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Biomedical subjects

M Zimmermann

Publications and source records attributed to M Zimmermann.

At least 181 records · Page 10Linked to original sources
PubMed1996

Immediate and day-to-day reproducibility of the signal-averaged electrocardiogram in patients with coronary artery disease.

The purpose of this study was to prospectively evaluate the immediate (5 minutes) and short-term (1 day) reproducibility of the signal-averaged electrocardiogram (SAECG) in patients with coronary artery disease. A total of 59 consecutive patients with coronary artery disease (50 male, 9 female, mean age 59 +/- 13 years) were included. Analysis was performed using a commercially available system with high-pass filters of 25, 40, and 80 Hz without any change in electrode position. The following time-domain parameters were measured: (1) total filtered QRS duration; (2) duration of high-frequency low-amplitude signals (HFLA); and (3) root-mean-square voltage of the terminal 40 ms of the QRS complex (RMS40). Correlation between pairs of measurements was excellent, ranging from 0.91-0.99 for QRS and HFLA duration, and from 0.83-0.98 for RMS40 value. However, the range of differences was wide for all parameters, especially at 25 and 80 Hz, revealing marked individual variations in selected cases. The immediate reproducibility of an initially normal SAECG was 95% at 25 Hz, 100% at 40 Hz, and 81% at 80 Hz; figures for an initially abnormal SAECG were 89%, 91%, and 93%, respectively, and the coefficient of agreement kappa was highest at 40 Hz than at 25 or 80 Hz. Discordant results were most frequently observed in patients with borderline values, or in cases with nonsimilar residual noise levels. In conclusion, the immediate and day-to-day reproducibility of the SAECG is excellent in patients with chronic stable coronary artery disease. However, individual variations are observed in selected cases, leading to modification in interpretation of the result. For this reason, individual reproducibility should be considered before evaluating the effect of any therapeutic intervention on the SAECG, especially in patients with borderline values of the quantitative parameters of the SAECG.

Coronary Disease↗
PubMed1996

Incidence and clinical outcome of children with BCR/ABL-positive acute lymphoblastic leukemia (ALL). A prospective RT-PCR study based on 673 patients enrolled in the German pediatric multicenter therapy trials ALL-BFM-90 and CoALL-05-92.

A variety of oncogenes are activated by specific chromosomal translocations, which are associated with distinct subtypes of leukemia. The identification of these rearrangements provides critical diagnostic and prognostic information, which may contribute to the selection of specific anti-leukemic therapy. The translocation t(9;22), the equivalent of the BCR/ABL rearrangement, is associated with a poor prognosis. We therefore used RT-PCR to detect this molecular event in a prospective study including 890 children. 673 of them suffered from acute lymphoblastic leukemia (ALL) at primary diagnosis and a transcription of the chimeric gene was detected in 21 of 648 with a successful analysis (3.2%). All children were treated by one of the two German multicenter childhood ALL therapy studies ALL-BFM-90 or COALL-05-92, respectively. Comparison of clinical features between BCR/ABL-positive and -negative children showed no significant differences regarding WBC, percentage of blasts, splenomegaly, hepatomegaly and age. Immunophenotypic studies at diagnosis in 21 BCR/ABL-positive children identified common ALL in 16 patients (76.2%), pre-B-ALL in four (19.0%), and an early T-lineage ALL in one (4.8%). Coexpression of myeloid antigens (CD13 and/or CD33) was observed in six of 16 common ALL patients as well as in the one child with early T-lineage ALL phenotype. The type of breakpoint (m-BCR/ABL: n = 14; M-BCR/ABL: n = 7) showed no correlation with clinical parameters. A comparison of cytogenetic and molecular data was performed in 16 positive patients and was concordant in all of them. We analyzed the response to the prednisone pretreatment and found a higher incidence of poor responders among the BCR/ABL-positive children. Regarding the event-free survival (EFS) of BCR/ABL-positive (0.53) and -negative patients (0.79) after a follow-up of 2 years, significant differences (P < 0.05) between both groups could be demonstrated.

