| 1. |
- Blokland, G. A. M., et al.
(författare)
-
Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
-
Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
|
|
| 2. |
- Karttunen, L, et al.
(författare)
-
An accurate method for comparing transcript levels of two alleles or highly homologous genes : application to fibrillin transcripts in Marfan patients' fibroblasts
- 1996
-
Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 6:5, s. 392-403
-
Tidskriftsartikel (refereegranskat)abstract
- We introduce here a novel and generally applicable, solid-phase minisequencing-based approach for rapid estimation of relative levels of transcripts with high sequence homology. This study was undertaken to screen for the consequences of different fibrillin-1 mutations on the transcript levels in patients with the Marfan syndrome (MFS). This dominantly inherited, connective tissue disorder is characterized by pleiotrophic symptoms in cardiovascular, skeletal, and ocular systems. A spectrum of disease mutations in the gene encoding fibrillin-1 (FBN1), a glycoprotein component of extracellular matrix microfibrils, has been identified in MFS patients, but the mechanisms by which mutations result in different phenotypic manifestations are still unknown to a large extent. Our data from the quantitation of FBN1 transcripts provide support for the hypothesis that mutations causing premature stop codons result in a milder phenotype than classical MFS by reducing the stability of the mutant transcript and, consequently, decreasing the interference of mutant polypeptide in the formation of fibrillin fibers. We also applied this mRNA quantitation method to determine the relative ratio between transcripts from the genes coding for two highly homologous microfibrillar components, FBN1 and FBN2, in control fibroblast cultures as well as in fibroblasts from MFS patients. Interestingly, these data show large variations between the levels of the two transcripts in fibroblast cultures, but these variations do not correlate either with the nature of the disease mutation or to the clinical MFS phenotype.
|
|
| 3. |
- Linnankivi, T, et al.
(författare)
-
Cerebroretinal microangiopathy with calcifications and cysts.
- 2006
-
Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 67:8, s. 1437-43
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Extensive cerebral calcifications and leukoencephalopathy have been reported in two rare disorders Coats plus and leukoencephalopathy with calcifications and cysts. In the latter, a progressive formation of parenchymal brain cysts is a special feature, whereas Coats plus is characterized by intrauterine growth retardation, bilateral retinal telangiectasias and exudations (Coats disease), sparse hair, and dysplastic nails without cyst formation. METHODS: We identified 13 patients, including two pairs of siblings, with extensive cerebral calcifications and leukoencephalopathy. We reviewed clinical, ophthalmologic, radiologic and neuropathologic data of seven deceased patients and studied five patients prospectively. RESULTS: Eleven patients were small for gestational age; the other symptoms emerged from infancy to adolescence. All patients had neurologic symptoms including seizures, spasticity, dystonia, ataxia, and cognitive decline. Progressive intracerebral calcifications involved deep gray nuclei, brainstem, cerebral and cerebellar white matter, and dentate nuclei and were accompanied by diffuse white matter signal changes and, in five patients, cerebral cysts. Eleven patients had retinal telangiectasias or angiomas. Additional features were skeletal and hematologic abnormalities, intestinal bleeding, and poor growth. Neuropathologic examination showed extensive calcinosis and abnormal small vessels with thickened, hyalinized wall and reduced lumen. CONCLUSIONS: Our data suggest that Coats plus syndrome and leukoencephalopathy with calcifications and cysts belong to the same spectrum. The primary abnormality seems to be an obliterative cerebral angiopathy involving small vessels, leading to dystrophic calcifications via slow necrosis and finally to formation of cysts and secondary white matter abnormalities.
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
- Lönnqvist, Håkan, et al.
(författare)
-
Generation of VLF saucer emissions observed by the Viking satellite
- 1993
-
Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 98, s. 13565-13574
-
Tidskriftsartikel (refereegranskat)abstract
- Simultaneous observations by the Viking satellite of electric and magnetic fields as well as charged particles have been used to investigate V-shaped wave phenomena. The intensity of these VLF and ELF emissions is V-shaped when shown in a frequency versus time plot. Simultaneous observations of V-shaped so-called VLF saucer emissions, particles and field-aligned currents strongly suggest, for the first time, that upgoing electrons with energies less than a few hundred electron volts can generate these waves. Broadband waves observed inside the saucer generation region, form frequencies much less than the ion cyclotron frequency up to the plasma frequency, may also be generated by these electrons. Viking observations of VLF saucers at altitudes between 4000 km and 13,500 km show that these emissions occur at higher altitudes tha discussed in previous reports. The generation regions seem to be more extended at these higher altitudes than what has been reported at lower altitudes by other observations.
|
|
| 7. |
- Lönnqvist, PA, et al.
