| 123281. |
- Rauthan, Manish, et al.
(författare)
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The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway.
- 2013
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 110:15, s. 5981-6
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Tidskriftsartikel (refereegranskat)abstract
- Statins are cholesterol-lowering drugs that inhibit 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the synthesis of cholesterol via the mevalonate pathway. This pathway also produces coenzyme Q (a component of the respiratory chain), dolichols (important for protein glycosylation), and isoprenoids (lipid moieties responsible for the membrane association of small GTPases). We previously showed that the nematode Caenorhabditis elegans is useful to study the noncholesterol effects of statins because its mevalonate pathway lacks the sterol synthesis branch but retains all other branches. Here, from a screen of 150,000 mutagenized genomes, we isolated four C. elegans mutants resistant to statins by virtue of gain-of-function mutations within the first six amino acids of the protein ATFS-1, the key regulator of the mitochondrial unfolded protein response that includes activation of the chaperones HSP-6 and HSP-60. The atfs-1 gain-of-function mutants are also resistant to ibandronate, an inhibitor of an enzyme downstream of HMG-CoA reductase, and to gliotoxin, an inhibitor acting on a subbranch of the pathway important for protein prenylation, and showed improved mitochondrial function and protein prenylation in the presence of statins. Additionally, preinduction of the mitochondrial unfolded protein response in wild-type worms using ethidium bromide or paraquat triggered statin resistance, and similar observations were made in Schizosaccharomyces pombe and in a mammalian cell line. We conclude that statin resistance through maintenance of mitochondrial homeostasis is conserved across species, and that the cell-lethal effects of statins are caused primarily through impaired protein prenylation that results in mitochondria dysfunction.
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| 123282. |
- Rautio, Elina, et al.
(författare)
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Implantable cardioverter defibrillator and cardiac resynchronization treatment in people with type 2 diabetes: a comparison with age- and sex matched controls from the general population
- 2024
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Ingår i: CARDIOVASCULAR DIABETOLOGY. - 1475-2840. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIncreased risk of severe tachyarrhythmias is reported in patients with type 2 diabetes mellitus (T2DM). The aim of this study was to explore if treatment with cardiac implantable electronic device (CIED) such as implantable cardioverter defibrillator (ICD), cardiac resynchronization therapy- pacemaker and -defibrillator (CRT-P/CRT-D) differed in patients with vs. without T2DM. A secondary aim was to identify patient characteristics indicating an increased CIED treatment.Method416 162 adult patients with T2DM from the Swedish National Diabetes Registry and 2 081 087 controls from the Swedish population, matched for age, sex and living area, were included between 1/1/1998 and 31/12/2012 and followed until 31/12/2013. They were compared regarding prevalence of ventricular tachycardia (VT) at baseline and the risk of receiving a CIED during follow-up. Multivariable Cox regression analysis was performed to estimate the risk of CIED-treatment and factors identifying patients with such risk.ResultsVentricular fibrillation (VF) (0.1% vs 0.0004%) and (VT) (0.2% vs. 0.1%) were more frequent among patients with T2DM compared to controls. CIED-treatment was significantly increased in patients with T2DM both in unadjusted and adjusted analyses. HR and 95% CI, after adjustment for sex, age, marital status, income, education, country of birth, coronary artery disease and congestive heart failure, were 1.32 [1.21-1.45] for ICD, 1.74 [1.55-1.95] for CRT-P and 1.69 [1.43-1.99] for CRT-D. Blood-pressure and lipid lowering therapies were independent risk factors associated to receiving CIED, while female sex was protective.ConclusionsAlthough the proportion of VT/VF was low, patients with T2DM had a higher prevalence of these conditions and increased risk for treatment with CIED compared to controls. This underlines the importance of recognizing that T2DM patients have an increased need of CIED.
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| 123283. |
- Rautio, E., et al.
(författare)
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Patients With Type 2 Diabetes Have an Increased Demand for Pacemaker Treatment: A Comparison With Age- and Sex-Matched Control Subjects From the General Population
- 2020
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Ingår i: Diabetes care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 43:11, s. 2853-2858
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE Patients with type 2 diabetes have an increased risk for cardiovascular disease, including arrhythmias. The prevalence of bradyarrhythmia and the subsequent need for treatment with pacemakers (PMs) is less well explored in a contemporary patient population. The current study explores1) whether patients with type 2 diabetes have an increased demand for PM implantation compared with an age- and sex-matched control population without diabetes and2) patient characteristics associated with an increased demand for receiving a PM. RESEARCH DESIGN AND METHODS In this population-matched registry study, a total of 416,247 patients with type 2 diabetes from the Swedish National Diabetes Registry and 2,081,235 age- and sex-matched control subjects selected from the general population were included between 1 January 1998 and 31 December 2012 and followed until 31 December 2013. Mean follow-up time was 7 years. Cox proportional hazards regression analyses were performed to estimate the demand of PM treatment and the factors identifying patients with such demand. RESULTS Type 2 diabetes was associated with an increased need of PM treatment (hazard ratio 1.65 [95% CI 1.60-1.69];P< 0.0001), which remained (1.56 [1.51-1.60];P< 0.0001) after adjustments for age, sex, educational level, marital status, country of birth, and coronary heart disease. Risk factors for receiving a PM included increasing age, HbA(1c), BMI, diabetes duration, and lipid- and blood pressure-lowering medication. CONCLUSIONS The need for PM treatment is higher in patients with type 2 diabetes than in matched population-based control subjects. Age, diabetes duration, and HbA(1c)seem to be risk factors for PM treatment.
