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Context: Although a large percentage of children with advanced-stage cancer die at home, remarkably little information is available regarding the experience of general practitioners (GPs) with respect to providing home-based palliative care to children with incurable cancer., Objectives: The objective of this study was to explore the perspectives of GPs who care for children with advanced-stage cancer in a home-based setting., Methods: In this cross-sectional study, 144 GPs who provided home-based palliative care to 150 children with incurable cancer from 2001 through 2010 were invited to complete a questionnaire addressing their perspectives regarding: 1) symptom management, 2) collaboration with other health care professionals, 3) the child's death and care after death, and 4) impact of having provided palliative care, scored on distress thermometer (range 0-10)., Results: A total of 112 GPs (78%) responded, and 91 GPs completed the questionnaire for 93 patients. The median interval between the child's death and completing the questionnaire was seven years. The most prevalent symptoms reported in the patients were fatigue (67%) and pain (61%). Difficulties with communicating with (14%), coordinating with (11%), collaborating with (11%), and contacting (2%) fellow members of the multidisciplinary treatment team were rare. Hectic (7%) and shocking (5%) situations and panic (2%) around the child's death were rare. GPs reported feelings of sadness (61%) and/or powerlessness (43%) around the time of the patient's death, and they rated their own distress level as relatively high during the terminal phase (median score 6, range 0-9.5). The majority of GPs (94%) reported that they ultimately came to terms with the child's death., Conclusion: In general, GPs appear to be satisfied with the quality of home-based palliative care that they provide pediatric patients with incurable cancer. Communication among health care professionals is generally positive and is considered important. Finally, although the death of a pediatric patient has a profound impact on the GP, the majority of GPs eventually come to terms with the child's death., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. All rights reserved.)

Study Question: Is the long-term decline of ovarian function, as reflected by a decrease in serum anti-Müllerian hormone (AMH) concentration, accelerated over time in female childhood cancer survivors (CCS) as compared to healthy women of the same age?, Summary Answer: The median decline of AMH levels in long-term female CCS is not accelerated and similar to that observed in healthy controls., What Is Known Already: Gonadal function is compromised in female CCS treated with chemotherapy and/or radiation therapy. Ovarian function is most compromised in survivors treated with total body irradiation, abdominal or pelvic irradiation, stem cell transplantation or high doses of alkylating agents., Study Design Size, Duration: Longitudinal single-centre cohort study in 192 CCS in Rotterdam, The Netherlands, between 2001 and 2014., Participants/materials, Setting, Methods: Serum AMH levels of 192 adult female CCS were assessed, at least five years after cessation of treatment and at a follow-up visit with a median of 3.2 years (range: 2.1-6.0) later and were compared to the age-based P 50 of AMH in healthy controls., Main Results and the Role of Chance: Median AMH levels were below the P 50 at both visit 1 (-0.59 µg/L) and at visit 2 (-0.22 µg/L). In women with a sustained ovarian function (AMH > 1.0 µg/L), the decline in AMH is similar to that in the normal population (difference in decline per year: -0.07 µg/L (range: -2.86 to 4.92), P  = 0.75). None of the treatment modalities was correlated with a significant acceleration of decline of AMH per year., Limitations Reasons for Caution: We selected CCS that visited our late effect outpatient clinic and who had two AMH levels available. It is conceivable that women without any apparent late effects of treatment as well as women with extreme late effects, which might be the ones with the largest impact on ovarian function, could be more likely to be lost to follow-up. However, general characteristics did not differ between the included and excluded patients., Wider Implications of the Findings: While prospective longitudinal research is required to strengthen our findings, they may help physicians to counsel female CCS about their expected reproductive lifespan., Study Funding/competing Interests: A.L.F.v.d.K., M.M.v.d.H.-E. and S.M.F.P. are supported by FP7-PanCare LIFE. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. The other authors have no conflicts of interest to declare., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Despite similarities in upfront treatment of childhood cancer, not every adult survivor of childhood cancer (CCS) has an impaired bone mineral density (BMD). No data are available on the role of genetic variation on impairment of BMD in CCS., Methods: This cross-sectional single-center cohort study included 334 adult CCSs (median follow-up time after cessation of treatment: 15 years; median age at follow-up: 26 years). Total body BMD (BMD TB ) and lumbar spine BMD (BMD LS ) were measured by dual x-ray absorptiometry. We selected 12 candidate single-nucleotide polymorphisms (SNPs) in 11 genes (COL1A1, TNFSF11, TNFRSF11, TNRFSA11B, VDR, ESR1, WLS, LRP5, MTHFR, MTRR, IL-6)., Results: Multivariate analyses revealed that lower BMD was associated with lower weight and height at follow-up, male sex, and previously administered radiotherapy. Survivors with the homozygous minor allele (GG) genotype of rs2504063 (ESR1: estrogen receptor type 1) had a lower BMD TB values (-1.16 vs. -0.82; P = 0.01) than those with the AG/AA genotype; however, BMD LS was not different. Carriers of two minor alleles (GG) of rs599083 (LRP5: low-density lipoprotein receptor) revealed lower BMD TB (-1.20 vs. -0.78; P = 0.02) and lower BMD LS (-0.95 vs. -0.46; P = 0.01) values than those with the TT/TG genotype., Conclusion: CCSs who are carriers of candidate SNPs in the ESR1 or LRP5 genes seem to have an impaired bone mass at an early adult age. Information on genetic variation, in addition to patient- and treatment-related factors, may be helpful in identifying survivors who are at risk for low bone density after childhood cancer treatment., (© 2016 Wiley Periodicals, Inc.)

Osteonecrosis is a disabling complication of treatment for pediatric acute lymphoblastic leukemia, and much effort has been made to predict which patients are prone to develop this disease. Multiple clinical and genetic factors have already been identified as being associated with osteonecrosis; however, a prediction model that combines pretreatment genetic biomarkers and clinical factors has not yet been designed. Such a prediction model can only be developed with continuing international collaborations and research efforts, including large genome-wide association studies.

Study Question: Are Inhibin B and testosterone levels reduced in boys with newly diagnosed cancer prior to therapy?, Summary Answer: Pretreatment serum levels of Inhibin B and testosterone are significantly reduced in boys with newly diagnosed cancer, compared to reference values., What Is Already Known: Disease-related gonadal impairment has been demonstrated in girls and young women diagnosed with cancer, prior to therapy., Study Design, Size, Duration: We conducted a descriptive study in boys newly diagnosed with cancer between January 2006 and February 2014., Participants/materials, Setting, Methods: Serum Inhibin B and testosterone levels were determined in 224 boys, up to the age of 18 years, with newly diagnosed cancer prior to therapy. Hormone levels were compared with age-matched reference values. The cohort consisted of patients with acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), Hodgkin lymphoma (HL), non-Hodgkin lym-phoma (NHL), nephroblastoma, neuroblastoma and sarcoma., Main Results and the Role of Chance: This study demonstrates reduced serum levels of Inhibin B in boys with newly diagnosed cancer, compared to reference values (standard deviation score (SDS) -0.9, P < 0.001). Median Inhibin B level in patients was 103.5 ng/l (range 20-422). Of all patients, 78.6% showed Inhibin B levels below the 50th percentile, and 58.5% had Inhibin B levels below the 25th percentile. Serum testosterone levels were significantly lower than the reference range population (SDS -1.2, P < 0.001). Median testosterone level in pubertal patients was 7.3 nmol/l (range 0.1-23.6). No correlation with clinical signs of general illness and hormone levels were observed., Limitations, Reasons for Caution: In this study, reproductive hormone levels were compared with age-matched reference values. Future studies may compare reproductive hormone levels with case controls., Wider Implications of the Findings: Future longitudinal studies are necessary to determine whether pretreatment impaired gonadal function at the time of cancer diagnosis is an important determinant of ultimate recovery of spermatogenesis after treatment and later on in adulthood., Study Funding/competing Interests: W.v.D. was supported by the Pediatric Oncology Center Society for Research (KOCR), Rotterdam, The Netherlands. A.-L.L.F.v.d.K. was supported by EU FP7 PanCare LIFE study. The authors have no conflicts of interest., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: Dexamethasone is a key component in the treatment of pediatric acute lymphoblastic leukemia (ALL), but can induce serious adverse effects. Recent studies have led to the hypothesis that neuropsychological adverse effects may be a result of cortisol depletion of the cerebral mineralocorticoid receptors. We examined whether including a physiologic dose of hydrocortisone in dexamethasone treatment can reduce neuropsychologic and metabolic adverse effects in children with ALL., Patients and Methods: We performed a multicenter, double-blind, randomized controlled trial with a crossover design. Of 116 potentially eligible patients (age 3 to 16 years), 50 were enrolled and were treated with two consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols. Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m(2)/d) during both dexamethasone courses. Primary outcome measure was parent-reported Strength and Difficulties Questionnaire in Dutch, which assesses psychosocial problems. Other end points included questionnaires, neuropsychological tests, and metabolic parameters., Results: Of 48 patients who completed both courses, hydrocortisone had no significant effect on outcome; however, a more detailed analysis revealed that in 16 patients who developed clinically relevant psychosocial adverse effects, addition of hydrocortisone substantially reduced their Strength and Difficulties Questionnaire in Dutch scores in the following domains: total difficulties, emotional symptoms, conduct problems, and impact of difficulties. Moreover, in nine patients who developed clinically relevant, sleep-related difficulties, addition of hydrocortisone reduced total sleeping problems and disorders of initiating and maintaining sleep. In contrast, hydrocortisone had no effect on metabolic parameters., Conclusion: Our results suggest that adding a physiologic dose of hydrocortisone to dexamethasone treatment can reduce the occurrence of serious neuropsychological adverse effects and sleep-related difficulties in pediatric patients with ALL., (© 2016 by American Society of Clinical Oncology.)

