptors in the caudate-putamen of rats.

The present study sought to determine, in more detail, the effects of an unselective and a selective adenosine A(2A) receptor blockade on catalepsy induced by a blockade of dopamine D1 or D2 receptors in rats. The results demonstrated that systemic administration of the unselective A1/A2 receptor antagonist, theophylline and the selective A(2A) receptor antagonist, CSC potently reversed catalepsy induced by a systemic D2 receptor blockade with raclopride or by a bilateral blockade of D2 receptors in the caudate-putamen (CPu) with S(-)sulpiride. Likewise, systemic administration of theophylline and CSC reversed catalepsy induced by a systemic D1 receptor blockade with SCH23390; theophylline also counteracted catalepsy after an intra-CPu D1 receptor blockade with SCH23390. Intracerebral co-microinfusions of the selective A(2A) receptor antagonist, MSX-3 together with a D1 (SCH23390) or D2 receptor [S(-) sulpiride] antagonist revealed that catalepsy due to intra-CPu D1 or D2 receptor blockade can be potently reversed by an intra-CPu A2A receptor blockade. In conclusion, our results with systemic and intra-CPu drug administration demonstrate that D1 and D2 receptor-mediated catalepsy can both be reversed by a concomitant blockade of A(2A) receptors. Our results implicate that the CPu is a critical neural substrate for antagonistic interactions of a D1/D2 receptor blockade and an A(2A) receptor blockade in control of motor activity. The present results provide further support for the view that A(2A) receptor antagonists may be potential therapeutics for the treatment of Parkinson's disease.

Adenosine↗
PubMed2000

Comprehensive allelotype and genetic anaysis of 466 human nervous system tumors.

Brain tumors pose a particular challenge to molecular oncology. Many different tumor entities develop in the nervous system and some of them appear to follow distinct pathogenic routes. Molecular genetic alterations have increasingly been reported in nervous system neoplasms. However, a considerable number of affected genes remain to be identified. We present here a comprehensive allelotype analysis of 466 nervous system tumors based on loss of heterozygosity (LOH) studies with 129 microsatellite markers that span the genome. Specific alterations of the EGFR, CDK4, CDKN2A, TP53, DMBT1, NF2, and PTEN genes were analyzed in addition. Our data point to several novel genetic loci associated with brain tumor development, demonstrate relationships between molecular changes and histopathological features, and further expand the concept of molecular tumor variants in neuro-oncology. This catalogue may provide a valuable framework for future studies to delineate molecular pathways in many types of human central nervous system tumors.

Alleles↗
PubMed1999

Deposition of fenoterol from pressurized metered dose inhalers containing hydrofluoroalkanes.

The imaging technique of gamma scintigraphy has been used to quantify the total amount of drug deposited in the lungs and the pattern of regional lung deposition, for formulations of Berodual (Boehringer Ingelheim GmbH) delivered from pressurized metered dose inhalers formulated with chlorofluorocarbons, and with hydrofluoroalkane-134a or -227. Data were expressed as the mass of fenoterol deposited in the lungs from the Berodual formulations. All the formulations tested gave a whole lung deposition less than 20% of the metered (exvalve) dose. The mass of fenoterol deposited in the lungs for a solution formulation containing hydrofluoroalkane-134a was inversely proportional to the actuator nozzle diameter. The data suggest that the total and regional lung deposition of hydrofluoroalkane-based pressurized aerosol formulations is highly product-specific and that changes in bioavailability can be brought about by varying both the constituents of the formulation and the design of the actuator.

Female↗
PubMed1998

Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen.

Motor effects mediated through adenosine A2A receptors within the caudate-putamen were investigated in rats using bilateral microinfusions of MSX-3 (9 microg in 1 microl per side), a water-soluble phosphate prodrug of the selective A2A receptor antagonist MSX-2. Blockade of striatal A2A receptors produced a significant motor stimulation measured by an enhanced sniffing activity. Furthermore, catalepsy induced by systemic dopamine D1 (0.75 mg/kg SCH23390, i.p.) or dopamine D2 receptor blockade (1.5 mg/kg raclopride, i.p.) was potently reversed. These findings suggest that A2A receptors within the caudate-putamen are tonically activated by endogenous adenosine and that a striatal A2A receptor blockade produces motor stimulant effects, in particular in animals with dopamine hypofunction. The present results support the view that A2A receptor antagonists may be potentially useful therapeutics for the treatment of Parkinson's disease.

Animals↗
PubMed1997

Investigation of the proton release channel of bacteriorhodopsin in different intermediates of the photo cycle. A molecular dynamics study.

Molecular dynamics simulations on bacteriorhodopsin were performed starting from a conformation based on electron cryomicroscopy studies [Henderson, R., et al. (1990) J. Mol. Biol. 213, 899-929]. We examined the proton release channel in different intermediates of the bacteriorhodopsin photocycle. In the simulations of the ground state, two stable sets of conformations were observed differing in the distance of the guanidinium group of Arg82 to the Schiff base. The set of conformations in which Arg82 is located closer to the Schiff base has a lower potential energy and agrees better with experimental data than the other set. With both sets, we performed a series of simulations in which the chromophore was isomerized to different states using purposive and nonpurposive methods. The energetic consideration of the different states argues for the location of the guanidinium group of Arg82 close to the Schiff base. The results also show that no C13-C14, C14-C15 dicis conformation of the retinal occurs in the K/L-intermediate of the photocycle instead supporting the occurrence of C13-C14 cis in these intermediates. In a last series of simulations, we modeled the M-intermediate of the bacteriorhodopsin photocycle. Again, comparison to different experimental data indicates that Arg82 points toward the Schiff base. We conclude that the guanidinium group of Arg82 is located close to the Schiff base at a distance of approximately 4.5 A and stays there at least up to the M-intermediate of the photocycle.

