| 1. |
- Grillner, Pernilla
(författare)
-
Afferent input to midbrain dopamine neurones and its modulation : an electrophysiological study i vitro
- 1999
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Dopamine (DA) neurones of the ventral mesencephalon are involved in the control of reward related behaviour, cognitive functions and motor performances, and provide a critical site of action for major categories of neuropsychiatric drugs, such as antipsychotic agents, dependence producing drugs and anti-Parkinson medication. The midbrain DA neurones are mainly located in the substantia nigra pars compacta (SNPC) and the ventral tegmental area (VTA). Their activity is regulated by the intrinsic properties of the DA neurones as well as by the activity of the afferent inputs. The aim of the present work was to study the function and modulatory role of the glutamatergic and cholinergic afferent inputs in regulating the midbrain DAergic neuronal activity. The slice preparation of the rat ventral mesencephalon in vitro was used and intracellular or whole-cell patch clamp recordings were performed from the DA neurones. Repetitive stimulation of the afferents in the slice preparation was shown to elicit a slow excitatory postsynaptic event that was blocked by application of the NMDA antagonist AP5. Moreover, the amplitude of the slow postsynaptic event was markedly reduced by L-type Ca2+ channel blockers such as nifedipine. Specific agonists to group I, II and III metabotropic glutamate receptors (mGluRs) were all shown to reduce the amplitude of both glutamatergic and GABAergic synaptic inputs to the DA neurones. A presynaptic site of action was indicated by a paired-pulse protocol. Also, muscarine depressed both glutamatergic and GABAergic synaptic transmission to the DA neurones. These effects were completely blocked by the M3/M1 receptor antagonist 4-DAMP, but not significantly affected by the M, receptor antagonist pirenzepine. Moreover, the postsynaptic responses to glutamate or GABA were not changed by muscarine. The nicotine-induced excitation of DA neurones was reduced in the presence of AP5 or the AMPA/kainate receptor antagonist CNQX. However, neither glutamate- nor GABA-mediated spontaneous synaptic transmission was affected by nicotine application. The results demonstrate that NMDA-mediated glutamatergic synaptic transmission to midbrain DA neurones involves activation of presynaptic L-type Ca2+ channels. Moreover, mGluRs and muscarinic receptors mediate presynaptic inhibition of both glutamatergic and GABAergic synaptic inputs to the midbrain DA neurones. Finally, the nicotine-induced excitation of the DA neurones in the slice preparation seems essentially to be mediated through postsynaptically located nicotinic receptors.
|
|
| 2. |
- Gronbaek, Jonathan Kjaer, et al.
(författare)
-
Left-handedness should not be overrated as a risk factor for postoperative speech impairment in children after posterior fossa tumour surgery : a prospective European multicentre study
- 2022
-
Ingår i: Child's Nervous System. - : Springer Nature. - 0256-7040 .- 1433-0350. ; 38:8, s. 1479-1485
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose Cerebellar mutism syndrome (CMS) is a severe neurological complication of posterior fossa tumour surgery in children, and postoperative speech impairment (POSI) is the main component. Left-handedness was previously suggested as a strong risk factor for POSI. The aim of this study was to investigate the relationship between handedness and the risk of POSI. Methods We prospectively included children (aged < 18 years) undergoing surgery for posterior fossa tumours in 26 European centres. Handedness was assessed pre-operatively and postoperative speech status was categorised as either POSI (mutism or reduced speech) or habitual speech, based on the postoperative clinical assessment. Logistic regression was used in the risk factor analysis of POSI as a dichotomous outcome. Results Of the 500 children included, 37 (7%) were excluded from the present analysis due to enrolment at a reoperation; another 213 (43%) due to missing data about surgery (n = 37) and/or handedness (n = 146) and/or postoperative speech status (n = 53). Out of the remaining 250 (50%) patients, 20 (8%) were left-handed and 230 (92%) were right-handed. POSI was observed equally frequently regardless of handedness (5/20 [25%] in left-handed, 61/230 [27%] in right-handed, OR: 1.08 [95% CI: 0.40-3.44], p = 0.882), also when adjusted for tumour histology, location and age. Conclusion We found no difference in the risk of POSI associated with handedness. Our data do not support the hypothesis that handedness should be of clinical relevance in the risk assessment of CMS.
|
|
| 3. |
- Jardemark, Kent, et al.
(författare)
-
Dopamine D3 and D4 receptor antagonists in the treatment of schizophrenia.