Osteonecrosis and decline of bone density are serious side effects during and after treatment of childhood acute lymphoblastic leukemia. It is unknown whether osteonecrosis and low bone density occur together in the same patients, or whether these two osteogenic side-effects can mutually influence each other's development. Bone density and the incidence of symptomatic osteonecrosis were prospectively assessed in a national cohort of 466 patients with acute lymphoblastic leukemia (4-18 years of age) who were treated according to the dexamethasone-based Dutch Child Oncology Group-ALL9 protocol. Bone mineral density of the lumbar spine (BMDLS) (n=466) and of the total body (BMDTB) (n=106) was measured by dual X-ray absorptiometry. Bone density was expressed as age- and gender-matched standard deviation scores. Thirty patients (6.4%) suffered from symptomatic osteonecrosis. At baseline, BMDLS and BMDTB did not differ between patients who did or did not develop osteonecrosis. At cessation of treatment, patients with osteonecrosis had lower mean BMDLS and BMDTB than patients without osteonecrosis (respectively, with osteonecrosis: -2.16 versus without osteonecrosis: -1.21, P<0.01 and with osteonecrosis: -1.73 versus without osteonecrosis: -0.57, P<0.01). Multivariate linear models showed that patients with osteonecrosis had steeper BMDLS and BMDTB declines during follow-up than patients without osteonecrosis (interaction group time, P<0.01 and P<0.01). We conclude that bone density status at the diagnosis of acute lymphoblastic leukemia does not seem to influence the occurrence of symptomatic osteonecrosis. Bone density declines from the time that osteonecrosis is diagnosed; this suggests that the already existing decrease in bone density during acute lymphoblastic leukemia therapy is further aggravated by factors such as restriction of weight-bearing activities and destruction of bone architecture due to osteonecrosis. Osteonecrosis can, therefore, be considered a risk factor for low bone density in children with acute lymphoblastic leukemia., (Copyright© Ferrata Storti Foundation.)

Objective: To investigate the rationale and consequences associated with a parent's decision to discuss death with a child with incurable cancer., Study Design: We present data from a larger retrospective study involving bereaved parents of a child who died of cancer. Parents were asked whether they had discussed the impending death with their child, whether they reflected on this discussion positively, their reasons for not discussing death with their child, and the manner in which the conversation regarding death occurred. The data were analyzed qualitatively using a framework approach., Results: Of the 86 parents of 56 children who answered the questions regarding discussing death with their child, 55 parents of 35 children did not discuss the impending death with their child. The following themes were identified: the parents' inability to discuss the impending death; the parents' desire to protect their child; views regarding talking with children; parents' views of child characteristics; the child's unwillingness to discuss the subject; lack of opportunity to talk; and the child's disability. The parents who did discuss death with their child generally used symbolic and/or religious narratives, or they had brief, direct conversations regarding death. The majority of parents felt positive regarding their decision about whether to talk with their child about his/her impending death., Conclusion: Most parents in this study cited several reasons for not discussing death with their child. Our findings highlight the sensitive and complex issues surrounding these conversations, indicating that there may be a role for clinicians in supporting parents., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Methotrexate (MTX) is an effective and toxic chemotherapeutic drug in the treatment of pediatric acute lymphoblastic leukemia(ALL). In this prospective study, we aimed to identify metabolic and genetic determinants of MTX toxicity. One hundred and thirty-four Dutch pediatric ALL patients were treated with four high infusions MTX (HD-MTX: 5 g m(-2)) every other week according to the DCOG-ALL-10 protocol. Mucositis (National Cancer Institute grade ⩾ 3) was the most frequent occurring toxicity during the HD-MTX phase (20%) and occurred especially after the first MTX course. Mucositis was not associated with plasma MTX, plasma folate or plasma homocysteine levels. Patients with mucositis had higher erythrocyte folate levels at the start of protocol M than patients without mucositis (median 1.4 vs 1.2 μmol l(-1), P<0.008), this could reflect an increased MTX uptake in mucosal cells of patients with mucositis. From 17 single-nucleotide polymorphisms in the MTX pathway, only patients with the wild-type variant of rs7317112 SNP in the ABCC4 gene had more mucositis (AA (39%) vs AG/GG (15%), P=0.016). We found no evidence that erythrocyte folate levels mediate in the association between the rs7317112 and mucositis.

Background: Methotrexate (MTX) is an effective and safe drug in the treatment of juvenile idiopathic arthritis (JIA). Despite its safety, MTX-related gastrointestinal adverse effects before and after MTX administration, termed MTX intolerance, occur frequently, leading to non-compliance and potentially premature MTX termination. The aim of this study was to construct a risk model to predict MTX intolerance., Methods: In a prospective JIA cohort, clinical variables and single nucleotide polymorphisms were determined at MTX start. The Methotrexate Intolerance Severity Score was employed to measure MTX intolerance in the first year of treatment. MTX intolerance was most prevalent at 6 or 12 months after MTX start, which was defined as the outcome for the prediction model. The model was developed in 152 patients using multivariable logistic regression analysis and subsequently internally validated using bootstrapping., Results: The prediction model included the following predictors: JIA category, antinuclear antibody, parent/patient assessment of pain, Juvenile Arthritis Disease Activity Score-27, thrombocytes, alanine aminotransferase and creatinine. The model classified 77.5% of patients correctly, and 66.7% of patients after internal validation by bootstrapping. The lowest predicted risk of MTX intolerance was 18.9% and the highest predicted risk was 85.9%. The prediction model was transformed into a risk score (range 0-17). At a cut-off of ≥6, sensitivity was 82.0%, specificity 56.1%, positive predictive value was 58.7% and negative predictive value 80.4%., Conclusions: This clinical prediction model showed moderate predictive power to detect MTX intolerance. To develop into a clinically usable tool, it should be validated in an independent cohort and updated with new predictors. Such an easy-to-use tool could then assist clinicians in identifying patients at risk to develop MTX intolerance, and in turn to monitor them closely and intervene timely in order to prevent the development of MTX intolerance., Trial Registration: ISRCTN register, www.isrctn.com, ISRCTN13524271.