Adolescent↗
PubMed1996

Systemic application of pyrethroid insecticides evokes differential expression of c-Fos and c-Jun proteins in rat brain.

Expression of the c-Fos and c-Jun transcription factor was investigated by immunocytochemistry in the thalamus, hypothalamus, hippocampus and cortex of adult rats following intraperitoneal application of proconvulsant doses of the pyrethroid insecticides, cypermethrin and permethrin. Pyrethroid insecticides are used world-wide and their uptake, e.g., by nutrition and inhalation evokes severe neurological symptoms in animals and humans, but their effects on neuronal gene expression has not been elucidated. Cypermethrin induced a strong expression of c-Fos and c-Jun in all the thalamic nuclei, except the ventro-posterior complex and substantia nigra, and in all the hypothalamic nuclei. In general, the immunoreactivities (IR) persisted for 8 h on their maximal levels, and were still above control levels after 24 h in several thalamic and hypothalamic areas. c-Fos-IR was strongly increased in all cortical layers with a predominance in the superficial layers II-IV, whereas c-Jun-IR was only slightly increased. In the hippocampus, cypermethrin induced a weak expression of c-Fos, but not of c-Jun, in the dentate gyrus and CA-3 area. Permethrin that has a lower pharmacological potency, evoked a similar pattern of c-Fos and c-Jun expression, however, intensity and persistence of the neuronal labeling were less pronounced. Our results demonstrate that the neurotoxic effects of pyrethroid insecticides comprise molecular genetic alterations in the brain such as early and lasting induction of Fos and Jun transcription factor proteins. These changes in the neuronal program are prominent in the hypothalamus and thalamus that are involved in the regulation of the autonomic and visceral nervous systems.

Animals↗
PubMed1996

Myelodysplasia and acute myelogenous leukemia in Down's syndrome. A report of 40 children of the AML-BFM Study Group.

Forty children with Down's syndrome have been identified among 633 patients in the cooperative pediatric BFM studies for acute myelogenous leukemia (AML) since 1987. The following features were characteristic for these patients: (1) a 500-fold higher than expected incidence of megakaryoblastic leukemia (M7) with a peak incidence under 4 years of age; (2) a myelodysplastic prephase with thrombocytopenia lasting for several months up to a few years; (3) frequent involvement of the red cell lineage as suggested by dyserythropoiesis in the bone marrow; (4) coexpression of the lymphoid cell surface antigen CD7 on the leukemic blasts; (5) absence of the translocation t(1;22), instead presence of complete or partial trisomies involving chromosomes 8 and 1; and (6) a good response to chemotherapy. Nearly half of the patients did not receive any or only palliative chemotherapy and subsequently died. In 21 patients treatment according to the AML-BFM protocols was intended, however, with major dose or protocol reductions in six patients. Four died early, 15 (71%) achieved remission. Nine of 11 patients remaining alive for 0.6-6.5 years had received intensive treatment including high-dose cytosine arabinoside (HD-Ara-C). The 5-year survival estimate of 48% +/- 12% was similar to patients without Down's syndrome. In conclusion, these clinical and biological features suggest that M7 leukemia in children with Down's syndrome (M7-Down) is distinct from megakaryoblastic leukemia in other children. Children with Down's syndrome show a favorable outcome if treated adequately. However, overtreatment should be avoided and life-threatening infections pose a particular problem. Therefore, standard-risk AML therapy (including HD-Ara-C) should be considered in children with Down's syndrome and AML.

Adolescent↗
PubMed1996

[Prevention of cerebral vasospasms after experimental subarachnoid hemorrhage by the endothelin receptor antagonist RO 47-0203].

