| 1. |
- Aksentijevich, Ivona, et al.
(författare)
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An Autoinflammatory Disease with Deficiency of the Interleukin-1-Receptor Antagonist
- 2009
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 360:23, s. 2426-2437
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from the Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1 beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
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| 2. |
- Bjursten, Malin, 1976, et al.
(författare)
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Long-term treatment with anti-alpha 4 integrin antibodies aggravates colitis in G alpha i2-deficient mice.
- 2005
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Ingår i: European journal of immunology. - : Wiley. - 0014-2980 .- 1521-4141. ; 35:8, s. 2274-83
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Tidskriftsartikel (refereegranskat)abstract
- Targeted deletion of the heterotrimeric G protein, Galphai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha4 integrins. In previous studies, short-term administration of anti-alpha4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha4 integrin antibodies on colitis in Galphai2(-/- )mice. Long-term blockade of alpha4 integrin significantly increased the severity of colitis in Galphai2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1beta, TNF-alpha and IFN-gamma. Blockade of alpha4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with alpha4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.
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| 3. |
- Breeman, Arno, et al.
(författare)
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Treatment decisions in stable coronary artery disease : insights from the Euro Heart Survey on Coronary Revascularization
- 2006
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Ingår i: Journal of Thoracic and Cardiovascular Surgery. - : Elsevier BV. - 0022-5223 .- 1097-685X. ; 132:5, s. 1001-1009
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Tidskriftsartikel (refereegranskat)abstract
- Objective: We sought to assess determinants of clinical decision making in patients with stable coronary artery disease. Methods: The 2936 patients with stable angina pectoris who enrolled in the Euro Heart Survey on Coronary Revascularization were the subject of this analysis. After the diagnosis has been confirmed, physicians decided on treatment: medical management or revascularization therapy by means of percutaneous coronary intervention or coronary bypass surgery. We applied logistic regression analyses to evaluate the relation between baseline characteristics and treatment decision: medical treatment versus percutaneous coronary intervention, medical treatment versus coronary bypass surgery, and percutaneous coronary intervention versus coronary bypass surgery. Results: The median age was 64 years, 77% were men, and 20% had diabetes. Medical therapy was intended in 690 (24%) patients, percutaneous coronary intervention in 1503 (51%) patients, and coronary bypass surgery in the remaining 743 (25%) patients, respectively. Revascularization was generally preferred in patients with more severe anginal complaints, an intermediate-to-large area of myocardium at risk, and preserved left ventricular function who had not undergone prior coronary revascularization, provided lesions were suitable for treatment. Coronary bypass surgery was preferred over percutaneous coronary intervention in multivessel or left main disease, as well as in those with concomitant valvular heart disease, provided a sufficient number of lesions were suitable for coronary bypass surgery. In those with previous coronary bypass surgeries, more often percutaneous coronary intervention was preferred than redo coronary bypass surgery. Diabetes was not associated with more frequent preference for coronary bypass surgery. Conclusions: In the hospitals that participated in the Euro Heart Survey on Coronary Revascularization, treatment decisions in stable coronary artery disease were largely in agreement with professional guidelines and determined by multiple factors. Most important deviations between guideline recommendations and clinical practice were seen in patients with extensive coronary disease, impaired left ventricular function, and diabetes.
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| 4. |
- Elgbratt, Kristina, 1969, et al.
(författare)
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Aberrant T-cell ontogeny and defective thymocyte and colonic T-cell chemotactic migration in colitis-prone Galphai2-deficient mice
- 2007
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Ingår i: Immunology. - : Wiley. - 0019-2805 .- 1365-2567. ; 122:2, s. 199-209
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Tidskriftsartikel (refereegranskat)abstract
- Galphai2-deficient mice, which spontaneously develop colitis, have previously been reported to have an increased frequency of mature, single positive thymocytes compared to wild-type mice. In this study we further characterized the intrathymic changes in these mice before and during overt colitis. Even before the onset of colitis, Galphai2(-/-) thymi weighed less and contained fewer thymocytes, and this was exacerbated with colitis development. Whereas precolitic Galphai2(-/-) mice had unchanged thymocyte density compared to Galphai2(+/-) mice of the same age, this was significantly decreased in mice with colitis. Thymic atrophy in Galphai2(-/-) mice involved mainly the cortex. Using a five-stage phenotypic characterization of thymocyte maturation based on expression of CD4, CD8, TCRalphabeta, CD69 and CD62L, we found that both precolitic and colitic Galphai2(-/-) mice had significantly increased frequencies of mature single-positive CD4(+) and CD8(+) medullary thymocytes, and significantly reduced frequencies and total numbers of immature CD4(+) CD8(+) double-positive thymocytes compared to Galphai2(+/-) mice. Furthermore, cortical and transitional precolitic Galphai2(-/-) thymocytes showed significantly reduced chemotactic migration towards CXCL12, and a trend towards reduced migration to CCL25, compared to wild-type thymocytes, a feature even more pronounced in colitic mice. This impaired chemotactic migration of Galphai2(-/-) thymocytes could not be reversed by increased chemokine concentrations. Galphai2(-/-) thymocytes also showed reduced expression of the CCL25 receptor CCR9, but not CXCR4, the receptor, for CXCL12. Finally, wild-type colonic lamina propria lymphocytes migrated in response to CXCL12, but not CCL25 and, as with thymocytes, the chemokine responsiveness was significantly reduced in Galphai2(-/-) mucosal lymphocytes.