Objective: To investigate if erythrocyte-methotrexate-polyglutamate (MTX-PG) concentrations in patients with rheumatoid arthritis (RA) are associated with disease activity or adverse events., Methods: We used a longitudinal study design with two cohorts. The derivation cohort included 102 and the validation cohort included 285 patients with RA on MTX. We measured erythrocyte-MTX-PG with 1-5 glutamate residues at 3 months, 6 months and 9 months after MTX start with a liquid chromatography (LC)-mass spectrometry (MS)/MS assay. Outcomes were disease activity score in 28 joints (DAS28) and adverse events. Longitudinal associations of MTX-PG concentrations after 3 months, 6 months and 9 months with DAS28 were tested with a linear mixed model adjusted for age, gender, baseline DAS28, MTX dose and comedication., Results: In the derivation cohort, mean DAS28 decreased from 4.26 (SE=0.14) at baseline to 2.72 (SE=0.13) after 9 months. Thirty per cent of patients in the derivation cohort experienced more than three adverse events after 3 months, which decreased to 18% after 9 months. In the validation cohort, DAS28 and adverse events were comparable with the derivation cohort. In the derivation cohort, MTX-PG1 (ß=-0.005), MTX-PG2 (ß=-0.022), MTX-PG3 (β=-0.007) and total MTX-PG (ß=-0.004) were associated (p<0.05) with lower DAS28 over 9 months. In the validation cohort, MTX-PG2 (ß=-0.015), MTX-PG3 (ß=-0.010), MTX-PG4 (ß=-0.008) and total MTX-PG (ß=-0.003) were associated with lower DAS28 over 9 months. None of the MTX-PGs was associated with adverse events., Conclusions: In this first longitudinal study, we showed that an increase in erythrocyte-MTX-PG concentration was associated with a decreased DAS28 over 9 months in two cohorts, and is therefore a potential tool for therapeutic drug monitoring of MTX in RA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Summary: More than 45 % of long-term childhood cancer survivors (CCS) were diagnosed with osteopenia. Our data suggest that greater awareness for osteopenia is warranted in long-term CCS, especially in survivors who are older than 30 years, male, and underweight and were treated with cranial-spinal radiotherapy and/or steroids., Introduction: Osteopenia is a potential complication of childhood cancer treatment, but the magnitude of this problem in survivors is unknown. We examined (determinants of) bone mineral density (BMD) status in long-term survivors of adult childhood cancer., Methods: This retrospective single-centre cohort study included 346 subjects with the most common types of childhood cancer. Subjects had a median age at diagnosis of 7.0 years (range 0.1-16.8 years), a median age at follow-up of 24.5 years (range 18.0-47.6 years) and a median follow-up time of 16.7 years (range 5.6-39.9 years). Total body BMD (BMDTB) and BMD of the lumbar spine (BMDLS) were measured by dual X-ray absorptiometry. Osteopenia was defined as BMD standardized deviation score (SDS) below -1., Results: Survivors had a lower BMDTB and BMDLS (mean SDS -0.55; p<0.001 and -0.30; p<0.001, respectively) as compared to healthy peers. Osteopenia (BMDTB and/or BMDLS) was present in 45% of the survivors. Multivariate logistic regression analyses identified age at diagnosis<12 years, age>30 years at follow-up, male gender, underweight at follow-up and treatment with cranial-spinal radiotherapy or prednisone as independent prognostic factors for osteopenia., Conclusions: This large cohort of childhood cancer survivors identified osteopenia in 45% of CCS. This indicates that greater awareness is warranted, especially in survivors who are older than 30 years, male, have underweight and were treated with cranial-spinal radiotherapy and/or steroids.

Body mass index and change in body mass index during treatment may influence treatment outcome of pediatric patients with acute lymphoblastic leukemia. However, previous studies in pediatric acute lymphoblastic leukemia reported contradictory results. We prospectively collected data on body composition from a cohort of newly diagnosed Dutch pediatric patients with acute lymphoblastic leukemia (n=762, age 2-17 years). Patients were treated from 1997-2004 and the median follow-up was 9 years (range, 0-10). Body mass index at diagnosis was expressed as age- and gender-matched standard deviation scores and on the basis of these scores the patients were categorized as being underweight, of normal weight or overweight. Multivariate analyses showed that patients who were underweight (8%) had a higher risk of relapse [hazard ratio: 1.88, 95% confidence interval (1.13-3.13)], but similar overall survival and event-free survival as patients who had a normal weight or who were overweight. Patients with loss of body mass index during the first 32 weeks of treatment had a similar risk of relapse and event-free survival, but decreased overall survival [hazard ratio: 2.10, 95% confidence interval (1.14-3.87)] compared to patients without a loss of body mass index. In addition, dual X-ray absorptiometry scans were performed in a nested, single-center cohort. Data from these scans revealed that a loss of body mass consisted mainly of a loss of lean body mass, while there was a gain in the percentage of fat. In conclusion, being underweight at diagnosis is a risk factor for relapse, and a decrease in body mass index early during treatment is associated with decreased survival. In addition, loss of body mass during treatment seems to consist mainly of a loss of lean body mass. This study was approved by the Medical Ethical Committee in 1996 (trial number NTR460/SNWLK-ALL-9)., (Copyright© Ferrata Storti Foundation.)

Objective: Low-dose methotrexate (MTX) is the anchor drug in the treatment for rheumatoid arthritis (RA). Response to MTX is related to the intracellular MTX-polyglutamate (MTX-PG) levels and little is known about its determinants. We aimed to define the determinants of erythrocyte MTX-PG concentrations in 2 prospective cohorts of patients with RA., Methods: Patients with RA treated with MTX from 2 longitudinal cohorts were included: 93 from the MTX-R study (Rotterdam, the Netherlands derivation cohort), and 247 from the treatment in Rotterdam Early Arthritis Cohort study (validation cohort). MTX-PG concentrations were measured at 3 months of treatment using liquid chromatography/mass spectrometry. The MTX-PG were used as outcome measure. Various sociodemographic, clinical, biochemical, and genetic factors were assessed at baseline. Associations with MTX-PG levels were analyzed using multivariate regression analysis., Results: Age was positively associated with MTX-PG1 (stβ 0.23, p=0.033) and total MTX-PG (stβ 0.23, p=0.018) in the derivation cohort, and with all MTX-PG in the validation cohort (MTX-PG1: stβ 0.13, p=0.04; MTX-PG2: stβ 0.21, p=0.001; MTX-PG3: stβ 0.22, p<0.001; MTX-PG4+5: stβ 0.25, p<0.001; and total MTX-PG: stβ 0.32, p<0.001). Erythrocyte folate levels were positively associated with MTX-PG3 (stβ 0.3, p=0.021) and total MTX-PG levels (stβ 0.32, p=0.022) in the derivation cohort, which was replicated for MTX-PG3 (stβ 0.15, p=0.04) in the validation cohort. Patients with the folylpolyglutamate synthase (FPGS) rs4451422 wild-type genotype had higher concentrations of MTX-PG3 (p<0.05), MTX-PG4+5 (p<0.05), and total MTX-PG (p<0.05) in both cohorts. In the combined cohort, MTX dose was positively associated with levels of MTX-PG3 (stβ 0.23, p<0.001), MTX-PG4+5 (stβ 0.30, p<0.001), and total MTX-PG (stβ 0.20, p=0.002), but negatively associated with MTX-PG2 levels (stβ -0.22, p<0.001)., Conclusion: Our prospective study shows that higher age, higher MTX dose, higher erythrocyte folate status, and the FPGS rs4451422 wild-type genotype are associated with higher MTX-PG concentrations. While only up to 21% of interpatient variability can be explained by these determinants, this knowledge may aid in the development of personalized treatment in RA.

