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Träfflista för sökning "WFRF:(Jakobsson Mattias) ;lar1:(ki)"

Sökning: WFRF:(Jakobsson Mattias) > Karolinska Institutet

  • Resultat 1-7 av 7
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1.
  • Jakobsson, J, et al. (författare)
  • A novel polymorphism in the 17beta-hydroxysteroid dehydrogenase type 5 (aldo-keto reductase 1C3) gene is associated with lower serum testosterone levels in caucasian men.
  • 2007
  • Ingår i: The pharmacogenomics journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 7:4, s. 282-9
  • Tidskriftsartikel (refereegranskat)abstract
    • Genetic variation in the androgen metabolizing enzymes is important to identify and feature as they may influence the risk of prostate cancer and help clarify the etiology of the disease. Human 17beta-hydroxysteroid dehydrogenase type 5 (AKR1C3) is highly expressed in the prostate gland and plays a major role in the formation and metabolism of androgens. We identified five novel polymorphisms in the AKR1C3 gene. One of those an A>G substitution in exon 2 that confers a Glu77Gly change occurred in 4.8% in Caucasians but was completely absent in Orientals. Interestingly, the testosterone level in serum was significantly lower in subjects with the Gly77 allele. A promoter A>G polymorphism was associated with significantly altered promoter activity in reporter constructs, but was not associated with any change in testosterone levels. In conclusion, the Glu77Gly polymorphism is associated with lower testosterone levels in serum.
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2.
  • Jakobsson, Jenny, et al. (författare)
  • Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-glucuronosyl transferase 2B17 polymorphism.
  • 2006
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 91:2, s. 687-93
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: The reproductive endocrinology in Asians and Caucasians is of great interest in view of large differences in prostate cancer rate and sensitivity to pharmacological male contraception. In addition, interpretation of certain antidoping tests is confounded by interethnic variation in androgen disposition. Uridine diphosphoglucuronosyl transferases have a key role in the homeostasis and metabolism of androgens. Recently a deletion polymorphism was detected in the UGT2B17 gene. OBJECTIVE: The objective of the study was to evaluate the contribution of the UGT2B17 deletion polymorphism to the interindividual and interethnic variation of androgen metabolism and excretion. METHODS AND RESULTS: Urine from 122 Swedish and 74 Korean healthy men was analyzed for several androgen glucuronides including testosterone. The distribution of the natural logarithms of urinary testosterone concentrations showed a distinct bimodal pattern in both groups, suggesting a monogenic inheritance. When the UGT2B17 genotypes were compared with urinary testosterone levels, all of the individuals of the UGT2B17 homozygous deletion/deletion genotype had no or negligible amounts of urinary testosterone. The deletion/deletion genotype was seven times more common in the Korean (66.7%) than the Swedish population (9.3%). In addition, the Swedes had significantly higher levels of serum testosterone, compared with the Koreans. CONCLUSIONS: Our results show that the UGT2B17 polymorphism is strongly associated with the bimodal distribution of the testosterone excretion and also with the large differences in testosterone excretion between Koreans and Swedes.
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3.
  • Salzer, Jonatan, et al. (författare)
  • Rituximab in multiple sclerosis : a retrospective observational study on safety and efficacy
  • 2016
  • Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 87:20, s. 2074-2081
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2-5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6-12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades >= 2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective.
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4.
  • Schulze, Jenny Jakobsson, et al. (författare)
  • Genetic aspects of epitestosterone formation and androgen disposition: influence of polymorphisms in CYP17 and UGT2B enzymes.
