| 1. |
- Brorsson, Anna Lena, 1964-, et al.
(författare)
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Does treatment with an insulin pump improve glycaemic control in children and adolescents with type 1 diabetes? : A retrospective case-control study
- 2015
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 16:7, s. 546-553
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate long-term effects on glycaemic control, ketoacidosis, serious hypoglycaemic events, insulin requirements, and body mass index standard deviation scores (BMI-SDS) in children and adolescents with type 1 diabetes starting on continuous subcutaneous insulin infusion (CSII) compared with children and adolescents treated with multiple daily injections (MDI).METHODS: This retrospective case-control study compares 216 patients starting CSII with a control group on MDI (n = 215), matched for glycated hemoglobin (HbA1c), sex, and age during a 2-yr period. Variables collected were gender, age, HbA1c, insulin requirement, BMI, BMI-SDS, ketoacidosis, and serious hypoglycaemic events.RESULTS: In the CSII group there was an improvement in HbA1c after 6 and 12 months compared with the MDI group. For boys and girls separately the same effect was detected after 6 months, but only for boys after 12 months. The incidence of ketoacidosis was higher in the CSII group compared with the MDI group (2.8 vs. 0.5/100 person-yr). The incidences of severe hypoglycaemic episodes per 100 person-yr were three in the CSII group and six in the MDI group (p < 0.05). After 6, 12, and 24 months, the insulin requirement was higher in the MDI group.CONCLUSIONS: This study shows that treatment with CSII resulted in an improvement in HbA1c levels up to 1 yr and decreased the number of severe hypoglycaemic events, but the frequency of ketoacidosis increased. The major challenge is to identify methods to maintain the HbA1c improvement, especially among older children and teenagers, and reduce the frequency of ketoacidosis.
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| 2. |
- Broström, Eva, et al.
(författare)
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Trunk and center of mass movements during gait in children with juvenile idiopathic arthritis
- 2007
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Ingår i: Human Movement Science. - : Elsevier BV. - 0167-9457 .- 1872-7646. ; 26:2, s. 296-305
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Tidskriftsartikel (refereegranskat)abstract
- Motion of the body center of mass (CoM) can often indicate the overall effect of the strategy of forward progression used. In the present study, focus is placed on trunk movements in the sagittal, coronal, and transverse/rotation plane, as well as placement of the CoM, during gait in children with juvenile idiopathic arthritis (JIA). Seventeen children with JIA, all with polyarticular lower extremity involvement were examined before and approximately two weeks after treatment with intra-articular cortico-steroid injections. Movement was recorded with a 6-camera 3D motion analysis system in both the children with JIA and in 21 healthy controls. Trunk and center of mass movements were compared between JIA and controls, and effects of intra-articular cortico-steroid treatment were evaluated. Children with JIA were more posteriorly tilted in the trunk, contrary to the common clinical impression, and had their CoM placed more posterior and off-centred, which may have been a result of pain. With such knowledge, it might be possible to better understand the effects of their pain and involvement, and ultimately to plan a treatment strategy for improving their gait patterns.
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| 3. |
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| 4. |
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| 5. |
- Jonsdottir, Berglind, et al.
(författare)
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Thyroid and islet autoantibodies predict autoimmune thyroid disease already at Type 1 diabetes diagnosis
- 2017
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 102:4, s. 1277-1285
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Screening of autoimmune thyroid disease in children and young adults with Type 1 diabetes is important but vary greatly between clinics.OBJECTIVE: The aim was to determine the predictive value of thyroid autoantibodies, thyroid function, islet autoantibodies, and HLA- DQ at diagnosis of Type 1 diabetes for autoimmune thyroid disease during subsequent follow-up.SETTING: 43 Paediatric Endocrinology units Sweden. Design, patients and main outcome measures: At diagnosis of Type 1 diabetes, samples from 2433 children were analysed for autoantibodies against thyroid peroxidase (TPOAb), thyroglobulin (TGAb), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), and the three variants of the zinc transporter 8 (ZnT8W/R/QA) as well as HLA-DQA1-B1 genotypes and thyroid function. After 5.1-9.5 years disease duration, children treated with thyroxine were identified in the Swedish National Board of Health and Welfare Prescribed Drug Register.RESULTS: Thyroxine had been prescribed to 6% (147/2433; 66% girls). In patients below 5 years, female gender (HR=4.60, p=0.008) and GADA (HR=5.80, p=0.02) were significant predictors. In patients 5-10 years, TPOAb (HR=20.56, p<0.0001), TGAb (HR=3.40, p=0.006) and TSH outside the reference limit (HR=3.64, p<0.001) were predictors while in the 10-15 year olds, TPOAb (HR=17.00, p<0.001) and TSH outside the reference limit (HR=4.11, p<0.001) predicted future thyroxine prescription.CONCLUSION: In addition to TPOAb and TSH, positive GADA tested at the diagnosis of type 1 diabetes is important for the prediction of autoimmune thyroid disease in children below 5 years of age.