(författare)
-
Effects of pronounced haemodilution on the plasma protein binding of lidocaine
- 1995
-
Ingår i: Perfusion. - : SAGE Publications. - 0267-6591 .- 1477-111X. ; 10:1, s. 17-20
-
Tidskriftsartikel (refereegranskat)abstract
- The effects of pronounced haemodilution on the protein binding of lidocaine was investigated in vitro in plasma from five healthy adult volunteers. The plasma was diluted with a phosphate buffer to reach a plasma protein concentration normally seen during paediatric cardiopulmonary bypass (CPB) and protein binding was determined at a low (1.5 μg/ml) and a moderate (4 μg/ml) total plasma concentration of lidocaine. The effects of different haematocrits on plasma protein binding was also determined over the haematocrit range 20-60%. The binding of lidocaine was found to be inversely related to the degree of dilution, i.e. the free fraction increased significantly with increasing dilution (p < 0.0001). Furthermore, the binding was dependent on the total plasma concentration of lidocaine, since a significantly higher percentage of free drug was found at the higher total lidocaine level (4 μg/ml) compared with the lower level (1.5 μg/ml) (p < 0.05). No significant difference in the free fraction of lidocaine could be found over the studied haematocrit range. The results of the present study indicate that plasma protein levels commonly associated with CPB in neonates and infants are associated with a significant increase in the free, unbound and pharmacologically active fraction of lidocaine compared with normal conditions. The use of commonly recommended dosages of lidocaine might result in toxic-free concentration in this setting.
|
|
| 8. |
- Remes, Tiina Maria, et al.
(författare)
-
Radiation-induced accelerated aging of the brain vasculature in young adult survivors of childhood brain tumors
- 2020
-
Ingår i: Neuro-Oncology Practice. - : Oxford University Press (OUP). - 2054-2577 .- 2054-2585. ; 7:4, s. 415-427
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundCranial radiotherapy may damage the cerebral vasculature. The aim of this study was to understand the prevalence and risk factors of cerebrovascular disease (CVD) and white matter hyperintensities (WMHs) in childhood brain tumors (CBT) survivors treated with radiotherapy.MethodsSeventy CBT survivors who received radiotherapy were enrolled in a cross-sectional study at a median 20 years after radiotherapy cessation. The prevalence of and risk factors for CVD were investigated using MRI, MRA, and laboratory testing. Tumors, their treatment, and stroke-related data were retrieved from patients’ files.ResultsForty-four individuals (63%) had CVD at a median age of 27 years (range, 16-43 years). The prevalence rates at 20 years for CVD, small-vessel disease, and large-vessel disease were 52%, 38%, and 16%, respectively. Ischemic infarcts were diagnosed in 6 survivors, and cerebral hemorrhage in 2. Lacunar infarcts were present in 7, periventricular or deep WMHs in 34 (49%), and mineralizing microangiopathy in 21 (30%) survivors. Multiple pathologies were detected in 44% of the participants, and most lesions were located in a high-dose radiation area. Higher blood pressure was associated with CVD and a presence of WMHs. Higher cholesterol levels increased the risk of ischemic infarcts and WMHs, and lower levels of high-density lipoprotein and higher waist circumference increased the risk of lacunar infarcts.ConclusionsTreating CBTs with radiotherapy increases the risk of early CVD and WMHs in young adult survivors. These results suggest an urgent need for investigating CVD prevention in CBT patients.
|
|
| 9. |
- Roberts, Daniel N., et al.
(författare)
-
Perioperative water and electrolyte balance and water homeostasis regulation in children with acute surgery
- 2023
-
Ingår i: Pediatric Research. - : Springer Science and Business Media LLC. - 0031-3998 .- 1530-0447. ; 94:4, s. 1373-1379
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Hospital-acquired hyponatremia remains a feared event in patients receiving hypotonic fluid therapy. Our objectives were to assess post-operative plasma-sodium concentration and to provide a physiological explanation for plasma-sodium levels over time in children with acute appendicitis. Methods: Thirteen normonatremic (plasma-sodium ≥135 mmol/L) children (8 males), median age 12.3 (IQR 11.5–13.5) years participated in this prospective observational study (ACTRN12621000587808). Urine was collected and analyzed. Blood tests, including renin, aldosterone, arginine-vasopressin, and circulating nitric oxide substrates were determined on admission, at induction of anesthesia, and at the end of surgery. Results: On admission, participants were assumed to be mildly dehydrated and were prescribed 50 mL/kg of Ringer’s acetate intravenously followed by half-isotonic saline as maintenance fluid therapy. Blood tests, urinary indices, plasma levels of aldosterone, arginine-vasopressin, and net water-electrolyte balance indicated that participants were dehydrated on admission. Although nearly 50% of participants still had arginine-vasopressin levels that would have been expected to produce maximum antidiuresis at the end of surgery, electrolyte-free water clearance indicated that almost all participants were able to excrete net free water. No participant became hyponatremic. Conclusions: The use of moderately hypotonic fluid therapy after correction of extracellular fluid deficit is not necessarily associated with post-operative hyponatremia. Impact: Our observations show that in acutely ill normonatremic children not only the composition but also the amount of volume infused influence on the risk of hyponatremia.Our observations also suggest that perioperative administration of hypotonic fluid therapy is followed by a tendency towards hyponatremia if extracellular fluid depletion is left untreated.After correcting extracellular deficit almost all patients were able to excrete net free water. This occurred despite nearly 50% of the cohort having high circulating plasma levels of arginine-vasopressin at the end of surgery, suggesting a phenomenon of renal escape from arginine-vasopressin-induced antidiuresis.
|
|