Arginine↗
PubMed1996

First-order projections activated by stimulation of hypothalamic sites eliciting attack and flight in rats.

14C-deoxyglucose autoradiographs of attack rats were compared densitometrically with those of control rats whose electrodes were located nearby and elicited nonaggressive behaviors like those that accompanied the attack. Most closely associated with attack was the path from the ventromedial hypothalamus through the ventral supraoptic commissural pathway to the peripeduncular area, subparafascicular nucleus, zona incerta, and cuneiform area. Moderately correlated with attack were 4 visual areas: the dorsal and ventral lateral geniculate nuclei, pretectal area, and superior colliculus. Activity in the periaqueductal gray was unrelated to attack ipsilaterally and only weakly related contralaterally. In an orthogonal analysis, upward-oriented flight thresholds were significantly correlated with medial activation extending anteriorly to the lateral septal nucleus, dorsally to the thalamic paraventricular-parataenial region, and posteriorly to the periaqueductal gray.

Aggression↗
PubMed1996

[Nationally produced 153SmEDTMP in the palliative treatment of metastatic bone cancer pain].

153SmEDTMP was obtained from enriched 152Sm irradiated at the 5 MW Chilean Research Reactor and labelled at a molar ratio of 15:1 pH 7.5. Biodistribution, autoradiography, radiochemical purity tests were done for evaluation. 40 patients were treated with 37-55 MBq/kg weight. Bone scans using 99mTcHMDP were obtained prior and after treatment. Bone marrow depression was observed in 37% of them and normal liver function in all of them. In 45% the pain dissapear completely, in 22.5% significantly decreased and partially in 30%. In 17 patients more than one dosis was injected. Our preliminary results indicate that 153SmEDTMP is a promising radiotherapeutic agent for palliative treatment of metastatic bone cancer pain and encourage its use specially because it can be produced in countries with low economic resources, thus a large number of patients can get the benefits of this new procedure.

Adult↗
PubMed1994

Deletion mapping of chromosome 19 in human gliomas.

There is evidence that a putative glioma tumor suppressor locus resides on the long arm of chromosome 19. We present data on 161 gliomas from 156 patients, which were studied by microsatellite analysis for loss of heterozygosity (LOH) on chromosome 19. Eight loci on the long arm and 2 loci on the short arm of chromosome 19 were examined. LOH on 19q was observed in 3/19 astrocytomas (WHO grade II), 12/27 anaplastic astrocytomas (WHO grade III), 16/76 cases of glioblastoma multiforme WHO (grade IV), 4/9 oligodendrogliomas (WHO grade II), 3/5 anaplastic oligodendrogliomas (WHO grade III), 5/9 mixed oligo-astrocytomas (WHO grade II) and 8/10 anaplastic oligo-astrocytomas (WHO grade III). While 31 of the tumors with LOH on chromosomal arm 19q exhibited allelic loss at every informative locus, 20 tumors showed terminal or interstitial deletions. In contrast to astrocytomas and glioblastomas, tumors with an oligodendroglial component had predominantly lost the entire long arm of chromosome 19. The common region of overlap in gliomas was located on 19q13.2-q13.4 between the markers D19S178 and D19S180. Our data confirm the involvement of a putative tumor suppressor gene on chromosomal arm 19q in gliomas and assign this gene to 19q13.2-q13.4.

Astrocytoma↗
PubMed1994

Loci associated with malignant progression in astrocytomas: a candidate on chromosome 19q.

WHO grades II and III astrocytomas frequently exhibit loss of genetic material on chromosomes 9p, 11p, 17p, 19q, and 22q, indicating that these chromosomal regions harbor tumor suppressor genes involved in the pathogenesis of astrocytic neoplasms. The present study was conducted to examine whether these genetic regions are involved in the process of malignant progression from astrocytoma WHO grade II (A II) to anaplastic astrocytoma WHO grade III (A III). We have analyzed 44 astrocytomas, i.e., 18 A II and 26 A III for loss of heterozygosity (LOH) on chromosomes 1p, 1q, 9p, 9q, 10p, 10q, 11p, 13q, 17p, 19p, 19q, and 22q and for amplification of the epidermal growth factor receptor gene. A polymerase chain reaction-based assay with microsatellite repeat sequences was used for the detection of polymorphisms on silver-stained polyacrylamide gels. LOH on 9p was seen in 1 of 18 (6%) informative cases of A II and 4 of 24 (17%) informative cases of A III. LOH on 17p was observed in 9 of 17 (53%) informative cases of A II and 15 of 26 (58%) informative cases of A III. LOH on 19q was detected in 2 of 18 (11%) informative cases of A II and in 12 of 26 (46%) informative cases of A III. The association of LOH on 19q with anaplasia in astrocytoma was significant (P = 0.015). Amplification of the epidermal growth factor receptor gene was not detected in A II or A III. These data suggest that a putative tumor suppressor gene on the long arm of chromosome 19 is a candidate for a gene associated with tumor progression in astrocytic gliomas.

Adult↗