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| 6. |
- Laine, Antti-Pekka, et al.
(författare)
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Two insulin gene single nucleotide polymorphisms associated with type 1 diabetes risk in the Finnish and Swedish populations
- 2007
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Ingår i: Disease Markers. - : Hindawi Limited. - 0278-0240 .- 1875-8630. ; 23:3, s. 139-45
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Tidskriftsartikel (refereegranskat)abstract
- We have developed high-throughput tests for the detection of the insulin gene region SNPs -23HphI and -2221MspI. The potential of these markers to enhance the efficiency of type 1 diabetes risk screening was then evaluated by analyzing them in Finnish and Swedish populations. Blood spots on filter paper were analyzed using PCR followed by sequence-specific hybridization and time-resolved fluorometry reading. Distribution of the genotypes at both positions differed significantly among the affected children compared to the controls. The risk genotypes (CC, AA) were significantly more common in Finland than in Sweden, both among patients and controls. The VNTR genotype homozygous for the protective class III alleles showed a significantly stronger protective effect than the heterozygote (p=0.02). Analyzing both SNPs enabled the detection of VNTR class III subclasses IIIA and IIIB. The observed significance between effects of the protective genotypes was due to the strong protective effect of the IIIA/IIIA genotype. IIIA/IIIA was the only genotype with significant discrepancy between protective effects compared to the other class III genotypes. These observations suggest that heterogeneity between the protective IDDM2 lineages could exist, and analyzing both -23HphI and -2221MspI would thus potentially enhance the sensitivity and specificity of type 1 diabetes risk estimation.
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| 7. |
- Ludvigsson, Johnny, 1943-, et al.
(författare)
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Combined vitamin D, ibuprofen and glutamic acid decarboxylase-alum treatment in recent onset Type I diabetes: lessons from the DIABGAD randomized pilot trial.
- 2020
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Ingår i: Future science OA. - London, United Kingdom : Future Science Ltd. - 2056-5623. ; 6:7
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Tidskriftsartikel (refereegranskat)abstract
- Double-blind placebo-controlled intervention using glutamic acid decarboxylase (GAD)-alum, vitamin D and Ibuprofen in recent onset Type I diabetes (T1D).64 patients (T1D since <4months, age 10-17.99, fasting sC-peptide ≥0.12nmol/l, GADA-positive) were randomized intoDay(D) 1-90 400mg/day Ibuprofen, D1-450 vitamin D 2000IU/day, D15, 45 sc. 20μg GAD-alum; as A but placebo instead of Ibuprofen; as B but 40μg GAD-alum D15, 45; placebo.Treatment was safe and tolerable. No C-peptide preservation was observed. We observed a linear correlation of baseline C-peptide, HbA1c and insulin/per kilogram/24h with change in C-peptide AUC at 15months (r=-0.776, p<0.0001).Ibuprofen, vitamin D + GAD-alum did not preserve C-peptide. Treatment efficacy was influenced by baseline clinical and immunological factors and vitamin D concentration. Clinical Trial Registration: NCT01785108 (ClinicalTrials.gov).
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| 8. |
- Ludvigsson, Johnny, 1943-, et al.
