| 1. |
- Agardh, Carl-David, et al.
(författare)
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GAD65 vaccination: 5 years of follow-up in a randomised dose-escalating study in adult-onset autoimmune diabetes.
- 2009
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1363-1368
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: The aim of this study was to ascertain whether treatment of GAD65 autoantibody (GADA)-positive diabetic patients with alum-formulated recombinant GAD65 (GAD-alum) is safe and does not compromise beta cell function. METHODS: This Phase 2, placebo-controlled, dose-escalation clinical trial, which was randomized through a central office, was performed in 47 GADA-positive type 2 diabetic patients, who received subcutaneous injections of GAD-alum (4 [n = 9], 20 [n = 8], 100 [n = 9] or 500 [n = 8] mug) or placebo (n = 13) at weeks 1 and 4 of the trial. Participants and caregivers were blinded to group assignments. The primary outcome was safety as assessed by neurological tests, medications and beta cell function evaluated over 5 years, representing the end of the trial. RESULTS: No severe study-related adverse events occurred during the 5 year follow-up. None of the dose groups was associated with an increased risk of starting insulin treatment compared with the placebo group. The use of oral hypoglycaemic agents did not differ between the dose groups. After 5 years, fasting C-peptide levels declined in the placebo group (-0.24; 95% CI -0.41 to -0.07 log(10) nmol/l; p = 0.01) and the 500 microg dose group (-0.37; 95% CI -0.57 to -0.17 log(10) nmol/l; p = 0.003), but not in the 4 microg (-0.10; 95% CI -0.28 to 0.07 log(10) nmol/l; p = 0.20), 20 microg (0.04; 95% CI -0.12 to 0.19 log(10) nmol/l; p = 0.58) and 100 microg (0.00; 95% CI -0.20 to -0.20 log(10) nmol/l; p = 0.98) dose groups. CONCLUSIONS/INTERPRETATION: The primary outcome of safety was achieved, since no severe study-related adverse events occurred. TRIAL REGISTRATION: Because the study was initiated before 1 July 2005, the protocol was not registered in a registry. FUNDING: This trial was funded by the National Institutes of Health (grant numbers DK26190 and DK53004), the Swedish Research Council (grant number 72X-14064) and Diamyd Therapeutics (Stockholm, Sweden).
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| 2. |
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| 3. |
- Aksglaede, Lise, et al.
(författare)
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47,XXY Klinefelter syndrome: Clinical characteristics and age-specific recommendations for medical management
- 2013
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Ingår i: American Journal of Medical Genetics. Part C: Seminars in Medical Genetics. - : Wiley. - 1552-4868. ; 163C:1, s. 55-63
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Tidskriftsartikel (refereegranskat)abstract
- 47,XXY (Klinefelter syndrome) is the most frequent sex chromosomal disorder and affects approximately one in 660 newborn boys. The syndrome is characterized by varying degrees of cognitive, social, behavioral, and learning difficulties and in adulthood additionally primary testicular failure with small testes, hypergonadotropic hypogonadism, tall stature, and eunuchoid body proportions. The phenotype is variable ranging from near-normal to a significantly affected individual. In addition, newborns with Klinefelter syndrome generally present with a normal male phenotype and the only consistent clinical finding in KS is small testes, that are most often not identified until after puberty. Decreased awareness of this syndrome among health professionals and a general perception that all patients with 47,XXY exhibit the classic textbook phenotype results in a highly under-diagnosed condition with up to 75% of the patients left undetected. Typically, diagnosis is delayed with the majority of patients identified during fertility workup in adulthood, and only 10% of patients diagnosed prior to puberty. Early detection of this syndrome is recommended in order to offer treatment and intervention at the appropriate ages and stages of development for the purpose of preventing osteopenia/osteoporosis, metabolic syndrome, and other medical conditions related to hypogonadism and to the XXY as well as minimizing potential learning and psychosocial problems. The aim of this review is to present the clinical aspects of XXY and the age-specific recommendations for medical management. (c) 2013 Wiley Periodicals, Inc.
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| 4. |
- Björk, Jonas, et al.
(författare)
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The utility of the GHRH-arginine test for diagnosing GH deficiency in adults with childhood acute lymphoblastic leukemia (ALL) treated with cranial irradiation.