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| 123284. |
- Rautio, Jorma, et al.
(författare)
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Scandcleft randomised trials of primary surgery for unilateral cleft lip and palate: 2. Surgical results
- 2017
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Ingår i: Journal of Plastic Surgery and Hand Surgery. - : TAYLOR & FRANCIS LTD. - 2000-656X .- 2000-6764. ; 51:1, s. 14-20
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Tidskriftsartikel (refereegranskat)abstract
- Background: Longstanding uncertainty surrounds the selection of surgical protocols for unilateral cleft lip and palate, and randomised trials have only rarely been performed. The Scandcleft Project consists of three trials commenced in 1997 involving ten centres in Denmark, Finland, Norway, Sweden, and the UK. Three groups of centres tested a newly-defined common technique for palatal repair (Arm A) against their local protocols (Arms B, C, D). Arm A was familiar to most of the surgeons in Trial 1, but not to the surgeons in the other Trials. Aim: To evaluate surgical events and complications of the 448 (293 boys, 155 girls) patients with complete unilateral cleft lip and palate (UCLP) enrolled in the three trials. Method: The three trials were carried out in parallel in adherence with a fully developed, ethically approved protocol. Operative time, bleeding, complications, and major dehiscence during and after both primary surgeries were recorded by the surgeon. Rates of fistula and surgery for velopharyngeal incompetence (VPI) were assessed until the youngest patient of the study had reached the age of 9 years. Pearson Chi-square statistical analysis was used to compare the outcomes. Results: No significant differences in bleeding, infection, anaesthetic complications or length of hospital stay between the different arms were found for Trial 1. However, in Trials 2 and 3 there were more airway problems in Arm A than with the traditional local protocols (Arms C or D). In Trial 3 fistula and VPI surgery rates were also higher in Arm A. Conclusions: The results do not provide statistical evidence that any technique is better than others, but indicate that surgery was more problematic for surgeons who were still gaining experience with an unfamiliar surgical protocol.
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| 123285. |
- Rauvala, M, et al.
(författare)
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Matrix metalloproteinases-2 and -9 in cervical cancer: different roles in tumor progression.
- 2006
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Ingår i: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. - : BMJ. - 1048-891X .- 1525-1438. ; 16:3, s. 1297-302
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of uterine cervical cancer has increased slightly in Western countries, with an increase in relatively young women. Overexpression of matrix metalloproteinases (MMPs)-2 and -9 has turned out as a prognostic factor in many cancers. We compared the expression of the proteins MMP-2 and MMP-9 in cervical primary tumors with clinical outcome and risk factors of cervical cancer. One hundred sixty-one patients with cervical cancer treated in Umeå University Hospital or Sahlgrenska University Hospital, Sweden, between 1991 and 1995 were included in the study. Paraffin-embedded tissue samples obtained prior to treatment were examined immunohistochemically by specific antibodies for MMP-2 and MMP-9. Forty-two percent of the tumors were intensively positive for MMP-2 and 31% for MMP-9. Nineteen percent of the samples were intensively positive for both proteinases and 47% negative or weak for both. Overexpression of MMP-2 seemed to predict unfavorable survival under Kaplan-Meier analysis and in the multivariate analysis. Early sexual activity and low parity seemed to correlate to overexpression of MMP-2. MMP-9 was not associated with survival or sexual behavior. Intensive MMP-9 was noted in grade 1 tumors. We conclude that MMP-2 and MMP-9 have different roles in uterine cervical cancer. MMP-2 could be associated with aggressive behavior, but MMP-9 expression diminishes in high-grade tumors.
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| 123286. |
- Rauwolf, K. K., et al.