(författare)
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GAD treatment and insulin secretion in recent-onset type 1 diabetes
- 2008
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Ingår i: New England Journal of Medicine. - Boston, Mass : Massachusetts medical society. - 0028-4793 .- 1533-4406. ; 359:18, s. 1909-1920
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Tidskriftsartikel (refereegranskat)abstract
- Background The 65-kD isoform of glutamic acid decarboxylase (GAD) is a major autoantigen in patients with type 1 diabetes mellitus. This trial assessed the ability of alum-formulated GAD (GAD-alum) to reverse recent-onset type 1 diabetes in patients 10 to 18 years of age. Methods We randomly assigned 70 patients with type 1 diabetes who had fasting C-peptide levels above 0.1 nmol per liter (0.3 ng per milliliter) and GAD autoantibodies, recruited within 18 months after receiving the diagnosis of diabetes, to receive subcutaneous injections of 20 μg of GAD-alum (35 patients) or placebo (alum alone, 35 patients) on study days 1 and 30. At day 1 and months 3, 9, 15, 21, and 30, patients underwent a mixed-meal tolerance test to stimulate residual insulin secretion (measured as the C-peptide level). The effect of GAD-alum on the immune system was also studied. Results Insulin secretion gradually decreased in both study groups. The study treatment had no significant effect on change in fasting C-peptide level after 15 months (the primary end point). Fasting C-peptide levels declined from baseline levels significantly less over 30 months in the GAD-alum group than in the placebo group (−0.21 vs. −0.27 nmol per liter [−0.62 vs. −0.81 ng per milliliter], P = 0.045), as did stimulated secretion measured as the area under the curve (−0.72 vs. −1.02 nmol per liter per 2 hours [−2.20 vs. −3.08 ng per milliliter per 2 hours], P = 0.04). No protective effect was seen in patients treated 6 months or more after receiving the diagnosis. Adverse events appeared to be mild and similar in frequency between the two groups. The GAD-alum treatment induced a GAD-specific immune response. Conclusions GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)
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| 9. |
- Nylander, Charlotte, 1979-, et al.
(författare)
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Self- and parent-reported executive problems in adolescents with type 1 diabetes are associated with poor metabolic control and low physical activity.
- 2018
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 19:1, s. 98-105
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Management of diabetes is demanding and requires efficient cognitive skills, especially in the domain of executive functioning. However, the impact of impaired executive functions on diabetes control has been studied to a limited extent. The aim of the study is to investigate the association between executive problems and diabetes control in adolescents with type 1 diabetes.MATERIALS AND METHODS: Two hundred and forty-one of 477 (51%) of 12- to 18-year-old adolescents, with a diabetes duration of >2 years in Stockholm, Uppsala, and Jönköping participated. Parents and adolescents completed questionnaires, including Behavioral Rating Inventory of Executive Function (BRIEF), Attention-Deficit/Hyperactivity Disorder (ADHD)-Rating Scale (ADHD-RS) and demographic background factors. Diabetes-related data were collected from the Swedish Childhood Diabetes Registry, SWEDIABKIDS. Self-rated and parent-rated executive problems were analyzed with regard to gender, glycosylated hemoglobin (HbA1c), frequency of outpatient visits, and physical activity, using chi-square tests or Fisher's test, where P-values <.05 were considered significant. Furthermore, adjusted logistic regressions were performed with executive problems as independent variable.RESULTS: Executive problems, according to BRIEF and/or ADHD-RS were for both genders associated with mean HbA1c >70 mmol/mol (patient rating P = .000, parent rating P = .017), a large number of outpatient visits (parent rating P = .015), and low physical activity (patient rating P = .000, parent rating P = .025). Self-rated executive problems were more prevalent in girls (P = .032), while parents reported these problems to a larger extent in boys (P = .028).CONCLUSION: Executive problems are related to poor metabolic control in adolescents with type 1 diabetes. Patients with executive problems need to be recognized by the diabetes team and the diabetes care should be organized to provide adequate support for these patients.
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| 10. |
- Salemyr, Jenny, et al.
(författare)
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Lower HbA1c after 1 year, in children with type 1 diabetes treated with insulin glargine vs. NPH insulin from diagnosis: a retrospective study
- 2011
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 12:5, s. 501-505
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Insulin glargine offers sustained insulin delivery for 24 h. Change to glargine treatment consistently results in lower fasting glucose and fewer hypoglycemic episodes in children with type 1 diabetes compared to continuation of NPH, although glargine has not been shown to improve HbA1c in randomized trials. Studies comparing glargine and NPH in multiple injection therapy in children treated from diagnosis of type 1 diabetes are lacking. Methods: HbA1c and insulin requirement were compared in a retrospective study of children (7-17 yr of age) with type 1 diabetes treated from diagnosis with basal insulin glargine (n = 49) or NPH (n = 49) in a multiple injection therapy (MIT) regimen with a rapid-acting insulin analogue. Patients were followed every third month for 1 yr. HbA1c, insulin dose, and weight data were retrieved. Results: HbA1c (mean +/- SD) was lower at 3-5 months (5.5 +/- 0.89 vs. 6.2 +/- 0.89%, p < 0.05) and 6-9 months (5.6 +/- 1.14 vs. 6.6 +/- 0.99%; p < 0.001) in glargine treated. After 12 months, HbA1c was significantly lower in glargine treated (6.3 +/- 1.56 vs. 7.1 +/- 1.28; p < 0.01). Reported total insulin doses were similar at nadir (0.5 U/kg BW x 24 h), but significantly lower at 12 months in glargine treated (0.64 +/- 0.23 vs. 0.86 +/- 0.3U/kg BW x 24 h; p < 0.001). Conclusions: HbA1c 1 yr from diagnosis was lower in children treated with glargine from start as compared with those on NPH. This observation should be viewed in the light of a significantly lower dose of total daily insulin in the glargine group.