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| 5. |
- Enthoven, Paul, 1955-, et al.
(författare)
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Predictive factors for 1-year and 5-year outcome for disability in a working population of patients with low back pain treated in primary care
- 2006
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Ingår i: Pain. - : Ovid Technologies (Wolters Kluwer Health). - 0304-3959 .- 1872-6623. ; 122:1-2, s. 137-144
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Tidskriftsartikel (refereegranskat)abstract
- Many patients seeking primary care for low back pain continue to report disability several years after their initial visit. The aims of this study were to assess the independent predictive value of a number of potential predictive factors for disability at the 1-year and 5-year follow-ups, and to examine whether prediction models were improved by replacing baseline health-state-related variables with corresponding variables after treatment. A further aim was to describe possible differences between those on sick leave, early retirement or disability pension, and those who were not. Baseline factors were age, gender, self-reported physical-activity-related and work-related factors, expectations of treatment, similar problems previously, duration of episode, more than one localization, sick leave, pain frequency, disability, and well-being. The study sample comprised 148 participants in a previous randomized trial who were eligible for sick-leave benefits. Multiple logistic regression was used to identify predictive factors. At the 5-year follow-up, 37% (n = 19/52) of the patients with disability were on sick leave or were receiving early retirement or disability pension. For those without disability the corresponding figure was 9% (n = 8/92). Being a woman, duration of the current episode, similar problems during the previous 5 years, exercise level before the current episode, pain frequency at baseline, and disability after treatment emerged as predictive factors for disability at the 5-year follow-up. Replacing baseline health-state-related measures with corresponding measures after the treatment period, and adding physical-activity-related and possibly work-related factors might improve the likelihood of predicting future disability.
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| 6. |
- Horvath, Rita, et al.
(författare)
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Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy.
- 2009
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Ingår i: Brain : a journal of neurology. - : Oxford University Press (OUP). - 1460-2156. ; 132:Pt 11, s. 3165-74
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Tidskriftsartikel (refereegranskat)abstract
- Childhood-onset mitochondrial encephalomyopathies are usually severe, relentlessly progressive conditions that have a fatal outcome. However, a puzzling infantile disorder, long known as 'benign cytochrome c oxidase deficiency myopathy' is an exception because it shows spontaneous recovery if infants survive the first months of life. Current investigations cannot distinguish those with a good prognosis from those with terminal disease, making it very difficult to decide when to continue intensive supportive care. Here we define the principal molecular basis of the disorder by identifying a maternally inherited, homoplasmic m.14674T>C mt-tRNA(Glu) mutation in 17 patients from 12 families. Our results provide functional evidence for the pathogenicity of the mutation and show that tissue-specific mechanisms downstream of tRNA(Glu) may explain the spontaneous recovery. This study provides the rationale for a simple genetic test to identify infants with mitochondrial myopathy and good prognosis.
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| 7. |
- Kollberg, Gittan, 1963, et al.
(författare)
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POLG1 mutations associated with progressive encephalopathy in childhood.