- 2002
-
Ingår i: Curr Opinion in Investigational Drugs. ; 3:1, s. 101-5
-
Forskningsöversikt (övrigt vetenskapligt/konstnärligt)abstract
- The findings that dopamine D3 and D4 receptors are highly expressed in limbic and cortical areas (D4 more than D3), and the fact that the atypical drug clozapine has preferential affinity for the D4 receptors have suggested an involvement of these receptors in schizophrenia. Subsequently, many pharmaceutical companies have pursued the approach of developing selective dopamine D3 or D4 antagonists as potential antipsychotics. This review will discuss the current status of selective dopamine D3 and D4 receptor antagonists for the treatment of schizophrenia.
|
|
| 4. |
|
|
| 5. |
- Tesi, Bianca, et al.
(författare)
-
Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
-
Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.MethodsgWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.FindingsThe prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).InterpretationOverall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.
|
|
| 6. |
- Tesi, Bianca, et al.
(författare)
-
Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors : a nationwide, prospective Swedish study
- 2024
-
Ingår i: The Lancet Regional Health. - : Elsevier. - 2666-7762. ; 39
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors.Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients.Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35).Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients.Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs.
|
|
| 7. |
- Wadensten, Elisabeth, et al.
(författare)
-
Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.
- 2023
-
Ingår i: JCO precision oncology. - : American Society of Clinical Oncology. - 2473-4284. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
|
|
| 8. |
- Wadensten, Elisabeth, et al.
(författare)
-
Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer
- 2023
-
Ingår i: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; :7
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored.Methods: We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes.Results: During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%).Conclusion: Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
|
|
| 9. |
- Wibroe, Morten, et al.
(författare)
-
Cerebellar mutism syndrome in children with brain tumours of the posterior fossa
- 2017
-
Ingår i: BMC Cancer. - : BIOMED CENTRAL LTD. - 1471-2407. ; 17
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Central nervous system tumours constitute 25% of all childhood cancers; more than half are located in the posterior fossa and surgery is usually part of therapy. One of the most disabling late effects of posterior fossa tumour surgery is the cerebellar mutism syndrome (CMS) which has been reported in up to 39% of the patients but the exact incidence is uncertain since milder cases may be unrecognized. Recovery is usually incomplete. Reported risk factors are tumour type, midline location and brainstem involvement, but the exact aetiology, surgical and other risk factors, the clinical course and strategies for prevention and treatment are yet to be determined.Methods: This observational, prospective, multicentre study will include 500 children with posterior fossa tumours. It opened late 2014 with participation from 20 Nordic and Baltic centres. From 2016, five British centres and four Dutch centres will join with a total annual accrual of 130 patients. Three other major European centres are invited to join from 2016/17. Follow-up will run for 12 months after inclusion of the last patient. All patients are treated according to local practice. Clinical data are collected through standardized online registration at pre-determined time points pre- and postoperatively. Neurological status and speech functions are examined pre- operatively and postoperatively at 1-4 weeks, 2 and 12 months. Pre- and postoperative speech samples are recorded and analysed. Imaging will be reviewed centrally. Pathology is classified according to the 2007 WHO system. Germline DNA will be collected from all patients for associations between CMS characteristics and host genome variants including pathway profiles.Discussion: Through prospective and detailed collection of information on 1) differences in incidence and clinical course of CMS for different patient and tumour characteristics, 2) standardized surgical data and their association with CMS, 3) diversities and results of other therapeutic interventions, and 4) the role of host genome variants, we aim to achieve a better understanding of risk factors for and the clinical course of CMS - with the ultimate goal of defining strategies for prevention and treatment of this severely disabling condition.
|
|
| 10. |
- Wickstrom, Ronny, et al.
(författare)
-
Viral triggering of anti-NMDA receptor encephalitis in a child : An important cause for disease relapse
- 2014
-
Ingår i: European journal of paediatric neurology. - : Elsevier BV. - 1090-3798 .- 1532-2130. ; 18:4, s. 543-546
-
Tidskriftsartikel (refereegranskat)abstract
- Herpes simplex encephalitis (HSE) in children is a potentially devastating condition which is occasionally complicated by a clinical relapse. An autoimmune component has long been suspected in these relapses and recent findings suggest that antibodies against N-methyl-D-aspartate receptors (NMDARs) may be part of this mechanism. We here report an 11 months old girl with acute HSE and with negative NMDAR antibody serology at presentation who after an initial response to antiviral treatment deteriorated with seizures, abnormal movements, focal neurologic deficits and psychiatric symptoms. We show that this relapse occurred as production of NMDAR antibodies developed and that clinical improvement followed immunotherapy with a concomitant decrease in NMDAR antibody titers in CSF. She also developed a characteristic 15-20 Hz activity over both hemispheres which has been previously described as an electroencephalographic presentation of anti-NMDAR encephalitis. We conclude that relapse or persisting symptoms in HSE in children may represent an immune-mediated mechanism rather than a viral reactivation and that NMDAR antibodies should be analyzed as this may be of importance for the choice of therapy.
|
|