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| 11. |
- Schollin Ask, Lina, et al.
(författare)
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Receiving early information and trusting Swedish child health centre nurses increased parents' willingness to vaccinate against rotavirus infections
- 2017
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 106:8, s. 1309-1316
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Tidskriftsartikel (refereegranskat)abstract
- Aim: Rotavirus vaccines are effective against severe infections, but have a modest impact on mortality in high-income countries. Parental knowledge and attitudes towards vaccines are crucial for high vaccination coverage. This study aimed to identify why parents refused to let their infant have the vaccination or were unsure. Methods: This cross-sectional study was based on 1,063 questionnaires completed by the parents of newborn children in 2014. Stepwise logistic regression was used to identify the main predictors. Results: Most (81%) parents intended to vaccinate their child against the rotavirus, while 19% were unwilling or uncertain. Parents with less education and children up to five weeks of age were more likely to be unwilling or uncertain about vaccinating their child. Factors associated with a refusal or uncertainty about vaccinating were not having enough information about the vaccine, no intention of accepting other vaccines, paying little heed to the child health nurses' recommendations, thinking that the rotavirus was not a serious illness and not believing that the vaccine provided protection against serious forms of gastroenteritis. Conclusion: Early information, extra information for parents with less education and close positive relationships between parents and child health nurses were important factors in high rotavirus vaccination rates.
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| 12. |
- Sjögren, Eva, et al.
(författare)
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Parental conceptions of the rotawirus vaccine during implementation in Stockholm: A phenomenographic study
- 2017
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Ingår i: Journal of Child Health Care. - : SAGE Publications. - 1367-4935 .- 1741-2889. ; 21:4, s. 476-487
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Tidskriftsartikel (refereegranskat)abstract
- In 2014, Stockholm became the first Swedish county to introduce the rotavirus vaccine, which is given from as early as six weeks of age. The aim of this study was to describe parental conceptions of rotavirus infection and vaccination during its implementation as part of the child immunization program, as their support is vital for any new vaccine. The study followed a descriptive, qualitative design with a phenomenographic approach. Ten in-depth interviews with parents were conducted in Stockholm County, transcribed and analyzed to describe qualitatively different conceptions of rotavirus infection and vaccination. Four main categories were identified: to vaccinate without doubt, hesitant to vaccinate, risky to vaccinate, and unnecessary to vaccinate. All the parents had in common the desire to protect their children from suffering, either by vaccinating their child in order to avoid rotavirus infection or by not vaccinating their child because of concerns about the side effects. It is important that child health-care professionals understand the variations of conceptions that influence the parents' decisions and that these conceptions may differ considerably. Individualized parental information about rotavirus infection and vaccination would help to achieve a successful implementation of the vaccination program.
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| 13. |
- Viklund, Gunnel, et al.
(författare)
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Assessment of an empowerment education programme. : A randomized study in teenagers with diabetes
- 2007
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Ingår i: Diabetic Medicine. - : Wiley. - 0742-3071 .- 1464-5491. ; 24:5, s. 550-556
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To determine the effects of an empowerment programme on glycaemic control and empowerment, and to study the role of parental involvement. Methods: The wait-list design is a randomized controlled trial lasting for 6 months, after which the control group participate in the same education programme as the intervention group. After 6 months, data from the two groups are analysed together (pre/post). Thirty-two teenagers with Type 1 diabetes (12-17 years) completed an empowerment group education programme, meeting weekly for 6 weeks. They were also offered an extra meeting together with their parents, which resulted in three groups: together with parents, only parents and no parent involvement at all. HbA1c was measured before intervention and after 6, 12, 18 and 24 months, and empowerment before, and 6 and 12 months after. Results: HbA1c and empowerment were similar in the intervention group and the control group 6 months after intervention. In pre/post analysis, HbA1c was significantly higher 6 and 12 months after intervention in teenagers > 14 years (from 8.4% to 9.3%; P < 0.05 to 9.6%; P < 0.01), but returned to baseline 18 months after the programme. In teenagers ≤ 14 years of age, HbA1c did not change during the study. The teenagers felt more ready for changes after the programme than before (3.9 sd = 0.5 to 4.1 sd = 0.5; P < 0.05). In the teenagers in the group that involved their parents, there was a significant decrease in HbA1c 12 and 24 months after intervention, from 8.9% (sd = 1.1) to 7.6% (sd = 1.3; P < 0.05, confidence interval 0.37, 2.26). Conclusion: This empowerment programme for teenagers with diabetes showed no positive glycaemic or empowerment effects. Empowerment programmes for diabetic teenagers in early and middle adolescence should include parental involvement.