- 2005
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 90:11, s. 6048-6054
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Tidskriftsartikel (refereegranskat)abstract
- Context: The insulin tolerance test ( ITT) is the current standard diagnostic test for the diagnosis of adult GH deficiency ( GHD), but alternative tests, such as the GHRH- arginine test, have been proposed. Objective: We investigated the sensitivity and specificity of the GHRH- arginine test using ITT as the gold standard in diagnosing GHD in a group of young adults treated with cranial irradiation ( CRT) for childhood acute lymphoblastic leukemia ( ALL). We estimated the positive and negative predictive values of the GHRH- arginine test among patients as well as a number of individual characteristics and therapy- related factors during both the GHRH- arginine test and ITT. Design: Forty- three young adults, treated for childhood ALL with 18 - 30 Gy CRT and chemotherapy, were studied, and comparison was made with matched controls. Results and Conclusions: We evaluated four different cutoff levels for GHD in the GHRH- arginine test: 5, 7.5, 9, and 16.5 mu g/ liter. Using 7.5 mu g/liter as the cutoff yielded high specificity ( 94%), but at the same time the sensitivity was only 66%, which leads to a low negative predictive value ( 27%). In contrast, a failed GH response to the GHRH- arginine test accurately reflects the presence of radiationinduced GHD, illustrated by a high positive predictive value ( 95% at 7.5 mu g/ liter). Only age at CRT and body mass index remained significant predictors of the peak GH during the GHRH- arginine test. Because a high proportion of GHD patients show a normal response to the GHRH- arginine test, it cannot be used reliably to exclude GHD in these patients. Complementary ITT is also warranted to confirm GHD in obese patients.
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| 5. |
- Bogefors, C., et al.
(författare)
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Hypogonadism in testicular cancer patients is associated with risk factors of cardiovascular disease and the metabolic syndrome
- 2017
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Ingår i: Andrology. - : Wiley. - 2047-2919. ; 5:4, s. 711-717
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Tidskriftsartikel (refereegranskat)abstract
- More than 95% of testicular cancer are cured but they are at increased long-term risk of cardiovascular disease. The risk of cardiovascular disease and treatment intensity was reported, but it is unknown whether this effect of cancer therapy is direct or indirect, mediated through androgen deficiency. Our aim was, therefore, to evaluate whether testicular cancer patients have increased the prevalence of risk factors of cardiovascular disease and if these risk factors are associated with hypogonadism and/or the cancer treatment given. In 92 testicular cancer patients (mean 9.2 years follow-up) and age-matched controls, blood samples were analysed for lipids, total testosterone, luteinizing hormone (LH), glucose and insulin. An estimate of insulin resistance, HOMAir was calculated. Hypogonadism was defined as total testosterone < 10 nmol/L and/or LH > 10 IU/L and/or androgen replacement. In testicular cancer men with hypogonadism, compared with eugonadal patients, higher insulin (mean difference: 3.10 mIU/L; p = 0.002) and HOMAir (mean difference: 0.792; p = 0.007) were detected. Hypogonadism group presented with increased risk (OR = 4.4; p = 0.01) of metabolic syndrome. Most associations between the treatment given and the metabolic parameters became statistically non-significant after adjustment for hypogonadism. In conclusion, testicular cancer patients with signs of hypogonadism presented with significantly increased risk of metabolic syndrome and investigation of endocrine and metabolic parameters is warranted in these patients.
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| 7. |
- Follin, Cecilia, et al.
