Aims
The aim was to comprehensively investigate the effects of genetic variability on the pharmacokinetics of rosuvastatin.
Methods
We conducted a genome‐wide association study and candidate gene ...analyses of single dose rosuvastatin pharmacokinetics in a prospective study (n = 159) and a cohort of previously published studies (n = 88).
Results
In a genome‐wide association meta‐analysis of the prospective study and the cohort of previously published studies, the SLCO1B1 c.521 T > C (rs4149056) single nucleotide variation (SNV) associated with increased area under the plasma concentration–time curve (AUC) and peak plasma concentration of rosuvastatin (P = 1.8 × 10−12 and P = 3.2 × 10−15). The candidate gene analysis suggested that the ABCG2 c.421C > A (rs2231142) SNV associates with increased rosuvastatin AUC (P = .0079), while the SLCO1B1 c.388A > G (rs2306283) and SLCO2B1 c.1457C > T (rs2306168) SNVs associate with decreased rosuvastatin AUC (P = .0041 and P = .0076). Based on SLCO1B1 genotypes, we stratified the participants into poor, decreased, normal, increased and highly increased organic anion transporting polypeptide (OATP) 1B1 function groups. The OATP1B1 poor function phenotype associated with 2.1‐fold (90% confidence interval 1.6–2.8, P = 4.69 × 10−5) increased AUC of rosuvastatin, whereas the OATP1B1 highly increased function phenotype associated with a 44% (16–62%; P = .019) decreased rosuvastatin AUC. The ABCG2 c.421A/A genotype associated with 2.2‐fold (1.5–3.0; P = 2.6 × 10−4) increased AUC of rosuvastatin. The SLCO2B1 c.1457C/T genotype associated with 28% decreased rosuvastatin AUC (11–42%; P = .01).
Conclusion
These data suggest roles for SLCO1B1, ABCG2 and SLCO2B1 in rosuvastatin pharmacokinetics. Poor SLCO1B1 or ABCG2 function genotypes may increase the risk of rosuvastatin‐induced myotoxicity. Reduced doses of rosuvastatin are advisable for patients with these genotypes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by
(RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short ...stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders.
interacts with the telomerase RT (TERT) subunit, but the influence of
mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features.
The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous
mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous
mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the
gene and measured RTL by qPCR.
Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in
mutation carriers (r=-0.482, p<0.001) and non-carriers (r=-0.498, p<0.001), but not in patients (r=-0.236, p=0.107). In particular children (<18 years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics.
Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.
The suitability of a non-fossil reductant in high-temperature treatment of a zinc leach residue was studied in laboratory-scale experiments. The pyrometallurgical experiments carried out at ...temperatures of 1200–1350 °C consisted of melting the residue under an oxidizing atmosphere to produce an intermediate, desulfurized slag, which was further cleaned of metals such as Zn, Pb, Cu, and Ag, using renewable biochar as a reductant. The aim was to recover valuable metals and produce a clean, stable slag for use as construction material, for example. The first experiments indicated that biochar is a viable alternative to fossil-based metallurgical coke. The capabilities of biochar as a reductant were studied in more detail after optimizing the processing temperature at 1300 °C and modifying the experimental arrangement by adding rapid quenching of the sample (to a solid state in less than 5 s) to the procedure. Modifying the slag viscosity by adding 5–10 wt % MgO was found to enhance the slag cleaning significantly. With an addition of 10 wt % MgO, the target Zn concentration in slag (Zn < 1 wt %) was reached after as little as 10 min of reduction, and the Pb concentration was also decreased relatively close to the target value (Pb < 0.03 wt %). With an addition of 0–5 wt % MgO, the target Zn and Pb levels were not reached within 10 min, but with longer treatment times of 30–60 min, 5 wt % of MgO was enough to decrease the Zn content in slag sufficiently. The lowest Pb concentration achieved with an addition of 5 wt % MgO was 0.09 wt % after a 60 min reduction time.
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IJS, KILJ, NUK, PNG, UL, UM, UPUK
The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features ...of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.
Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.
In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.
Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We studied the associations between inflammation‐related proteins in circulation and complications after pediatric allogenic hematopoietic stem cell transplantation (HSCT), to reveal proteomic ...signatures or individual soluble proteins associated with specific complications after HSCT. We used a proteomics method called Proximity Extension Assay to repeatedly measure 180 different proteins together with clinical variables, cellular immune reconstitution and blood viral copy numbers in 27 children (1–18 years of age) during a 2‐year follow‐up after allogenic HSCT. Protein profile analysis was performed using unsupervised hierarchical clustering and a regression‐based method, while the Bonferroni‐corrected Mann–Whitney U‐test was used for time point–specific comparison of individual proteins against outcome. At 6 months after allogenic HSCT, we could identify a protein profile pattern associated with occurrence of the complications such as chronic graft‐versus‐host disease, viral infections, relapse and death. When protein markers were analyzed separately, the plasma concentration of the inhibitory and cytotoxic T‐cell surface protein FCRL6 (Fc receptor‐like 6) was higher in patients with cytomegalovirus (CMV) viremia log2‐fold change 1.5 (P = 0.00099), 2.5 (P = 0.00035) and 2.2 (P = 0.045) at time points 6, 12 and 24 months. Flow cytometry confirmed that FCRL6 expression was higher in innate‐like γδ T cells, indicating that these cells are involved in controlling CMV reactivation in HSCT recipients. In conclusion, the potentially druggable FCRL6 receptor on cytotoxic T cells appears to have a role in controlling CMV viremia after HSCT. Furthermore, our results suggest that system‐level analysis is a useful addition to the studying of single biomarkers in allogenic HSCT.
In this study, the cytotoxic T‐cell inhibitory FCRL6 (Fc receptor‐like 6) emerged as a potentially relevant biomarker or a therapy target for cytomegalovirus reactivation after pediatric hematopoietic stem cell transplantation (HSCT). Furthermore, the proteomic approach revealed several potential other biomarkers that showed different kinetics in patients with and without complications after HSCT.
Ecology of the glacial relict macrocrustacean Gammaracanthus lacustris, a rare inhabitant of deep Fennoscandian lakes, is poorly understood. We studied the life cycle and trophic position of this ...cold‐stenothermic amphipod in Lake Paasivesi, eastern Finland. The study is based on intensive sampling and analyses of fatty acid composition as well as stable carbon (δ13C) and nitrogen (δ15N) isotope ratios.
Both day and night, the G. lacustris population occurred at depths below 25 m at temperatures <8°C, and the density increased towards the bottom of the lake, where it was 0.4–0.6 individuals/m3.
Gammaracanthus lacustris was observed to reach a length of >40 mm and live up to 4 years. The oldest and the largest individuals and females seemed to favour the deepest zones.
In October, almost 100% of females with length at least 25 mm (i.e. females presumably at least 1‐year‐old) had an embryo sack with 20–200 eggs or embryos—the larger the female, the more young it had.
The developing eggs of G. lacustris had a very high fatty acid content, indicating that the females invest heavily on provisioning their young. Furthermore, the fatty acid composition differed among life stages, and in particular the eggs had a higher proportion of eicosapentaenoic acid than juveniles or adults.
The stable δ13C and δ15N isotope ratios and fatty acid biomarkers of the food web, together with visual observations, indicate that G. lacustris is a carnivore that feeds mainly on zooplankton and other relict macrocrustaceans.
Due to its high content of essential polyunsaturated fatty acids, G. lacustris is a valuable prey for fish and other predators in the food web. However, as a glacial relict with strict habitat requirements the species is vulnerable to global warming and local environmental changes. These facts should be considered in the management of lakes and their catchments.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Surgery, needle fasciotomy, and collagenase injection are used to treat Dupuytren contracture. The treatment decision requires balancing initial morbidity and costs of surgery against its potential ...long-term benefits over needle fasciotomy and collagenase.
To compare the effectiveness of surgery, needle fasciotomy, and collagenase injection at 3 months and 2 years (secondary time points of the trial).
