| 1. |
- Chen, X., et al.
(författare)
-
A genome-wide association study of IgM antibody against phosphorylcholine: shared genetics and phenotypic relationship to chronic lymphocytic leukemia
- 2018
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 27:10, s. 1809-1818
-
Tidskriftsartikel (refereegranskat)abstract
- Phosphorylcholine (PC) is an epitope on oxidized low-density lipoprotein (oxLDL), apoptotic cells and several pathogens like Streptococcus pneumoniae. Immunoglobulin M against PC (IgM anti-PC) has the ability to inhibit uptake of oxLDL by macrophages and increase clearance of apoptotic cells. From our genome-wide association studies (GWASs) in four European-ancestry cohorts, six single nucleotide polymorphisms (SNPs) in 11q24.1 were discovered (in 3002 individuals) and replicated (in 646 individuals) to be associated with serum level of IgM anti-PC (the leading SNP rs35923643-G, combined beta = 0.19, 95% confidence interval 0.13-0.24, P = 4.3 x 10-11). The haplotype tagged by rs35923643-G (or its proxy SNP rs735665-A) is also known as the top risk allele for chronic lymphocytic leukemia (CLL), and a main increasing allele for general IgM. By using summary GWAS results of IgM anti-PC and CLL in the polygenic risk score (PRS) analysis, PRS on the basis of IgM anti-PC risk alleles positively associated with CLL risk (explained 0.6% of CLL variance, P = 1.2 x 10-15). Functional prediction suggested that rs35923643-G might impede the binding of Runt-related transcription factor 3, a tumor suppressor playing a central role in the immune regulation of cancers. Contrary to the expectations from the shared genetics between IgM anti-PC and CLL, an inverse relationship at the phenotypic level was found in a nested case-control study (30 CLL cases with 90 age- and sex-matched controls), potentially reflecting reverse causation. The suggested function of the top variant as well as the phenotypic association between IgM anti-PC and CLL risk needs replication and motivates further studies.
|
|
| 2. |
- Björklund, Erik, et al.
(författare)
-
Pre-hospital thrombolysis delivered by paramedics is associated with reduced time delay and mortality in ambulance-transported real-life patients with ST-elevation myocardial infarction
- 2006
-
Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 27:10, s. 1146-1152
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: There are sparse data on the impact of pre-hospital thrombolysis (PHT) in real-life patients. We therefore evaluated treatment delays and outcome in a large cohort of ambulance-transported real-life patients with ST-elevation myocardial infarction (STEMI) according to PHT delivered by paramedics or in-hospital thrombolysis. METHODS AND RESULTS: Prospective cohort study used data from the Swedish Register of Cardiac intensive care on patients admitted to the coronary care units of 75 Swedish hospitals in 2001-2004. Ambulance-transported thrombolytic-treated patients younger than age 80 with a diagnosis of acute myocardial infarction were included. Patients with PHT (n=1690) were younger, had a lower prevalence of co-morbid conditions, fewer complications, and a higher ejection fraction (EF) than in-hospital-treated patients (n=3685). Median time from symptom onset to treatment was 113 min for PHT and 165 min for in-hospital thrombolysis. One-year mortality was 7.2 vs. 11.8% for PHT and in-hospital thrombolysis, respectively. In a multivariable analysis, after adjusting for baseline characteristics and rescue angioplasty, PHT was associated with lower 1-year mortality (odds ratio 0.71, 0.55-0.92, P=0.008). CONCLUSION: When compared with regular in-hospital thrombolysis, pre-hospital diagnosis and thrombolysis with trained paramedics in the ambulances are associated with reduced time to thrombolysis by almost 1 h and reduced adjusted 1-year mortality by 30% in real-life STEMI patients.
|
|
| 3. |
|
|
| 4. |
- Diwakarla, Shanti, et al.
(författare)
-
Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures
- 2016
-
Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:10, s. 1383-1392
-
Tidskriftsartikel (refereegranskat)abstract
- The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of TRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors:A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.
|
|
| 5. |
- Duberg, Ann-Sofi, et al.
(författare)
-
Cause of death in individuals with chronic HBV and/or HCV infection, a nationwide community-based register study
- 2008
-
Ingår i: Journal of Viral Hepatitis. - : Wiley. - 1352-0504 .- 1365-2893. ; 15:7, s. 538-550
-
Tidskriftsartikel (refereegranskat)abstract
- Studies on chronic viral hepatitis and mortality have often been made on selected populations or in high-endemic countries. The aim of this study was to investigate the causes of death and the mortality rates in the nationwide cohorts of people chronically infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV) in Sweden, a low-endemic country. All notifications on chronic HBV infection and HCV infection 1990-2003 were linked to the Cause of Death Register. A total of 9517 people with chronic HBV infection, 34 235 people with HCV infection and 1601 with chronic HBV-HCV co-infection were included, and the mean observation times were 6.4, 6.3 and 7.9 years, respectively. The mortality in the cohorts was compared with age- and gender-specific mortality in the general population and standardized mortality ratios (SMR) were calculated. All-cause mortality was significantly increased, SMR 2.3 (HBV), 5.8 (HCV) and 8.5 (HBV-HCV), with a great excess liver-related mortality in all cohorts, SMR 21.7, 35.5 and 46.2, respectively. In HCV and HBV-HCV infected there was an increased mortality due to drug-related psychiatric diagnoses (SMR: 20.7 and 27.6) and external causes (SMR: 12.4 and 11.4), predominantly at younger age. To conclude, this study demonstrated an increased all-cause mortality, with a great excess mortality from liver disease, in all cohorts. In people with HCV infection the highest excess mortality in younger ages was from drug-related and external reasons.PMID: 18397223 [PubMed - indexed for MEDLINE]
|
|
| 6. |
|
|
| 7. |
- Frånberg, Olivia, et al.