Endothelins have attracted scientific interest because of their extremely potent and long lasting vasoconstrictive effects, similar to cerebral vasospasm in man. In this study the efficacy of the orally active endothelin-receptor-antagonist RO 47-0203 for prevention and treatment of cerebral vasospasm after experimental subarachnoid hemorrhage (SAH), using the canine two-hemorrhage model, was investigated. In the preventive study 28 beagle dogs were used. Fourteen animals each were assigned to the treatment and to the control group. In the treatment group each dog received two single doses of 30 mg/kg RO 47-0203 orally per day. The diameter of the basilar artery decreased from 1.36 +/- 0.17 mm at day one to 1.19 +/- 0.23 mm at day eight in the treatment group while in the control group the vessel diameter decreased from 1.48 +/- 0.19 mm at day one to 1.02 +/- 0.22 mm at day eight. These results corresponded to a decrease of vessel diameter of 13.1% +/- 11.2% in the treatment group and a decrease of vessel diameter of 30,7 +/- 12,4% in the control group (p < 0.001). In the therapeutic study the intraarterial infusion of 15.0 mg/kg RO 47-0203, at day 8 after experimental subarachnoid hemorrhage, caused no significant increase of the vessel diameter after 10 min., 20 min. or 30 min. These results underline the important role of endothelin in the development of cerebral vasospasm, and give for the first time evidence that prevention of cerebral vasospasm can be achieved by the endothelin-receptor-antagonist RO 47-0203.

Animals↗
PubMed1995

Calcitonin gene-related peptide and nitric oxide are involved in ultraviolet radiation-induced immunosuppression.

Contact hypersensitivity responsiveness to dinitrofluorobenzene is depressed in mice that are sensitized through skin sites exposed to ultraviolet (UV) radiation. Local impairment of contact hypersensitivity by UV has been associated with a reduction in antigen-presenting cell activity within UV-irradiated skin sites marked by a decrease in the density of Ia-positive epidermal Langerhans cells. Our recent studies have demonstrated that neurogenic mediators (e.g. calcitonin gene-related peptide (CGRP) and nitric oxide (NO) contribute to cutaneous inflammation following exposure of rats to high-dose UV radiation. Since CGRP and NO inhibit antigen presentation by dendritic cells in vitro, we have investigated the possible involvement of CGRP and NO in local immunosuppression in UV-irradiated rodents. Hindpaw skin of Sprague-Dawley rats and back skin of UV-susceptible C57BL/6 mice was exposed to acute UV radiation (2.0 J/cm2 and 0.5 J/cm2, respectively). Alterations in cutaneous CGRP content were analyzed by a specific radioimmunoassay (RIA). In separate experiments, the CGRP receptor antagonist CGRP-(8-37) (10-5 M) and the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (2 X 10-5 M) were topically applied to UV-exposed skin before induction of contact hypersensitivity with dinitrofluorobenzene. Finally, we examined the effects of UV irradiation and epicutaneous application of CGRP on Ia-positive Langerhans cells by immunohistochemical analysis of epidermal sheets. It was found that UV exposure lead to a decrease in skin CGRP levels starting already 2 h after irradiation and reaching a minimum (less than 40% of non-irradiated control skin) at 6-12 h. Contact hypersensitivity reactions were significantly suppressed by UV radiation in rat skin (by 51%) and murine skin (by 80%). Topical administration of both CGRP-(8-37) and L-NAME before sensitization restored the capacity to respond to haptens applied to UV-exposed skin. Both UV exposure and topical CGRP reduced the density of Ia-positive epidermal cells. Our data indicate that CGRP may be released from sensory neurons following cutaneous UV irradiation and that CGRP and NO contribute of UV-induced local immunosuppression. Moreover, topical administration of CGRP or its antagonist may be able to modulate epidermal Langerhans cell activity in vivo.

Animals↗
PubMed1995

Substance P and nitric oxide mediate would healing of ultraviolet photodamaged rat skin: evidence for an effect of nitric oxide on keratinocyte proliferation.