Objective: Although obesity is associated with gonadal dysfunction in the general population, gonadotoxic treatment might diminish the impact of obesity in childhood cancer survivors (CCS). The aim was to evaluate whether altered body composition is associated with gonadal dysfunction in male CCS, independent of gonadotoxic cancer treatment., Methods: Three hundred fifty-one male CCS were included. Median age at diagnosis was 5.9 years (0-17.8) and median age at follow-up 25.6 years (18.0-45.8). Total and non-SHBG-bound testosterone, sex hormone-binding globulin, inhibin B, and follicle-stimulating hormone (FSH) were studied. Potential determinants were BMI, waist circumference, waist-hip ratio, and body composition measures (dual energy X-ray absorptiometry)., Results: Non-SHBG-bound testosterone was significantly decreased in survivors with BMI ≥ 30 kg/m(2) (adjusted mean 9.1 nmol/L vs. 10.2 nmol/L, P = 0.015), high fat percentage (10.0 vs. 11.2, P = 0.004), and high waist circumference (>102 cm) (9.0 vs. 11.0, P = 0.020). Survivors with high fat percentage (≥25%) had significantly lower inhibin B/FSH ratios (inhibin B/FSH ratio: β -34%, P = 0.041)., Conclusion: Obesity is associated with gonadal dysfunction in male CCS, independent of the irreversible effect of previous cancer treatment. Randomized controlled trials are required to evaluate whether weight normalization could improve gonadal function, especially in obese survivors with potential other mechanisms than lifestyle causing their obesity., (Copyright © 2014 The Obesity Society.)

Objective: To investigate whether methotrexate (MTX) use, as compared to other therapies, and erythrocyte methotrexate polyglutamate (MTXGlu) concentrations are associated with changes in glycosylated hemoglobin (HbA1c ) levels in rheumatoid arthritis (RA) patients., Methods: The derivation cohort consisted of patients selected from the Treatment in the Rotterdam Early Arthritis Cohort who fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. Patients were randomized to 6 treatment arms: triple disease-modifying antirheumatic drug (DMARD) therapy (consisting of MTX, sulfasalazine, and hydroxychloroquine [HCQ]) + intramuscular (IM) glucocorticoids, triple DMARD therapy + oral glucocorticoids, MTX + oral glucocorticoid therapy, MTX therapy, oral glucocorticoid therapy, and HCQ therapy. HbA1c levels were determined at baseline and at 3 months. Concentrations of erythrocyte MTXGlu1-5 were measured after 3 months of treatment. Within treatment arms, changes in the level of HbA1c were compared by paired t-test. Associations of MTXGlu concentrations with changes in the level of HbA1c were tested using multiple linear regression analysis, adjusted for age, sex, body mass index, and comedication. Significant associations were validated using data on RA patients taking MTX who were enrolled in the Methotrexate in Rotterdam cohort., Results: In the derivation cohort, the mean change in HbA1c level after 3 months of treatment was -1.9 mmoles/mole (-0.18%) (P = 0.001). Levels of HbA1c decreased in 4 of the individual treatment groups, as follows: for the triple DMARD therapy + IM glucocorticoids treatment arm, -5.5 mmoles/mole (-0.50%) (P < 0.001), for the triple DMARD therapy + oral glucocorticoids treatment arm, -3.7 mmoles/mole (-0.34%) (P < 0.001), for the MTX treatment arm, -0.8 mmoles/mole (-0.08%) (P = 0.018), and for the HCQ treatment arm, -2.0 mmoles/mole (-0.19%) (P = 0.175). Increased levels of MTXGlu2 (β = -0.20, P = 0.005), MTXGlu3 (β = -0.31, P < 0.001), MTXGlu4 (β = -0.33, P < 0.001) after treatment, MTXGlu5 (β = -0.39, P < 0.001), and total MTXGlu (β = -0.29, P < 0.001) were associated with decreased levels of HBA1c . In the validation cohort, levels of HbA1c were decreased by 2.6 mmoles/mole (0.23%) (P < 0.001) after treatment, and MTXGlu3 was associated with decreased levels of HbA1c (β = -0.26, P = 0.018)., Conclusion: MTX use and higher concentrations of erythrocyte MTXGlu are associated with decreased levels of HbA1c in RA patients. Triple DMARD therapy and HCQ treatment resulted in reduced HbA1c levels, and glucocorticoid treatment resulted in increased levels of HbA1c ., (Copyright © 2014 by the American College of Rheumatology.)

Study Question: Are anti-Müllerian hormone (AMH) levels reduced in girls with newly diagnosed cancer before the start of treatment?, Summary Answer: AMH levels are already compromised in girls at the time of cancer diagnosis compared with healthy girls., What Is Known Already: In women diagnosed with cancer, evidence of reduced ovarian function has been described even before treatment has started. In girls with newly diagnosed cancer, no data are available., Study Design, Size, Duration: We performed an age-matched case-control study in girls with newly diagnosed cancer., Participants/materials, Setting, Methods: We determined serum AMH levels in a cohort of 208 girls with newly diagnosed cancer, up to 18 years of age at diagnosis, and compared them with AMH levels of 250 age-matched healthy girls. The diagnoses included were acute lymphoblastic leukaemia, acute myeloid leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, nephroblastoma, sarcoma and neuroblastoma., Main Results and the Role of Chance: The median age was 6.6 years (range 0.0-17.4), comparable with that in the control group (median 6.3 years, range 0.3-18.0). Girls with childhood cancer presented with significantly lower serum AMH levels compared with healthy age-matched controls (standard deviation scores (SDS) -0.8, P < 0.001). Median AMH level in patients was 1.4 μg/l (0.1-10.2) versus 3.0 μg/l (0.1-18.3) in controls. Specifically, 84% of all patients had AMH levels below the 50th percentile of normal AMH levels, and 19% below the 10th percentile. Surrogate markers of general health status (temperature, C-reactive protein and haemoglobin levels at diagnosis) were significantly correlated with AMH SDS., Limitations, Reasons for Caution: Some caution is warranted because AMH levels increase with age in healthy children but the cases and controls were age-matched in our study. Although our sample size was large, additional studies are still required in an independent cohort., Wider Implications of the Findings: Our study shows that AMH levels are reduced in girls with newly diagnosed cancer even before the cancer treatment has started. AMH levels correlate with impairment of general health status in girls. Therefore, besides (pre) antral follicle number, other factors may influence serum AMH levels. Longitudinal studies during and after childhood cancer are currently being performed in order to evaluate possible ovarian recovery after discontinuation of treatment., Study Funding/competing Interest(s): W.v.D. is supported by the Paediatric Oncology Centre Society for Research (KOCR), Rotterdam, The Netherlands. J.S.E.L. has received grants from the following companies (in alphabetical order): Ferring, Genovum, Merck Serono, Merck Sharp and Dome, Organon, Serono, Shering Plough and Shering. All other authors have nothing to disclose.

Objective: To investigate whether baseline concentrations of one-carbon metabolism biomarkers are associated with treatment nonresponse and adverse events in rheumatoid arthritis (RA) patients receiving methotrexate (MTX)., Methods: A prospective derivation cohort (n = 285) and validation cohort (n = 102) of RA patients receiving MTX were studied. Concentrations of plasma homocysteine, serum vitamin B12 , serum folate, erythrocyte vitamin B6 , and erythrocyte folate were determined at baseline and after 3 months of treatment. Nonresponse after 3 months was assessed using the Disease Activity Score in 28 joints (DAS28) and the European League Against Rheumatism (EULAR) response criteria. Adverse events at 3 months were assessed using biochemical parameters and health status questionnaires. Analyses were corrected for baseline DAS28, age, sex, MTX dose, comedications, and presence of the methylenetetrahydrofolate reductase 677TT genotype., Results: In the derivation cohort, the mean DAS28 scores at baseline and 3 months were 4.94 and 3.12, respectively, and 78% of patients experienced adverse events. This was similar between the 2 cohorts, despite a lower MTX dose in the validation cohort. Patients with lower levels of erythrocyte folate at baseline had a higher DAS28 at 3 months in both the derivation cohort (β = -0.15, P = 0.037) and the validation cohort (β = -0.20, P = 0.048). In line with these results, lower baseline erythrocyte folate levels were linearly associated with a 3-month DAS28 of >3.2 in both cohorts (derivation cohort, P = 0.049; validation cohort, P = 0.021) and with nonresponse according to the EULAR criteria (derivation cohort, P = 0.066; validation cohort, P = 0.027). None of the other biomarkers (levels at baseline or changes over 3 months) were associated with the DAS28 or treatment nonresponse. Baseline levels of the biomarkers and changes in levels after 3 months were not associated with incidence of adverse events., Conclusion: A low baseline concentration of erythrocyte folate is associated with high disease activity and nonresponse at 3 months after the start of MTX treatment and could be used in prediction models for MTX outcome. None of the investigated one-carbon metabolism biomarkers were associated with incidence of adverse events at 3 months., (Copyright © 2013 by the American College of Rheumatology.)