(författare)
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Bone loss after childhood acute lymphoblastic leukaemia: an observational study with and without GH therapy
- 2011
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 164:5, s. 695-703
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Bone mineral density (BMD) in survivors of acute lymphoblastic leukaemia (ALL) seems to vary with time, type of treatments and GH status. We aimed to evaluate BMD in ALL patients with growth hormone deficiency (GHD), with and without GH therapy. DESIGN: Case-control study. METHODS: 44 (21 women) GHD patients (median 25 years), treated with cranial radiotherapy (18-24 Gy) and chemotherapy and matched population controls were examined for BMD with DXA (Dual-energy X-ray absorptiometry). Two subgroups; with (0.5 mg/day) (n=16) and without GH therapy (n=13), and matched controls, were followed for 5 and 8 years, respectively. RESULTS: At baseline, no significant differences in BMD or Z-scores at femoral neck and L2-L4 were recorded (all P > 0.3). After another 8 years with GHD, Z-scores at femoral neck had decreased significantly compared to baseline (0.0 to -0.5; P<0.03), and became lower at femoral neck (P=0.05), and at L2-L4 (P<0.03), compared to controls. After 5 years of GH therapy only female ALL patients had a significantly lower femoral neck Z-scores (P=0.03). The female ALL patients reached an IGF-I level of -0.7 SD and in men the level was +0.05 SD. CONCLUSIONS: On average 25 years since diagnosis GH deficient ALL patients experienced a significant decrease in Z-scores at femoral neck and if Z-scores continuous to decrease there is a premature risk for osteoporosis. GH therapy was not shown to have a clear beneficial effect on BMD. Whether higher GH doses, particularly in women, will improve Z-scores needs further investigation.
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| 8. |
- Follin, Cecilia, et al.
(författare)
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Prolactin insufficiency but normal thyroid hormone levels after cranial radiotherapy in long-term survivors of childhood leukaemia.
- 2013
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Ingår i: Clinical Endocrinology. - : Wiley. - 1365-2265 .- 0300-0664. ; 79:1, s. 71-78
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Acute lymphoblastic leukaemia (ALL) patients treated with cranial radiotherapy (CRT) have an increased risk of GH deficiency (GHD). Little is known about insufficiencies of prolactin (PRL) and TSH, but also lactation failure has been reported in this population. OBJECTIVE: To study the long-term outcome of CRT on PRL and thyroid hormone levels in GHD ALL patients, and the prevalence of lactation failure. DESIGN: CASE-CONTROL STUDY: PATIENTS: We examined 40 GHD and 4 GH insufficient ALL patients, in median 20 years (range 8-27) after ALL diagnosis and 44 matched population controls. MEASUREMENTS: PRL secretion (area under the curve; AUC) after GHRH-arginine test in all patients and matched controls, and PRL and TSH AUC after a TRH test in 13 patients and 13 controls. And basal PRL and thyroid hormone levels after 5 years with GH therapy and 8 years without GH therapy. RESULTS: Compared to controls ALL patients had significantly lower basal and AUC PRL after GHRH-Arginine (P = 0.03, P = 0.02), and AUC PRL after TRH (P = 0.001). After 5 and 8 years, PRL levels decreased further (P = 0.01, P = 0.03), but thyroid hormones remained normal at baseline and at follow up. PRL insufficiency was significantly associated with increased levels of BMI and insulin. Six out of seven pregnant ALL women reported lactation failure. CONCLUSIONS: Long-term ALL survivors treated with CRT have GHD and PRL insufficiency, and a high prevalence of lactation failure, but thyroid hormones remained normal. PRL insufficiency was associated with cardiovascular risk. © 2012 Blackwell Publishing Ltd.
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| 9. |
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| 10. |
- Kisand, Kai, et al.
(författare)
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Interferon autoantibodies associated with AIRE-deficiency decrease the expression of IFN-stimulated genes
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 112:7, s. 2657-2666
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Tidskriftsartikel (refereegranskat)abstract
- Neutralizing autoantibodies to type I, but not type II, interferons (IFNs) are found at high titers in almost every patient with autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), a disease caused by AIRE gene mutations that lead to defects in thymic T-cell selection. Combining genome-wide expression array with real time RT-PCR assays, we here demonstrate that antibodies against IFN-alpha cause highly significant down-regulation of interferon-stimulated gene expression in cells from APECED patients' blood by blocking their highly dilute endogenous IFNs. This down-regulation was lost progressively as these APECED cells matured in cultures without neutralizing autoantibodies. Most interestingly, a rare APECED patient with autoantibodies to IFN-omega but not IFN-alpha showed a marked increase in expression of the same interferon-stimulated genes. We also report unexpected increases in serum CXCL10 levels in APECED. Our results argue that the breakdown of tolerance to IFNs in AIRE deficiency is associated with impaired responses to them in thymus, and highlight APECED as another autoimmune disease with associated dysregulation of IFN activity.
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