(författare)
-
Asenapine, a novel psychopharmacologic agent : preclinical evidence for clinical effects in schizophrenia.
- 2008
-
Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 196:3
-
Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder.MATERIALS AND METHODS: The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed.RESULTS: Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC.CONCLUSIONS: These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.
|
|
| 8. |
- Guan, Jikui, et al.
(författare)
-
Clinical response of the novel activating ALK-I1171T mutation in neuroblastoma to the ALK inhibitor ceritinib.
- 2018
-
Ingår i: Cold Spring Harbor molecular case studies. - : Cold Spring Harbor Laboratory. - 2373-2873. ; 4:4
-
Tidskriftsartikel (refereegranskat)abstract
- Tumors with Anaplastic Lymphoma Kinase (ALK) fusion rearrangements, including non-small cell lung cancer and anaplastic large cell lymphoma, are highly sensitive to ALK tyrosine kinase inhibitors (TKIs), underscoring the notion that such cancers are addicted to ALK activity. While mutations in ALK are heavily implicated in childhood neuroblastoma, response to the ALK TKI crizotinib has been disappointing. Embryonal tumors in patients with DNA repair defects such as Fanconi anemia (FA) often have a poor prognosis, due to lack of therapeutic options. Here we report a child with underlying FA and ALK mutant high-risk neuroblastoma responding strongly to precision therapy with the ALK TKI ceritinib. Conventional chemotherapy treatment caused severe, life-threatening toxicity. Genomic analysis of the initial biopsy identified germ-line FANCA mutations as well as a novel ALK-I1171T variant. ALK-I1171T generates a potent gain-of-function mutant, as measured in PC12 cell neurite outgrowth and NIH3T3 transformation. Pharmacological inhibition profiling of ALK-I1171T in response to various ALK TKIs identified an 11-fold improved inhibition of ALK-I1171T with ceritinib when compared with crizotinib. Immunoaffinity-coupled LC-MS/MS phosphoproteomics analysis indicated a decrease in ALK signaling in response to ceritinib. Ceritinib was therefore selected for treatment in this child. Mono-therapy with ceritinib was well tolerated and resulted in normalized catecholamine markers and tumor shrinkage. After 7.5 months treatment, residual primary tumor was surgically removed and exhibited hallmarks of differentiation together with reduced Ki67 levels. Clinical follow-up after 21 months treatment revealed complete clinical remission including all metastatic sites. Therefore, ceritinib presents a viable therapeutic option for ALK-positive neuroblastoma.
|
|
| 9. |
- Gustafsson Stolt, Ulrica, 1965-, et al.
(författare)
-
Information and informed consent in a longitudinal screening involving children : a questionnaire survey
- 2005
-
Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 13, s. 376-383
-
Tidskriftsartikel (refereegranskat)abstract
- This empirical study explores participants' perceptions of information and understanding of their children's and their own involvement in a longitudinal screening, the ABIS Study. ABIS (All Babies In Southeast Sweden) is a multicentre, longitudinal research screening for Type 1 diabetes and multifactorial diseases involving 17 005 children and their families. For this study, a random selection of mothers was made, using perinatal questionnaire serial numbers from the ABIS study. In total, 293 of these mothers completed an anonymous questionnaire (response rate 73.3%). Our findings from the questionnaire indicate a marked difference between the reported satisfaction with and understanding of the information provided on the one hand and the significant lack of knowledge of some of the aims and methods of the ABIS screening on the other, namely concerning high-risk identification of involved children, potential prevention and future questionnaires. Two questions evoked by our results are: (1) what information is required for participants in longitudinal studies involving children? and (2) how do we ensure and sustain understanding, and thus in a prolonging, informed consent in these studies? This study underlines the importance of an increased understanding of the ethical issues that longitudinal research on children raise and the need to discuss how information and informed consent strategies should be analysed and designed in longitudinal studies.
|
|
| 10. |
- Henriksson, Catrin, et al.
(författare)
-
Knowledge and attitudes toward seeking medical care for AMI-symptoms
- 2011
-
Ingår i: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 147:2, s. 224-227
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Time is crucial when an acute myocardial infarction (AMI) occurs, but patients often wait before seeking medical care. Aim: To investigate and compare patients' and relatives' knowledge of AMI, attitudes toward seeking medical care, and intended behaviour if AMI-symptoms occur. Methods: The present study was a descriptive, multicentre study. Participants were AMI-patients <= 75 years (n = 364) and relatives to AMI-patients (n = 319). Questionnaires were used to explore the participants' knowledge of AMI and attitudes toward seeking medical care. Results: Both patients and relatives appeared to act more appropriate to someone else's chest pain than to their own. Patients did not have better knowledge of AMI-symptoms than relatives. Women would more often contact someone else before seeking medical care. A greater percentage of elderly (65-75 years), compared to younger individuals, reported that they would call for an ambulance if chest pain occurred. Conclusions: There were only minor differences between patients and relatives, regarding both knowledge and attitudes. It seems easier to act correctly as a bystander than as a patient. Therefore, in order to decrease patients' delay time it is important to educate relatives as well as patients on how to respond to symptoms of an AMI.
|
|