Objective: One-sided nephrectomy is followed by increased levels of IGF1, associated with linear growth during childhood. The aim was to evaluate final height and IGF1 levels in nephrectomized Wilms tumour survivors when compared with healthy Dutch references and survivors of other cancer types., Design: Cross-sectional retrospective study., Methods: Data of 575 adult childhood cancer survivors were analysed. median follow-up time was 17.8 (range 5.048.8) years. Analysis of (co)variance was performed to evaluate differences between subgroups: nephrectomized Wilms survivors treated with or without abdominal irradiation (n=41 and n=36) and survivors of other cancer types treated with or without irradiation involving the cranium, abdomen or total body (n=149 and n=349). Main outcome measures were IGF1 and height, expressed as SDS., Results: After adjustment for age at diagnosis, former corticosteroid treatment and renal impairment, height SDS in non-irradiated nephrectomized Wilms survivors was significantly higher than that in non-irradiated survivors of other cancer types (estimated mean SDS -0.09 vs -0.49, P=0.044), abdominal irradiated survivors (SDS -0.70, P=0.015) and other irradiated survivors (SDS -1.47, P<0.001). Non-irradiated nephrectomized Wilms tumour survivors had significantly higher IGF1 SDS than other irradiated survivors (estimated mean SDS -0.05 vs -1.36, P<0.001 and 0.11 vs 1.37, P<0.001), while there was no significant difference with the other two subgroups., Conclusions: Adult survivors of Wilms tumour showed better attainment of final height and relatively higher IGF1 levels than those of other cancer types who had significantly shorter stature and lower IGF1 levels than Dutch references.

Background and Objectives: Because little is known about long-term treatment-related nephrotoxicity, the aim was to determine risk factors for renal impairment long after childhood cancer treatment., Design, Setting, Participants, & Measurements: Data from 763 adult childhood cancer survivors (414 men) were obtained during regular visits at the late-effects clinic between 2003 and 2009. Median follow-up time was 18.3 years (range=5.0-58.2). Glomerular function was assessed by estimated GFR (using the Modification of Diet in Renal Disease formula), urinary albumin creatinine ratio, and tubular function by urinary β2-microglobulin creatinine ratio. The association with treatment factors was analyzed with covariance analysis for estimated GFR and logistic regression for urinary albumin and urinary β2-microglobulin creatinine ratios., Results: Survivors treated with nephrectomy and abdominal irradiation had significantly lower estimated GFR than survivors not treated with nephrectomy/abdominal irradiation (estimated mean=90 ml/min per 1.73 m(2) versus 106, P<0.001). Estimated GFR was significantly lower in survivors after treatment with high-dose ifosfamide (88 versus 98, P=0.02) and high-dose cisplatin (83 versus 101, P=0.004) compared with survivors not treated with these regimen. Nephrectomy combined with abdominal radiotherapy (odds ratio=3.14, 95% confidence interval=1.02; 9.69) and high-dose cisplatin (odds ratio=5.19, 95% confidence interval=1.21; 22.21) was associated with albuminuria. High-dose ifosfamide (odds ratio=6.19, 95% confidence interval=2.45; 15.67) was associated with increased urinary β2-microglobulin creatinine ratio. Hypertension was present in 23.4% of survivors and 31.4% of renal tumor survivors., Conclusions: Treatment with unilateral nephrectomy, abdominal radiotherapy, cisplatin, and ifosfamide was associated with lower estimated GFR. Persisting tubular damage was related to ifosfamide treatment.

Objectives: Methotrexate (MTX) is a cheap and efficacious drug in juvenile idiopathic arthritis (JIA) treatment. If JIA patients are unresponsive to MTX, early and effective combination treatment with biologicals is required to prevent joint damage. The authors developed a prediction model to identify JIA patients not responding to MTX., Methods: In a cohort of 183 JIA patients, clinical variables and single nucleotide polymorphisms (SNPs) in genes involved in the mechanism of action of MTX were determined at the start of MTX treatment. These variables were used to construct a prediction model for non-response to MTX treatment during the first year of treatment. Non-response to MTX was defined according the American College of Rheumatology paediatric 70 criteria. The prediction model was validated in a cohort of 104 JIA patients., Results: The prediction model included: erythrocyte sedimentation rate and SNPs in genes coding for methionine synthase reductase, multidrug resistance 1 (MDR-1/ABCB1), multidrug resistance protein 1 (MRP-1/ABCC1) and proton-coupled folate transporter (PCFT). The area under the receiver operating characteristics curve (AUC) was 0.72 (95% CI: 0.63 to 0.81). In the validation cohort, the AUC was 0.65 (95% CI: 0.54 to 0.77). The prediction model was transformed into a total risk score (range 0-11). At a cut-off of ≥3, sensitivity was 78%, specificity 49%, positive predictive value was 83% and negative predictive value 41%., Conclusions: The prediction model that we developed and validated combines clinical and genetic variables to identify JIA patients not responding to MTX treatment. This model could assist clinicians in making individualised treatment decisions.

Background/objectives: Decreases in physical performance are associated with multiple negative health outcomes. The objective of this study was to examine whether high plasma homocysteine and low serum vitamin B12 are independent risk factors for lower physical performance, both cross-sectionally and longitudinally., Subjects/methods: This study was performed in persons aged ≥65 years of the LASA (Longitudinal Aging Study Amsterdam), an ongoing cohort study. Blood was collected in 1995/1996 (n=1352). Physical performance was assessed in 1995/1996 and in 1998/1999 using three tests: the walking test, the chair stands test and the tandem stand (n=901-1155)., Results: After adjustment for confounding, women in the highest quartile of homocysteine had a significantly lower physical performance than did those in the lowest quartile in the cross-sectional analyses (β=-0.93, s.e.=0.34, P<0.01). This association was borderline statistically significant in the longitudinal analyses (β=-0.69, s.e.=0.35, P=0.05). After additional adjustment for serum vitamin B12, both associations were statistically significant (P<0.05). For vitamin B12 in women, and for homocysteine and vitamin B12 in men, the observed associations were less consistent., Conclusions: High plasma homocysteine is an independent risk factor for lower physical performance in older women. The association between vitamin B12 and physical performance is less clear.