- 2006
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Ingår i: Journal of neuropathology and experimental neurology. - : Oxford University Press (OUP). - 0022-3069 .- 1554-6578. ; 65:8, s. 758-68
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Tidskriftsartikel (refereegranskat)abstract
- We have identified compound heterozygous missense mutations in POLG1, encoding the mitochondrial DNA polymerase gamma (Pol gamma), in 7 children with progressive encephalopathy from 5 unrelated families. The clinical features in 6 of the children included psychomotor regression, refractory seizures, stroke-like episodes, hepatopathy, and ataxia compatible with Alpers-Huttenlocher syndrome. Three families harbored a previously reported A467T substitution, which was found in compound with the earlier described G848S or the W748S substitution or a novel R574W substitution. Two families harbored the W748S change in compound with either of 2 novel mutations predicted to give an R232H or M1163R substitution. Muscle morphology showed mitochondrial myopathy with cytochrome c oxidase (COX)-deficient fibers in 4 patients. mtDNA analyses in muscle tissue revealed mtDNA depletion in 3 of the children and mtDNA deletions in the 2 sibling pairs. Neuropathologic investigation in 3 children revealed widespread cortical degeneration with gliosis and subcortical neuronal loss, especially in the thalamus, whereas there were only subcortical neurodegenerative findings in another child. The results support the concept that deletions as well as depletion of mtDNA are involved in the pathogenesis of Alpers-Huttenlocher syndrome and add 3 new POLG1 mutations associated with an early-onset neurodegenerative disease.
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| 8. |
- Mastroiacovo, Pierpaolo, et al.
(författare)
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Gastroschisis and associated defects : an international study
- 2007
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Ingår i: American Journal of Medical Genetics, Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 143A:7, s. 660-671
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Tidskriftsartikel (refereegranskat)abstract
- Our objective was to evaluate the frequency and type of malformations associated with gastroschisis in a large pool of international data, to identify malformation patterns, and to evaluate the role of maternal age in non-isolated cases. Case-by-case information from 24 registries, all members of the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), were evaluated. After the exclusion of other abdominal wall defects cases were classified as: (a) isolated; (b) recognizable syndrome, chromosomal or not; (c) multiple congenital anomalies (MCA). Our results showed that out of 3,322 total cases 469 non-isolated cases were registered (14.1%): 41 chromosomal syndromes, 24 other syndromes, and 404 MCA. Among MCA four groups of anomalies were most frequent: CNS (4.5%), cardio-vascular (2.5%), limb (2.2%), and kidney anomalies (1.9%). No similar patterns emerged except two patterns resembling limb-body wall complex and OEIS. In both of them the gastroschisis could be however misclassified. Chromosomal trisomies and possibly non-syndromic MCA are associated with an older maternal age more than isolated cases. On consideration of our data and the most valid studies published in the literature, the best estimate of the proportion of gastroschisis associated with major unrelated defects is about 10%, with a few cases associated to recognizable syndromes. Recognized syndromes with gastroschisis seem to be so exceptional that the well documented and validated cases are worth being published as interesting case report. An appropriate case definition in etiological studies should include only isolated gastroschisis after an appropriate definition of isolated and non-isolated cases and a thorough case-by-case review.
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| 9. |
- Olsson, Catharina, 1968, et al.
(författare)
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Identification of genes for the ghrelin and motilin receptors and a novel related gene in fish, and stimulation of intestinal motility in zebrafish (Danio rerio) by ghrelin and motilin.
- 2008
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Ingår i: General and comparative endocrinology. - : Elsevier BV. - 0016-6480. ; 155:1, s. 217-26
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Tidskriftsartikel (refereegranskat)abstract
- In mammals ghrelin has a diverse range of effects including stimulation of gut motility but although present in teleost fish its effects on motility have not been investigated. The present study used bioinformatics to search for fish paralogues of the ghrelin receptor and the closely related motilin receptor, and investigated the effects of ghrelin and motilin on gut motility in zebrafish, Danio rerio. Fish paralogues of the human ghrelin and motilin receptor genes were identified, including those from the zebrafish. In addition, a third gene was identified in three species of pufferfish (the only fish genome completely sequenced), which is distinct from the ghrelin and motilin receptors but more closely aligned to these receptors relative to other G-protein coupled receptors. Immunohistochemistry demonstrated strong ghrelin receptor-like reactivity in the muscle of the zebrafish intestine. In isolated intestinal bulb and mid/distal intestine preparations, ghrelin, motilin, and the motilin receptor agonist erythromycin all evoked contraction; these responses ranged between 9% and 51% of the contractions evoked by carbachol (10(-6) M). There were some variations in the concentrations found to be active in the different tissues, e.g., whereas motilin and rat ghrelin caused contraction of the intestinal bulb circular muscle at concentrations as low as 10(-8) M, human ghrelin (10(-8) to 10(-6) M) was without activity. Neither ghrelin (10(-7) M) nor erythromycin (10(-5) M) affected the contractions evoked by electrical field stimulation. The results suggest that both ghrelin and motilin can regulate intestinal motility in zebrafish and most likely other teleosts, and are discussed in relation to the evolution of these regulatory peptides.
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| 10. |
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