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| 14. |
- Wang, Ning, et al.
(författare)
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Selective IgA deficiency in autoimmune diseases
- 2011
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Ingår i: Molecular Medicine. - Baltimore, Md. : Johns Hopkins University Press. - 1076-1551 .- 1528-3658. ; 17:11-12, s. 1383-
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Forskningsöversikt (refereegranskat)abstract
- Selective IgA deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves' disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) based both on our own, recent, large scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the MHC region has been reported. In addition, non-MHC genes, such as IFIH1 and CLEC16A, are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders.
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| 15. |
- Örtqvist, Eva
(författare)
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The importance of immunological, genetic and clinical factors for beta cell function in childhood diabetes
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type I diabetes is caused by environmentally initiated, progressive autoimmune destruction of pancreatic beta cells in genetically susceptible individuals, which results in insulin deficiency and hyperglycemia. At diagnosis, about 10-20 % of beta cells remain, but after insulin therapy is started, a period with regained secretive capacity follows. This period, called the clinical remission, offers an opportunity to arrest beta cell destruction by intervention with immune-modulation, antioxidant treatment and beta cell rest. Diabetes risk is strongly influenced by age-related genetic factors, and diabetes-specific autoantibodies can be found already before diagnosis. Although, extensive data on genetic and immunological factors which influence the process exist, uncertainty remains concerning the complicated combined effect, of genetic, immunological and clinical influences, that befall the growing child who develops type I diabetes. The aims of our studies were: To investigate prevalence of GAD65Ab with a new radioimmunoassay; to study immunological, genetic and clinical factors which influence the duration of the clinical remission and rate of progression of beta cell destruction in newly onset childhood diabetes; to study evolution and species-specificity of GAD65Ab; and to evaluate the effect of initial diazoxide treatment on residual endogenous insulin secretion. We have studied, in total, 330 children, with newly diagnosed type 1 diabetes, and a reference group of 119 healthy children. 56 children were randomized to either diazoxide or placebo for the first 3 months of diabetes and followed for two years. Insulin secretion was evaluated indirect as duration of clinical remission, or as fasting- and breakfast-stimulated C-peptide. Autoantibodies were analyzed by radioimmunoassay (GAD65Ab, GAD65Ab epitopes and IA-2Ab) and indirect immunofluorescence (ICA) and HLA-DQ and -DR haplotypes were analyzed by PCR-techniques. In conclusion we have found: Higher prevalence and index levels of GAD65Ab in female than male patients and a positive age-correlation of GAD65Ab in boys; Age- and gender-dependent divergence in the duration of the clinical remission and also dependence on ICA; HLA-DQ- and GAD65Ab-influences on the rate of change in beta cell function, with the fastest loss of endogenous insulin secretion in DQ2-positive individuals with GAD65Ab; Maturation of the humoral immunity towards GAD65, with a change from preference for rodent GAD65 to human GAD65 during the first year after diagnosis; and, although a 50% reduction in C-peptide secretion was achieved during treatment with diazoxide, the subsequent effect on residual insulin secretion was of shorter duration in children than in adults. We propose, that the increased risk for a faster reduction in beta cell function in HLA-DQ2 positive patients, with GAD65Ab, should be taken into consideration when new intervention protocols are planned. The fact, that male and female patients differ in their physiological response to growth also needs to be accounted for. The high rate of adverse effects for diazoxide and the short term effect achieved, prompt the development of new beta cell-specific inhibiting drugs, which may also be tried in pre-diabetic individuals. The time, when autoimmune markers have revealed that a process involving beta cell destruction is started, and during the first months of clinical disease (when preservation of remaining beta cells may be possible), is an important window of opportunity for intervention. Still, many questions remain to be answered until we find the optimal screening procedures and intervention strategies that are safe and effective in large groups of children.