Objectives: The fall risk profile developed in the Longitudinal Aging Study Amsterdam (LASA) identifies community-dwelling elderly at high risk for recurrent falling. This study assessed the predictive validity of this profile in older persons seeking care after a fall., Study Design and Setting: The LASA fall risk profile was completed for 408 persons of 65 years and older who consulted the emergency department or general practitioner after a fall. Falls were prospectively reported with a calendar during 1 year. Recurrent falling was defined as ≥ 2 falls within a period of 6 months., Results: During 1 year of followup, 76 (18.6%) participants became recurrent fallers. The area under the receiver operating characteristic curve was 0.65 (95% confidence interval [95% CI]: 0.58-0.72). At a cutoff value of 8, the sensitivity was 56.6% (CI: 51.8-61.4), the specificity was 71.4% (CI: 67.0-75.8), the positive predictive value was 34.1% (CI: 29.5-38.7), and the negative predictive value was 85.6% (CI: 82.2-89.0)., Conclusion: The discriminative ability of the LASA fall risk profile was moderate. The predictive validity of the LASA fall risk profile to identify recurrent fallers is limited among older persons who consulted the emergency department or general practitioner after a fall., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Unlabelled: This study tests whether the relationship between physical activity and (recurrent) falling is U-shaped. Among 1,337 community-dwelling older persons, no evidence for a nonlinear association was found. If all older persons increase their physical activity level with 100 units, 4% may be prevented to become recurrent fallers., Introduction: Previous studies suggest a U-shaped relationship between physical activity and falling. This study tests this hypothesis and examines whether this relationship is modified by level of physical functioning., Methods: Community-dwelling persons (65+) from the Longitudinal Aging Study Amsterdam (LASA) were prospectively followed on falls for 3 years after baseline assessment in 1995/1996 (n = 1,337). Outcome measures were time to first fall and time to recurrent falling. The LASA Physical Activity Questionnaire was used to calculate physical activity in minutes per day weighted for intensity (range 0-2000). Physical functioning was measured with physical performance tests and self reported functional limitations. Confounders were age, sex, body mass index, chronic diseases, psychotropic medication, cognitive functioning, depressive symptoms, and fear of falling., Results: No evidence for a nonlinear association was found (p for physical activity(2) > 0.20). No significant association was found between physical activity and time to first fall. An increase in physical activity of 100 units led to a 4% decrease in risk of recurrent falling (adjusted hazard ratio 0.96, 95% confidence interval 0.92, 0.99). No interactions with physical performance or functional limitations were found (p > 0.50)., Conclusions: The hypothesized U-shaped relationship between physical activity and falling could not be confirmed. At higher levels of physical activity, the risk of recurrent falling decreased, while no association was found with fall risk.

Background: This study explored the associations between various types of activities, their underlying physical components, and recurrent falling in community-dwelling older persons., Methods: This study included 1,329 community-dwelling persons (>or=65 years) of the Longitudinal Aging Study Amsterdam (LASA). The time spent in walking, cycling, light and heavy household activities, and two sports was measured using the LASA Physical Activity Questionnaire (LAPAQ). Physical activity components included strength, intensity, mechanical strain, and turning. Time to second fall in a 6-month period was measured during 3 years with fall calendars. Cox proportional hazards models were adjusted for confounders and stratified for physical performance and sex in case of significant (p < .10) interaction., Results: During 3 years, 325 (24.5%) persons became recurrent fallers. In women, doing light (hazard ratios [HRs] = 0.40, 95% confidence intervals [CIs] = 0.20-0.79) or heavy household activities (HR = 0.63, CI = 0.44-0.79) was associated with a decreased risk of recurrent falling. In persons with good physical performance, doing sports (HR = 1.56, CI = 1.07-2.28), high intensity (HR > 1.75, CI = 1.09-3.16), and high mechanical strain (HR = 1.70, CI = 1.01-2.83) activities was associated with an increased risk of recurrent falling., Conclusions: The results suggest that the relationship between physical activity and recurrent falling differs per type of activity and is modified by physical performance. Doing household activities was associated with a decreased risk of recurrent falling in women. In physically fit older persons, doing sports or activities with high intensity or mechanical strain demands was associated with an increased risk of recurrent falling.

Background: There is growing evidence that higher levels of inflammatory markers are associated with physical decline in older persons, possibly through the catabolic effects of inflammatory markers on muscle. The aim of this study was to investigate the association between serum levels of inflammatory markers and loss of muscle mass and strength in older persons., Methods: Using data on 2,177 men and women in the Health, Aging, and Body Composition Study, we examined 5-year change in thigh muscle area estimated by computed tomography and grip and knee extensor strength in relation to serum levels of interleukin-6 (IL-6), C-reactive protein, tumor necrosis factor-alpha (TNF-alpha), and soluble receptors (measured in a subsample) at baseline., Results: Higher levels of inflammatory markers were generally associated with greater 5-year decline in thigh muscle area. Most associations, with the exception of soluble receptors, were attenuated by adjustment for 5-year change in weight. Higher TNF-alpha and interleukin-6 soluble receptor levels remained associated with greater decline in grip strength in men. Analyses in a subgroup of weight-stable persons showed that higher levels of TNF-alpha and its soluble receptors were associated with 5-year decline in thigh muscle area and that higher levels of TNF-alpha were associated with decline in grip strength., Conclusions: TNF-alpha and its soluble receptors showed the most consistent associations with decline in muscle mass and strength. The results suggest a weight-associated pathway for inflammation in sarcopenia.

The aim of this prospective study was to develop a risk score, based on putative risk factors in current guidelines, which can be used to identify women at high risk of fractures in general practice. The study sample included 4157 women >/=60 yr of age (mean +/- SD: 74.1 +/- 9.1 yr), with a median follow-up of 8.9 yr of the Rotterdam Study (ERGO), and 762 women >/=65 yr of age (mean +/- SD: 76.0 +/- 6.7.yr), with a median follow-up of 6.0 yr of the Longitudinal Aging Study Amsterdam (LASA). Potential risk factors were those proposed in risk scores of three recent guidelines on osteoporosis: age, family history of fractures, prior fracture, low body weight/body mass index (BMI), serious immobility, rheumatoid arthritis, current smoking, alcohol consumption >2 units daily, prevalent vertebral fracture, and systemic corticosteroid use. Five-year absolute risk of hip fracture was 3.9% in the Rotterdam Study and 3.1% in LASA, and 10-yr absolute risk of hip fracture was 8.4% in the Rotterdam Study. Using Cox regression analysis, age (70-79 and 80+ versus <60-69) and four other risk factors were included in the risk profiles of hip fractures and fragility fractures: any prior fracture after age 50, body weight <64 kg, use of a walking aid as a proxy measure of serious immobility, and current smoking. Estimated 10-yr absolute risk of hip fracture ranged from 1.4% in women, age 60-69 years, without any of these predictors to 29% in women, >/=80 yr of age, having two or more positive risk factors. A simple risk score can satisfactorily identify older women at high risk of osteoporotic fractures in general practice. Future studies are needed to validate this score.

Poor vitamin D status is common in the elderly and is associated with bone loss and fractures. The aim was to assess worldwide vitamin D status in postmenopausal women with osteoporosis according to latitude and economic status, in relation to parathyroid function, bone turnover markers, and BMD. The study was performed in 7441 postmenopausal women from 29 countries participating in a clinical trial on bazedoxifene (selective estrogen receptor modulator), with BMD T-score at the femoral neck or lumbar spine 75 nM was 5.9%, 29.4%, 43.5%, and 21.2%, respectively, in winter and 3.0%, 22.2%, 47.2%, and 27.5% in summer. Worldwide, a negative correlation between 25(OH)D and latitude was observed. With increasing 25(OH)D categories of <25, 25-50, 50-75, and >75 nM, mean PTH, OC, and CTX were decreasing (p < 0.001), whereas BMD of all sites was increasing (p < 0.001). A threshold in the positive relationship between 25(OH)D and different BMD parameters was visible at a 25(OH)D level of 50 nM. Our study showed a high prevalence of low 25(OH)D in postmenopausal women with osteoporosis worldwide. Along with latitude, affluence seems to be an important factor for serum 25(OH)D level, especially in Europe, where it is strongly correlated with latitude.