  • 2008
  • Ingår i: Pharmacogenetics and genomics. - 1744-6872. ; 18:6, s. 477-85
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: Testosterone is a commonly abused androgen in sports and in the gym culture of the society. Its abuse is conventionally disclosed by urinary assay of the testosterone/epitestosterone (T/E) glucuronide ratio, which should not exceed 4. A noteworthy number of athletes, however, have higher natural ratios than 4, most likely because of decreased excretion of epitestosterone glucuronide. Falsely positive doping test results are of great concern for the legal rights of the sportsman. Our objective was to study the genetic aspects of epitestosterone formation, and to elucidate the impact of genetic variation in androgen-metabolizing enzymes. METHODS: Urine from different study populations was analysed for androgen glucuronides by gas chromatography-mass spectrometry. All men were genotyped for the uridine diphospho-glucuronosyltransferase (UGT) 2B17 deletion polymorphism and single nucleotide polymorphisms in the cytochrome P-450c17alpha (CYP17), UGT2B15 and UGT2B7 genes. Expression of UGT2B15 mRNA in human liver samples was analysed using real-time PCR. RESULTS: A T>C (A1>A2) promoter polymorphism in the CYP17 gene was associated with the urinary glucuronide levels of epitestosterone and its putative precursor androstene-3beta, 17alpha-diol, resulting in 64% higher T/E ratios in A1/A1 homozygotes. Individuals devoid of UGT2B17 had significantly higher UGT2B15 mRNA levels in liver than individuals carrying two functional UGT2B17 alleles. CONCLUSION: The CYP17 promoter polymorphism may partly explain high natural (>4) T/E ratios. Our data indicate that 5-androstene-3beta, 17alpha-diol is an important precursor of epitestosterone and that CYP17 is involved in its production. In addition, we found that lack of the UGT2B17 enzyme may be compensated for by increase in UGT2B15 transcription.
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5.
  • Silva, Antero Vieira, et al. (författare)
  • A probabilistic approach to evaluate the risk of decreased total triiodothyronine hormone levels following chronic exposure to PFOS and PFHxS via contaminated drinking water
  • 2020
  • Ingår i: Environmental Health Perspectives. - 0091-6765 .- 1552-9924. ; 128:7, s. 1-11
  • Forskningsöversikt (refereegranskat)abstract
    • BACKGROUND: Extensive exposure to per-and polyfluoroalkyl substances (PFAS) have been observed in many countries. Current deterministic frame-works for risk assessment lack the ability to predict the likelihood of effects and to assess uncertainty. When exposure exceeds tolerable intake levels, these shortcomings hamper risk management and communication. OBJECTIVE: The integrated probabilistic risk assessment (IPRA) combines dose-response and exposure data to estimate the likelihood of adverse effects. We evaluated the usefulness of the IPRA for risk characterization related to decreased levels of total triiodothyronine (T3) in humans following a real case of high exposure to PFAS via drinking water. METHODS: PFAS exposure was defined as serum levels from residents of a contaminated area in Ronneby, Sweden. Median levels were 270 ng=mL [perfluorooctane sulfonic acid (PFOS)] and 229 ng=mL [perfluorohexane sulfonic acid (PFHxS)] for individuals who resided in Ronneby 1 y before the exposure termination. This data was integrated with data from a subchronic toxicity study in monkeys exposed daily to PFOS. Benchmark dose modeling was employed to describe separate dose–effect relationship for males and females, and extrapolation factor distributions were used to estimate the corresponding human benchmark dose. The critical effect level was defined as a 10% decrease in total T3. RESULTS: The median probability of critical exposure, following a combined exposure to PFOS and PFHxS, was estimated to be [2.1% (90% CI: 0:4%–13:1%)]. Gender-based analysis showed that this risk was almost entirely distributed among women, namely [3.9% (90% CI: 0:8%–21:6%)]. DISCUSSION: The IPRA was compared with the traditional deterministic Margin of Exposure (MoE) approach. We conclude that probabilistic risk characterization represents an important step forward in the ability to adequately analyze group-specific health risks. Moreover, quantifying the sour-ces of uncertainty is desirable, as it improves the awareness among stakeholders and will guide future efforts to improve accuracy. https://doi.org/10.1289/EHP6654.
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6.
  • Swanson, Charlotte, 1975, et al. (författare)
  • Sex steroid levels and cortical bone size in young men are associated with a uridine diphosphate glucuronosyltransferase 2B7 polymorphism (H268Y).