A multicenter, randomized, outcome assessor-blinded, superiority trial. (ClinicalTrials.gov: NCT03192020).
6 public hospitals in Finland.
302 persons with treatment-naive Dupuytren contracture (contracture angle <135°).
Surgery (
= 101), needle fasciotomy (
= 101), or collagenase (
= 100).
The primary outcome was the success rate, defined as greater than 50% contracture release and patients reaching the patient acceptable symptom state. Secondary outcomes included hand function, pain, quality of life, patient satisfaction, residual contracture angle, finger flexion, risk for retreatment, and serious adverse events.
A total of 292 (97%) and 284 (94%) participants completed the 3-month and 2-year follow-ups. Success rates were similar at 3 months: 71% (95% CI, 62% to 80%) for surgery, 73% (CI, 64% to 82%) for needle fasciotomy, and 73% (CI, 64% to 82%) for collagenase. At 2 years, surgery had superior success rates compared with both needle fasciotomy (78% vs. 50%; adjusted risk difference aRD, 0.30 CI, 0.17 to 0.43) and collagenase (78% vs. 65%; aRD, 0.13 CI, 0.01 to 0.26). Secondary analyses paralleled with the primary analysis.
Participants were not blinded.
Initial outcomes are similar between the treatments, but at 2 years success rates were maintained in the surgery group but were lower with both needle fasciotomy and collagenase despite retreatments.
Research Council of Finland.
Viral infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although immune suppression plays a central role, the literature shows conflicting ...results on interplay between post-transplant immune reconstitution (IR) and viral infections.
We prospectively studied viral infections and IR in 30 pediatric patients undergoing allogenic HSCT, with a follow-up time of 24 months. In total, 1337 blood (CMV, EBV, HHV-6, ADV and BKV) and urine (BKV and JCV) virus samples were analyzed. IR including B-cells (CD19+), T cells (CD3+, CD4+, CD8+) and NK-cells were measured. Clinical outcomes included overall survival (OS), non-relapse mortality (NRM), graft-versus-host disease (GVHD) and occurrence of blood culture positive bacterial infections.
We found BKV reactivation to be most frequent, 47% of the children had viremia and 77% viruria. The frequencies of CMV, HHV-6 and adeno viremia were 37%, 37% and 6%, respectively. Viremias beyond 3 months post-HSCT were uncommon. Factors such as GVHD, use of steroids, EBV and CMV infections and pre-transplant irradiation affected IR. No specific viral infection or IR related factor was associated to OS or NRM.
Viral infections and IR interact in a bi-directional manner. Accordingly, close follow-up of both IR and viral loads is warranted.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IntroductionNoise exposure during pregnancy may affect a child's auditory system, which may disturb fetal learning and language development. We examined the impact of occupational noise exposure ...during pregnancy on children's language acquisition at the age of one.MethodsA cohort study was conducted among women working in the food industry, as kindergarten teachers, musicians, dental nurses, or pharmacists who had a child aged <1 year. The analyses covered 408 mother-child pairs. Language acquisition was measured using the Infant-Toddler Checklist. An occupational hygienist assessed noise exposure individually as no (N = 180), low (70-78 dB; N = 108) or moderate/high exposure (>79 dB; N = 120).ResultsAmong the boys, the adjusted mean differences in language acquisition scores were -0.4 (95% CI -2.5, 1.8) for low, and -0.7 (95% CI -2.9, 1.4) for moderate/high exposure compared to no exposure. Among the girls the respective scores were +0.1 (95% CI -2.2, 2.5) and -0.1 (95% CI -2.3, 2.2). Among the children of kindergarten teachers, who were mainly exposed to human noise, low or moderate exposure was associated with lower language acquisition scores. The adjusted mean differences were -3.8 (95% CI -7.2, -0.4) for low and -4.9 (95% CI -8.6, -1.2) for moderate exposure.ConclusionsIn general, we did not detect an association between maternal noise exposure and children's language acquisition among one-year-old children. However, the children of kindergarten teachers exposed to human noise had lower language acquisition scores than the children of the non-exposed participants. These suggestive findings merit further investigation by level and type of exposure.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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