Context: Serum 25-hydroxyvitamin D [25(OH)D] may influence serum PTH and other parameters of bone health up to a threshold concentration, which may be between 25 and 80 nmol/liter., Objective: The aim of the study was to assess the threshold serum 25(OH)D with regard to PTH, bone turnover markers, and bone mineral density (BMD)., Design and Setting: This was part of the Longitudinal Aging Study Amsterdam, an ongoing cohort study., Participants: A total of 1319 subjects (643 men and 676 women) between the ages of 65 and 88 yr participated in the study., Main Outcome Measures: Serum 25(OH)D, PTH, osteocalcin, urinary deoxypyridinoline/creatinine, quantitative ultrasound of the heel, BMD of lumbar spine and hip, total body bone mineral content, and physical performance. The relationship between the variables was explored by analysis of covariance and the locally weighted regression (LOESS) plots., Results: Serum 25(OH)D was below 25 nmol/liter in 11.5%, below 50 nmol/liter in 48.4%, below 75 nmol/liter in 82.4%, and above 75 nmol/liter in 17.6% of the respondents. Mean serum PTH decreased gradually from 5.1 pmol/liter when serum 25(OH)D was below 25 nmol/liter to 3.1 pmol/liter when serum 25(OH)D was above 75 nmol/liter (P < 0.001) without reaching a plateau. All BMD values were higher in the higher serum 25(OH)D groups, although only significantly for total hip (P = 0.01), trochanter (P = 0.001), and total body bone mineral content (P = 0.005). A threshold of about 40 nmol/liter existed for osteocalcin and deoxypyridinoline/creatinine, 50 nmol/liter for BMD, and 60 nmol/liter for physical performance., Conclusions: Low serum 25(OH)D concentrations are common in the elderly. Bone health and physical performance in older persons are likely to improve when serum 25(OH)D is raised above 50-60 nmol/liter.

Several guidelines on osteoporosis have proposed algorithms to identify persons at high risk of fractures. Although these algorithms include well-known risk factors, it is not clear how they can best be operationalized for use in general practice. The aim of this study was to compare the predictive performance of different operationalizations of four categories of risk factors for fractures that can be used in general practice. This study included 4157 women of > or =60 yr of age (mean +/- SD: 74.1 +/- 9.1 yr) with a median follow-up of 8.9 yr of the Rotterdam Study and 762 women of > or =65 yr of age (mean +/- SD: 76.0 +/- 6.7.yr) with a median follow-up of 6.0 yr of the Longitudinal Aging Study Amsterdam (LASA). At baseline, information on four categories of risk factors was obtained, including (1) family history of hip fractures, (2) type of prior fractures, (3) low body weight/body mass index (BMI), and (4) mobility impairment. The occurrence of fragility fractures, including hip, pelvic, humerus, and wrist fractures, was used as outcome measure. We quantified the predictive performance of each risk factor by a chi(2) statistic, calculated as the difference in -2 Log likelihood attributable to the risk factor, with adjustment for age and other risk factors. In the Rotterdam Study, 399 fragility fractures occurred during 31,472 person-years (PY) of follow-up. In this study, any prior fracture in the past 5 yr (chi(2) = 6; p = 0.02), body weight < 64 kg (versus > or =64 kg; chi(2) = 6.7; p = 0.01), BMI < 22 kg/m(2) (versus > or =22 kg/m(2); chi(2) = 8.7; p = 0.003), and use of a walking aid (chi(2) = 7.5; p = 0.004) were the most practical operationalizations of the risk factor categories, after adjustment for age and other risk factors. In LASA, 52 fragility fractures occurred during 3935 PY of follow-up. Associations were similar as in the Rotterdam Study, except that low body weight and BMI were not associated with fragility fracture. None of the usual operationalizations of family history of hip fractures was independently associated with fragility fracture in either study. Prior osteoporotic fracture, body weight <64 kg, a BMI <22 kg/m(2), and the use of a walking aid are practical operationalizations of risk factors for fragility fractures. On the basis of the results of this study, a simple, practical algorithm can be developed for use in general practice.

Context: Neurofibromatosis type 1 (NF1) is among the most common genetic disorders that cause learning disabilities. Recently, it was shown that statin-mediated inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase restores the cognitive deficits in an NF1 mouse model., Objective: To determine the effect of simvastatin on neuropsychological, neurophysiological, and neuroradiological outcome measures in children with NF1., Design, Setting, and Participants: Sixty-two of 114 eligible children (54%) with NF1 participated in a randomized, double-blind, placebo-controlled trial conducted between January 20, 2006, and February 8, 2007, at an NF1 referral center at a Dutch university hospital., Intervention: Simvastatin or placebo treatment once daily for 12 weeks., Main Outcome Measures: Primary outcomes were scores on a Rey complex figure test (delayed recall), cancellation test (speed), prism adaptation, and the mean brain apparent diffusion coefficient based on magnetic resonance imaging. Secondary outcome measures were scores on the cancellation test (standard deviation), Stroop color word test, block design, object assembly, Rey complex figure test (copy), Beery developmental test of visual-motor integration, and judgment of line orientation. Scores were corrected for baseline performance, age, and sex., Results: No significant differences were observed between the simvastatin and placebo groups on any primary outcome measure: Rey complex figure test (beta = 0.10; 95% confidence interval [CI], -0.36 to 0.56); cancellation test (beta = -0.19; 95% CI, -0.67 to 0.29); prism adaptation (odds ratio = 2.0; 95% CI, 0.55 to 7.37); and mean brain apparent diffusion coefficient (beta = 0.06; 95% CI, -0.07 to 0.20). In the secondary outcome measures, we found a significant improvement in the simvastatin group in object assembly scores (beta = 0.54; 95% CI, 0.08 to 1.01), which was specifically observed in children with poor baseline performance (beta = 0.80; 95% CI, 0.29 to 1.30). Other secondary outcome measures revealed no significant effect of simvastatin treatment., Conclusion: In this 12-week trial, simvastatin did not improve cognitive function in children with NF1. Trial Registration isrctn.org Identifier: ISRCTN14965707.

Background and Purpose: Hyperintensities on T2-weighted images are seen in the brains of most patients with neurofibromatosis type I (NF-1), but the origin of these unidentified bright objects (UBOs) remains obscure. In the current study, we examined the diffusion characteristics of brain tissue in children with NF-1 to test the hypothesis that a microstructural abnormality is present in NF-1., Materials and Methods: Diffusion tensor imaging (DTI) was performed in 50 children with NF-1 and 8 controls. Circular regions of interest were manually placed in 7 standardized locations in both hemispheres, including UBO sites. Apparent diffusion coefficients (ADC), fractional anisotropy (FA), and axial anisotropy (A(m)) were used to differentiate quantitatively between healthy and disordered brain matter. Differences in eigenvalues (lambda(1), lambda(2), lambda(3)) were determined to examine parenchymal integrity., Results: We found higher ADC values for UBOs than for normal-appearing sites (P < .01) and higher ADC values for normal-appearing sites than for controls (P < .04 in 5 of 7 regions). In most regions, we found no differences in FA or A(m). Eigenvalues lambda(2) and lambda(3) were higher at UBO sites than in normal-appearing sites (P < .04)., Conclusion: With ADC, it was possible to differentiate quantitatively between normal- and abnormal-appearing brain matter in NF-1 and also between normal-appearing brain matter in NF-1 and healthy brain matter in controls, indicating subtle pathologic damage disrupting the tissue microstructure in the NF-1 brain. Higher diffusivity for lambda(1), lambda(2), and lambda(3) indicates that this disturbance of microstructure is caused by accumulation of fluid or vacuolation.