  • 2007
  • Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:9, s. 3697-704
  • Tidskriftsartikel (refereegranskat)abstract
    • CONTEXT: Sex steroids are involved in the regulation of pubertal cortical bone expansion in males. In vitro studies have indicated that the enzyme uridine diphosphate glucuronosyltransferase (UGT) 2B7 has the capacity to glucuronidate sex steroids and their metabolites. OBJECTIVE: Our objective was to determine the impact of the H(268)Y polymorphism in the UGT2B7 gene on interindividual variation of serum levels of sex steroids and cortical bone dimensions. PARTICIPANTS: The population-based cohort Gothenburg Osteoporosis and Obesity Determinants study consists of 1068 young adult Swedish men (age 18.9 yr). MAIN OUTCOME MEASURES: Serum levels of sex steroids and the three major glucuronidated androgen metabolites, androstane-3alpha,17beta-diol-17glucuronide, androstane-3alpha,17beta-diol-3glucuronide, and androsterone-glucuronide, were analyzed. Cortical and trabecular volumetric bone mineral density and cortical bone size were measured by peripheral quantitative computer tomography. RESULTS: Serum levels of testosterone (YY 9% over HH; P < 0.01), dihydrotestosterone (YY 10% over HH; P < 0.01), and estradiol (YY 8% over HH; P < 0.01) were associated with the UGT2B7 H(268)Y polymorphism. The polymorphism was associated with androstane-3alpha,17beta-diol-17glucuronide and androstane-3alpha,17beta-diol-3glucuronide (P < 0.01), but not with androsterone-glucuronide serum levels. In addition, the UGT2B7 H(268)Y polymorphism was an independent predictor of cortical bone size, reflected by periosteal circumference and cortical moment of inertia (P < 0.01), in both the weight-bearing tibia and nonweight-bearing radius. CONCLUSIONS: The UGT2B7 H(268)Y polymorphism is independently associated with cortical bone size and serum sex steroid levels in young adult men. Subjects homozygous for the Y allele had higher serum testosterone and larger cortical bone size than subjects homozygous for the H allele. However, the underlying mechanism behind these associations is unknown and has to be studied further.
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7.
  • Åkesson, Karolina, et al. (författare)
  • Kynurenine pathway is altered in patients with SLE and associated with severe fatigue
  • 2018
  • Ingår i: Lupus Science and Medicine. - : BMJ Publishing Group Ltd. - 2053-8790. ; 5:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Fatigue has been reported as the most disturbing symptom in a majority of patients with SLE. Depression is common and often severe. Together these symptoms cause significant morbidity and affect patients with otherwise relatively mild disease. Tryptophan and its metabolites in the kynurenine pathway are known to be important in several psychiatric conditions, for example, depression, which are often also associated with fatigue. We therefore investigated the kynurenine pathway in patients with SLE and controls.Methods: In a cross-sectional design plasma samples from 132 well-characterised patients with SLE and 30 age-matched and gender-matched population-based controls were analysed by liquid chromatography tandem mass spectrometry to measure the levels of tryptophan and its metabolites kynurenine and quinolinic acid. Fatigue was measured with Fatigue Severity Scale and depression with Hospital Anxiety and Depression Scale. SLE disease activity was assessed with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).Results: The kynurenine/tryptophan ratio, as a measure of indoleamine 2,3-dioxygenase (IDO) activity, was increased in patients with SLE. Patients with active disease (SLEDAI >= 6) showed lower tryptophan levels compared with controls (54 mu M, SD=19 vs 62 mu M, SD=14, p=0.03), although patients with SLE overall did not differ compared with controls. Patients with SLE had higher levels of tryptophan metabolites kynurenine (966 nM, SD=530) and quinolinic acid (546 nM, SD=480) compared with controls (kynurenine: 712 nM, SD=230, p=0.0001; quinolinic acid: 380 nM, SD=150, p=0.001). Kynurenine, quinolinic acid and the kynurenine/tryptophan ratio correlated weakly with severe fatigue (r(s)=0.34, r(s)=0.28 and r(s)=0.24, respectively) but not with depression.Conclusions: Metabolites in the kynurenine pathway are altered in patients with SLE compared with controls. Interestingly, fatigue correlated weakly with measures of enhanced tryptophan metabolism, while depression did not. Drugs targeting enzymes in the kynurenine pathway, for example, IDO inhibitors or niacin (B12) supplementation, which suppresses IDO activity, merit further investigation as treatments in SLE.
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