Since it has been demonstrated recently that neuropeptides are involved in wound healing in vivo we investigated the role of substance P (SP), calcitonin gene-related peptide (CGRP) and nitric oxide (NO) in regeneration of ultraviolet (UV) photodamaged rat skin by topical administration of specific antagonists. Topical application of the neurokinin (NK)1-receptor antagonist (2S,3S)-cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-1-azabi cyclo[ 2.2.2]octan-3-amine (CP-96,345) significantly delayed the reduction of the necrotic area at all timepoints post UV-irradiation, whereas topically administered NO synthase inhibitor NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) resulted in an increased necrotic area only at 7 days post-irradiation. More important, topically administered L-NAME but not SP reduced nuclear immunolabelling for proliferating cell nuclear antigen (PCNA) of the UV-exposed epidermis, suggesting a NO-mediated stimulation of keratinocyte proliferation. These findings suggest that endogenous SP and NO have a trophic function in wound healing after UV-induced damage of the skin which may be mediated by stimulation of angiogenesis or epidermal cell proliferation.

Animals↗
PubMed1995

Clinical significance of surface antigen expression in children with acute myeloid leukemia: results of study AML-BFM-87.

Immunophenotyping using a panel of 15 antibodies was performed in 267 (87%) and cytogenetic analysis in 196 (64%) of 307 children under 17 years of age enrolled in the AML-BFM-87 study. Treatment consisted of cytosine arabinoside, daunorubicin, etoposide induction and a 6-week seven-drug consolidation chemotherapy, followed by two blocks of high-dose cytosine arabinoside with or without cranial irradiation and maintenance therapy for 1 year. Five-year event-free survival for patients with immunophenotypic data was .43 +/- .03 SE. The diagnostic value of the pan-myeloid reagents CD13, CD33, and CDw65 for the recognition of childhood acute myeloid leukemia (AML) was high with a sensitivity of 98% (positivity of at least one of these antigens), whereas, with the exception of CD41 for French American British (FAB) subtype M7, the expression of single cell-surface antigens showed no correlation with morphologic or cytogenetic subgroups. On the other hand, characteristic subgroups of AML defined by morphologic features and karyotypes could be described by low or high rates of surface antigen expression compared with those of other patients. These immunophenotypic features most probably associated with specific entities include expression of CD34 or CD13 and absence of CD14 or CD4 in M2 with Auer rods/t(8;21); absence of HLA-DR, CD34, and CD14, but expression of CD33 in M3/t(15;17); positivity of either CD34 or CD13 and either CD14 or CD2 for M4Eo/inv(16); and absence of either CD34 or CD13 and expression of either CD33 or CDw65 and either CD15 or CD4 for M5/t(9;11). In FAB M0, negativity of one or two of the three panmyeloid-associated markers (CD13/33/w65) was common; and cytogenetic results frequently showed random abnormalities. Expression of lymphoid-, progenitor- and most myeloid-associated antigens had no influence on the prognosis, whereas the outcome was significantly better for children with M2 with Auer rods, M3, or M4Eo or for those with the associated karyotypes t(8;21);t(15;17) and inv(16) than for other patients.

Acute Disease↗
PubMed1995

DNA fragmentation and activation of c-Jun in the cerebellum of mutant mice (weaver, Purkinje cell degeneration).

Weaver and Purkinje cell degeneration (pcd) are autosomal recessive mutations in the mouse characterized by an almost complete loss of cerebellar Purkinje neurones and granule cells, respectively. Developmental neuronal death occurs by activation of an apoptotic pathway and chromatin condensation has been observed in degenerating granule cells of weaver mutants. In the present study we demonstrate nuclear DNA fragmentation in Purkinje cells of pcd mice and in granule cells of weaver mutants during the period of neuronal degeneration using in situ end labelling by terminal transferase and fluorescein-dUTP. Furthermore, activation of candidate cell death effector gene c-jun has been detected exclusively within the affected cell populations by immunohistochemistry. Both labelled DNA fragments and nuclear c-Jun immunoreactivity were virtually absent in wild-type animals. Thus, genetically determined cell death in pcd and weaver mutant mice has features of apoptosis and may require activation of cell death effector genes.

Animals↗
PubMed1995

Differential regulation of bcl-2, bax, c-fos, junB, and krox-24 expression in the cerebellum of Purkinje cell degeneration mutant mice.