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| 16. |
- Örtqvist, Maria, et al.
(författare)
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Reliability of a new instrument for measuring plantarflexor muscle strength
- 2007
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Ingår i: Archives of Physical Medicine and Rehabilitation. - : Elsevier BV. - 0003-9993 .- 1532-821X. ; 88:9, s. 1164-1170
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To test the reliability of a new muscle strength testing instrument (the Strength Measuring Chair [SMC]) designed to quantify isometric strength in the lower extremities, and to determine the agreement between the SMC and an isokinetic dynamometer (Biodex). Design: Isometric strength tests were performed in plantar-flexors with 2 different knee positions (60 degrees, 30 degrees). Measurements were taken at 3 different sessions. Setting: Strength testing laboratory. Participants: Twenty-three able-bodied adults and 15 able-bodied children. Interventions: Not applicable. Main Outcome Measure: Isometric plantarflexor strength. Results: The reliability of isometric strength measurements of plantarflexors taken in the SMC was excellent for both the adult and children groups (intraclass correlation coefficient range,.84-.87). A Bland-Altman 95% limit of agreement test showed no systematic variation in 3 of the 4 SMC test observations; systematic variation was only observed in the adult group at a knee position of 30 degrees. There was no systematic difference in the adult group between the SMC and the isokinetic dynamometer, but there was a systematic variation in the children's group. Conclusions: The SMC reliably measured isometric plantarflexor strength in the tested populations.
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| 17. |
- Örtqvist, Pernilla, et al.
(författare)
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Phenylglycine as a Novel P2 Scaffold in Hepatitis C Virus NS3 Protease Inhibitors
- 2007
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Ingår i: Bioorganic & Medicinal Chemistry. - : Elsevier BV. - 0968-0896 .- 1464-3391. ; 15:3, s. 1448-1474
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Tidskriftsartikel (refereegranskat)abstract
- Molecular modeling and inhibitory potencies of tetrapeptide protease inhibitors of HCV NS3 proposed phenylglycine as a new promising P2 residue. The results suggest that phenylglycine might be capable of interacting with the NS3 (protease-helicase/NTPase) in ways not possible for the common P2 proline-based inhibitors. Thus, a series of tripeptides, both linear and macrocyclic, based on p-hydroxy-phenylglycine in the P2 position were prepared and their inhibitory effect determined. When the p-hydroxy group was replaced by methoxy, isoquinolin-, or quinolinyloxy functions, inhibitors with improved potencies were obtained. The P2 phenylglycine-based inhibitors were further optimized by C-terminal extension to acyl sulfonamides and by P1–P3 cyclization, which gave products with inhibition constants in the nanomolar range (75 nM).
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| 18. |
- Örtqvist, Pernilla, et al.
(författare)
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Structure-activity relationships of HCV NS3 protease inhibitors evaluated on the drug-resistant variants A156T and D168V
- 2010
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Ingår i: Antiviral Therapy. - 1359-6535 .- 2040-2058. ; 15:6, s. 841-852
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: HCV infections are a serious threat to public health. An important drug target is the NS3 protease, for which several inhibitors are in clinical trials. Because of the high mutation rate of the virus, resistance against any HCV-specific drug is likely to become a substantial problem. Structure-activity data for the major resistant variants are therefore needed to guide future designs of protease inhibitors. METHODS: The inhibitory potency of tripeptide NS3 protease inhibitors, with either a P2 proline or phenylglycine, in combination with different P3 and P1-P1' groups, was assessed in enzyme activity assays using the full-length NS3 protein with known resistance-conferring substitutions A156T or D168V. The results obtained from these variants were compared with the inhibition of the wild-type enzyme. Molecular modelling was used to rationalize the biochemical results. RESULTS: Inhibitors combining the P2 proline and P1 (1R,2S)-1-amino-2-vinylcyclopropyl-carboxylic acid (vinylACCA) lost much of their potency on the resistant variants. Exchange of the P2 proline for phenylglycine yielded inhibitors that were equipotent on the wild-type and on the A156T and D168V variants. The same result was obtained from the combination of either the P2 residue with a norvaline or an aromatic scaffold in the P1 position. CONCLUSIONS: The combination of a substituted P2 proline and P1 vinylACCA appears to be the main problem behind the observed resistance. Molecular modelling suggests an enforced change in binding conformation for the P2 proline-based inhibitors, whereas the phenylglycine-based inhibitors retained their wild-type binding conformation in the substituted forms of the enzyme.
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| 19. |
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