(författare)
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The Influence of Smoking and Smokeless Tobacco on the Progression, Severity and Treatment Outcome in Alcohol-Dependent Individuals
- 2017
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Ingår i: Alcohol and Alcoholism. - : Oxford University Press (OUP). - 0735-0414 .- 1464-3502. ; 52:4, s. 477-482
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Tidskriftsartikel (refereegranskat)abstract
- The influence of tobacco use in alcohol-dependent individuals is not well understood, especially the role of snuffing, which is common in Northern Europe. The aim was therefore to investigate the influence of smoking and snuffing on the progression, severity and treatment outcome in alcohol-dependent individuals. The hypotheses were that concomitant tobacco use (i.e. smoking or snuffing) would enhance the progression and severity of alcohol dependence and be less beneficial for treatment outcome, relative to tobacco non-users. Alcohol-dependent individuals (n = 347) were recruited from three treatment units specialized in alcohol use disorders. Participants were interviewed about their current and past alcohol and tobacco use at treatment entry and at a follow-up interview 2.5 years thereafter. The tobacco users (smokers and snuffers) had an earlier alcohol debut compared to the tobacco never-users. Snuffers reported regular alcohol consumption and inebriation at an earlier age in contrast to smokers and tobacco never-users. There were no difference between the groups regarding treatment outcome. This study highlights the importance of studying not only the influence of smoking but also of snuffing on the progression, severity and treatment outcome in individuals with alcohol dependence.
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| 123287. |
- Ravaioli, A, et al.
(författare)
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p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.
- 2008
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Ingår i: Annals of oncology. - : Elsevier BV. - 1569-8041 .- 0923-7534. ; 19:4, s. 660-668
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.
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| 123288. |
- Ravara, A., et al.
(författare)
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Four new species and further records of Dorvilleidae (Annelida, Polychaeta) from deep-sea organic substrata, NE Atlantic
- 2021
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Ingår i: European Journal of Taxonomy. - : Museum National D'Histoire Naturelle. - 2118-9773. ; 736, s. 44-81
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Tidskriftsartikel (refereegranskat)abstract
- Eight species of Ophryotrocha and one of Parougia were identified from organic substrata (wood and alfalfa) sampled at the Gulf of Cadiz and Western Iberian Margin (NE Atlantic). Morphological examination and molecular phylogenetic analyses, based on the nuclear gene H3 and the mitochondrial gene 16S, indicate the presence of four species new to science: Ophryotrocha chemecoli sp. nov., O. nunezi sp. nov., O. geoffreadi sp. nov. and Parougia ougi sp. nov. The geographic and/or bathymetric distribution is extended for four previously known species: O. cantabrica, O. hartmanni, O. mammillata and O. scutellus. Another species may also have its distribution extended, pending the molecular confirmation of its identity: O. lipscombae. Full descriptions and figures are given for all the new species and, when justified, also for the previously known ones. The original description of O. scutellus is amended. New DNA sequences are given for eight of the nine species studied here. The ecology and geographic distribution of the reported species is discussed.
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| 123289. |
- Ravara, A., et al.
(författare)
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Nephtyidae (Annelida, Polychaeta) from southern Europe
- 2010
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Ingår i: Zootaxa. - 1175-5326. ; :2682, s. 1-68
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Tidskriftsartikel (refereegranskat)abstract
- Eighteen nephtyid species belonging to four different genera are known from southern Europe. In this study we revise the nephtyids from this area and provide descriptions of all the known species. Geographical and bathymetrical distributions are given, together with ecological notes. Inermonephtys foretmontardoi, new species, is described, Micronephthys maryae is newly synonymized with M. stammeri and Aglaophamus rubellus with A. agilis. New diagnoses are provided for southern European genera and a key to all species from the region is included.
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| 123290. |
- Ravara, A., et al.
(författare)
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Phylogenetic relationships within Nephtyidae (Polychaeta, Annelida)
- 2010
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Ingår i: Zoologica Scripta. - : Wiley. - 0300-3256 .- 1463-6409. ; 39:4, s. 394-405
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Tidskriftsartikel (refereegranskat)abstract
- We present the first phylogeny of nephtyids, a common, soft-bottom living polychaete family comprising five genera and over 100 species. Characters used to distinguish nephtyid genera are a matter of controversy and considerable confusion remains as to the generic delineations. The phylogeny is estimated with molecular data from the mitochondrial genes cytochrome oxidase I and 16S rDNA, the nuclear genes 18S rDNA and 28S rDNA and morphological data. The results reveal two well-supported major clades, corresponding in part to the two main genera of the family, Aglaophamus and Nephtys. The species Nephtys pulchra and Nephtys australiensis are transferred to Aglaophamus, and new diagnoses for the genera are provided. Dentinephtys is synonymized with Nephtys, and Nephtys cornuta is sister to the remaining nephtyids and is referred to the new genus Bipalponephtys, together with Nephtys danida and Micronephthys neotena. Micronephthys is sister to Nephtys and Inermonephtys is of uncertain position.
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