Purkinje cell degeneration (pcd) is an autosomal recessive mutation in the mouse characterized by an almost complete loss of cerebellar Purkinje neurons between postnatal days 22 and 28. The pcd gene has not been identified, however, a relationship between activation of specific genes and cell death has been suggested in other models of neuronal cell death. In the present study we analyzed the expression of several candidate cell death effector genes (bax, c-fos, junB, krox-24) and a cell death repressor gene (bcl-2) in the cerebellum of pcd homozygotes and wild-type mice. At postnatal day 22, when Purkinje cells start to degenerate, levels of c-fos, junB, and krox-24 mRNA increased about 5-fold in mutants. To the contrary, the amount of bcl-2 mRNA declined and bax transcripts remained unchanged compared to wild-type animals. Immunoreactivity for c-Fos and Jun could be detected exclusively in cerebellar Purkinje neurons of pcd mice but not in wild-types, whereas the number of Bcl-2 immunopositive Purkinje cells decreased significantly in mutants. Both double labeling experiments and immunostaining of consecutive sections revealed lack of colocalization of Jun with Bcl-2. These results demonstrate an induction of members of the fos and jun family and a downregulation of antiapoptotic bcl-2 in cerebellar Purkinje neurons that are destined to die. Fos and Jun transcription factor proteins may be implicated in the regulation of bcl-2 expression and in the signal cascade leading to Purkinje cell death.

Animals↗
PubMed1995

Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood.

A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor-suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.

Age Factors↗
PubMed1995

Involvement of substance P in ultraviolet irradiation-induced inflammation in rat skin.

The possible involvement of substance P released from primary afferents in rat skin was investigated in cutaneous inflammation following ultraviolet (UV) irradiation. Recordings from c-fibres innervating the UV-exposed hindpaw skin showed long-lasting low-frequency (0.8-1.25 Hz) spontaneous activity. Spontaneously active c-fibres increased to constitute 35.3% of the total population 72 h after UV exposure. Immunohistochemical analysis of substance P-containing nerve fibres in hindpaw skin revealed a significant increase in substance P immunoreactivity 24 h after UV irradiation. Average length of substance P-immunolabelled nerve fibres was about two times higher in UV-exposed compared to control skin. UV-induced oedema was investigated in rat ears using an ear-swelling test. Intradermal injection of either peptide (Spantide) or nonpeptide (CP-96,345) substance P antagonists and epicutaneous application of CP-96,345 reduced UV-induced oedema significantly in the late phase of sunburn (> 12 h after UV exposure). The UV-induced increase in skin blood flow was investigated in hindpaw skin up to 72 h by the laser Doppler technique. Epicutaneous application of CP-96,345 reduced erythema significantly between 12 and 72 h after UV exposure. Thus, our findings suggest the involvement of neurogenic substance P as a proinflammatory mediator in the late phase of UV-induced cutaneous inflammation in rats.

Animals↗
PubMed1995

Up-regulation of bax and down-regulation of bcl-2 is associated with kainate-induced apoptosis in mouse brain.

Systemic administration of kainate induces cell death in vulnerable regions of the rodent brain. Neuronal degeneration is associated with internucleosomal DNA fragmentation and induction of presumptive cell death effector genes (e.g. p53, c-fos) suggesting that kainate activates an apoptotic pathway. In the present study, kainate-induced DNA damage has been demonstrated at the cellular level by in situ nick translation in the mouse hippocampus and neocortex at 24 h and 48 h after intraperitoneal injections. In the same regions, the intensity of Bcl-2 immunoreactivity decreased by about 45% as measured by digital image analysis. Most important, kainate treatment evoked a nearly 3-fold increase in bax mRNA levels within the mouse brain. The down-regulation of bcl-2, which promotes cell survival, and the up-regulation of bax, which promotes programmed cell death, may have functional significance in kainate-mediated excitotoxicity and in the selective vulnerability of specific brain regions.

Animals↗
PubMed1995

Basal expression of the inducible transcription factors c-Jun, JunB, JunD, c-Fos, FosB, and Krox-24 in the adult rat brain.

Jun, Fos, and Krox proteins are inducible transcription factors contributing to the control of gene expression. The elucidation of their individual expression patterns in the nervous system provides new insights into the ability of neurons to react with changes of gene expression to external stimulation under physiological or pathological conditions. The expression of c-Jun, JunB, JunD, c-Fos, FosB, and Krox-24 was investigated in the brain of untreated male Sprague-Dawley and female BDIX rats by immunocytochemistry using specific antibodies. JunD immunoreactivity (IR) labeled the highest number of neurons, being present in almost all neurons of the brain. JunD was expressed at high levels in those areas that also exhibit c-Jun, JunB, c-Fos, and FosB-IR, such as locus coeruleus, periolivary nuclei (ncl.), pontine and central gray, lateral lemniscal ncl., inferior and superior colliculi, leaflet of geniculate ncl., midline nuclei of thalamus, dorsomedial and paraventricular ncl. of hypothalamus, ncl. supraopticus, dorsolateral part of caudate putamen and lateral septal ncl. In contrast to the high number of JunD-positive neurons, c-Jun, JunB, c-Fos, and FosB proteins were detected in rather low numbers of neurons in these brain areas; the rank of the number of immunopositive neurons was c-Fos > JunB > c-Jun > FosB. Particularly high levels of expression were observed for c-Jun in medullary motoneurons, medial geniculate ncl., arcuate ncl., and dentate gyrus, and for JunB in the CA-1 area of the hippocampus and islands of Calleja. The zinc finger protein Krox-24 was expressed in many neurons of these brain areas, with only discrete Jun- and Fos-IR; additionally, many intensely labeled nuclei were present in spinal ncl. of the trigeminal ventromedial ncl. of the hypothalamus and the CA-1 area of the hippocampus. In the cerebellum, nuclear labeling was detected only for c-Jun, JunD, and Krox-24 in granule cells. JunD-IR was also found in glial cells of gray matter and fiber tracts, whereas glial c-Jun-IR was observed only in fiber tracts. Apart from a weak JunD-IR, some areas did not express Jun, Fos, and Krox proteins such as cuneate and gracile ncl., venterobasal complex of thalamus, globus pallidum, and Purkinje cells of the cerebellum. Our data indicate that inducible transcription factors of the fos, jun, and krox gene families show patterns of individual expression in untreated animals, thereby reflecting different mechanisms and/or thresholds for induction under physiological conditions.

Animals↗
PubMed1995

Block of c-Fos and JunB expression by antisense oligonucleotides inhibits light-induced phase shifts of the mammalian circadian clock.

Light-induced phase shifts of circadian rhythmic locomotor activity are associated with the expression of c-Jun, JunB, c-Fos and FosB transcription factors in the rat suprachiasmatic nucleus, as shown in the present study. In order to explore the importance of c-Fos and JunB, the predominantly expressed AP-1 proteins for the phase-shifting effects of light, we blocked the expression of c-Fos and JunB in the suprachiasmatic nucleus of male rats, housed under constant darkness, by intracerebroventricular application of 2 microliters of 1 mM antisense phosphorothioate oligodeoxynucleotides (ASO) specifically directed against c-fos and junB mRNA. A light pulse (300 lux for 1 h) at circadian time 15 induced a significant phase shift (by 125 +/- 15 min) of the circadian locomotor activity rhythm, whereas application of ASO 6 h before the light pulse completely prevented this phase shift. Application of control nonsense oligodeoxynucleotides had no effect. ASO strongly reduced the light-induced expression of c-Fos and JunB proteins. In contrast, light pulses with or without the control nonsense oligodeoxynucleotides evoked strong nuclear c-Fos and JunB immunoreactivity in the rat suprachiasmatic nucleus. These results demonstrate for the first time that inducible transcription factors such as c-Fos and JunB are an essential part of fundamental biological processes in the adult mammalian nervous system, e.g. of light-induced phase shifts of the circadian pacemaker.

Animals↗