The evidence on the association between vitamin D deficiency and fracture incidence is contradictory. Therefore, the objective of this study was to examine whether low serum 25-hydroxyvitamin D (25(OH)D) levels are associated with osteoporotic fractures. The study was conducted among 1311 community-dwelling older men and women of the Longitudinal Aging Study Amsterdam (LASA), an ongoing multidisciplinary cohort study. Serum 25(OH)D was determined using a competitive protein binding assay. Fractures were assessed during six years of follow-up. The data were analyzed using Cox proportional hazards model. In total, 11.3% of the persons had a serum 25(OH)D below 10 ng/ml, 48.4% had a value below 20 ng/ml, and 82.4% had a value below 30 ng/ml. Furthermore, 115 persons (8.5%) had one or more osteoporotic fractures. Different cut points of serum 25(OH)D were examined with a cut point of 12 ng/ml giving the best discrimination between persons with and without fractures (17.5% of the persons fell below this cut point). The lowest percentage of fractures (5.6%) was found above 30 ng/ml. Because an interaction effect with age was found (p=0.04), further analyses were conducted separately for persons aged 65-75 years (n=656) and for persons aged 75-89 years (n=664) at baseline. After adjustment for age, sex, season of blood collection, body mass index, number of chronic diseases, serum creatinine, cognition, smoking and alcohol use, serum 25(OH)D below or equal to 12 ng/ml was associated with an increased fracture risk in the youngest age group (HR=3.1; 95% CI: 1.4-6.9), but not in the oldest age group (HR=1.3; 95% CI: 0.7-2.2). For commonly used cut points of serum 25(OH)D (<10 ng/ml, 10-19.9 ng/ml, 20-29.9 ng/ml, > or =30 ng/ml), no statistically significant associations were found after adjustment for confounding. Serum 25(OH)D levels below or equal to 12 ng/ml were associated with an increased fracture risk in persons aged 65-75 years. The relatively low cut point of serum 25(OH)D in our population is possibly caused by high calcium intake in the Netherlands.

Objective: Progressive declines in serum levels of testosterone parallel the decline in physical performance and muscle strength in ageing men, although findings are not conclusive. We examined whether levels of testosterone were associated with 3-year decline in physical performance and muscle strength in older men., Design: Longitudinal data were available for 486 men (mean age 74.9 years, SD 6.4) from the Longitudinal Ageing Study Amsterdam (LASA) and 1071 well-functioning men (mean age 73.7 years, SD 2.8) from the Health, Ageing and Body Composition (Health ABC) study., Measurements: Three-year change in physical performance score and grip strength according to categories of total testosterone (TT) and free testosterone (FT) levels., Results: The mean 3-year change in physical performance was -1.1 (SD 2.7, -13.6%) in LASA and -0.3 (SD 1.5, -2.9%) in Health ABC. The mean 3-year change in grip strength was -9.7 kg (SD 12.2, -13.2%) in LASA and -4.4 kg (SD 11.4,-5.8%) in Health ABC. Low levels of TT were not associated with decline in physical performance or with decline in muscle strength [e.g. mean change in physical performance -1.09 (SD 0.26) in the lowest quartile (Q1) and -0.88 (0.24) in the highest quartile (Q4) of total testosterone in LASA, and -0.26 (0.07) vs.-0.36 (0.11) in Health ABC]. Similar results were found for FT., Conclusions: Low levels of TT and FT were neither associated with 3-year decline in physical performance nor with 3-year decline in muscle strength in two independent samples of older men.

Objective: Sex steroids play an important role in the maintenance of bone health. Association studies on sex steroids and fractures are not consistent. Our objective was to examine whether serum oestradiol (E2) and testosterone (T) are associated with quantitative ultrasound (QUS), bone mineral density (BMD), bone turnover markers and fracture incidence., Design: The Longitudinal Ageing Study Amsterdam (LASA), an ongoing cohort study including 623 men and 634 women, aged 65-88 years., Measurements: Serum levels of E2, T, SHBG, albumin, bone turnover markers serum osteocalcin (OC) and urinary deoxypyridinoline (DPD/Cr) were measured. QUS of the heel and BMD of the hip were assessed, and a 6-year fracture follow-up was performed., Results: Men in the lowest quartile (Q1) of bioavailable E2 (bioE2) had higher levels of bone turnover and lower BMD (B = -0.09, P < 0.01) and QUS than men in the highest quartile (Q4). This also applied to Q1 of bioT. Women in Q1 of bioE2 had higher levels of bone turnover and lower BMD (B = -0.07, P < 0.01) and QUS than women in Q4. In men and women, levels of bioE2 below the median were associated with an increased risk of osteoporotic fractures after all adjustments [hazard ratio (HR) 1.53, 95% confidence interval (CI) 1.02-2.29]. In men, univariate analysis revealed that low bioT was associated with an increased fracture risk (HR 1.91, 95% CI 1.03-3.56), but after adjustment for age, this association was no longer significant., Conclusions: Low levels of bioE2 and bioT were found to be associated with high bone turnover, low QUS and BMD and high risk of osteoporotic fractures in both men and women.

Background: Annually, about 30% of the persons of 65 years and older falls at least once and 15% falls at least twice. Falls often result in serious injuries, such as fractures. Therefore, the prevention of accidental falls is necessary. The aim is to describe the design of a study that evaluates the efficacy and cost-effectiveness of a multidisciplinary assessment and treatment of multiple fall risk factors in independently living older persons with a high risk of falling., Methods/design: The study is designed as a randomised controlled trial (RCT) with an economic evaluation. Independently living persons of 65 years and older who recently experienced a fall are interviewed in their homes and screened for risk of recurrent falling using a validated fall risk profile. Persons at low risk of recurrent falling are excluded from the RCT. Persons who have a high risk of recurrent falling are blindly randomised into an intervention (n = 100) or usual care (n = 100) group. The intervention consists of a multidisciplinary assessment and treatment of multifactorial fall risk factors. The transmural multidisciplinary approach entails close cooperation between geriatrician, primary care physician, physical therapist and occupational therapist and can be extended with other specialists if relevant. A fall calendar is used to record falls during one year of follow-up. Primary outcomes are time to first and second falls. Three, six and twelve months after the home visit, questionnaires for economic evaluation are completed. After one year, during a second home visit, the secondary outcome measures are reassessed and the adherence to the interventions is evaluated. Data will be analysed according to the intention-to-treat principle and also an on-treatment analysis will be performed., Discussion: Strengths of this study are the selection of persons at high risk of recurrent falling followed by a multidisciplinary intervention, its transmural character and the evaluation of adherence. If proven effective, implementation of our multidisciplinary assessment followed by treatment of fall risk factors will reduce the incidence of falls., Trial Registration: Current Controlled Trials ISRCTN11546541.

Background and Aims: This study aimed at examining the association between unhealthy lifestyle in young age, midlife and/or old age and physical decline in old age, and between chronic exposure to an unhealthy lifestyle throughout life and physical decline in old age., Methods: The study sample included 1297 respondents of the Longitudinal Aging Study Amsterdam (LASA). Lifestyle in old age (55-85 y) was assessed at baseline, whereas lifestyle in young age (around 25 y) and midlife (around 40 y) were assessed retrospectively. Lifestyle factors included physical activity, body mass index (BMI), number of alcohol drinks per week and smoking. Physical decline was calculated as a change in physical performance score between baseline and six-year followup., Results: Of the lifestyle factors present in old age, a BMI of 25-29 vs BMI < 25 kg/m2 (OR=1.6; 95% CI: 1.1-2.2) and a BMI of > or = 30 vs BMI < 25 kg/m2 (OR=1.8; 95% CI: 1.2-2.7) were associated with physical decline in old age. Being physically inactive in old age was not significantly associated with an increased risk of physical decline, although, being physically inactive in both midlife and old age increased the odds of physical decline in old age to 1.6 (95% CI: 1.1-2.4), compared with respondents who were physically inactive in midlife and physically active in old age. Being overweight in both age periods was associated with an OR of 1.5 (95% CI: 1.1-2.2)., Conclusions: These data suggest that overweight in old age, and chronic exposure to physical inactivity or overweight throughout life, increases the risk of physical decline in old age. Therefore, physical activity and prevention of excessive weight at all ages should be stimulated, to prevent physical decline in old age.

This study aimed to examine the association between unhealthy lifestyle in young age, midlife and/or old age and physical decline in old age, and to examine the association between chronic exposure to an unhealthy lifestyle throughout life and physical decline in old age. The study sample included 1297 respondents of the Longitudinal Aging Study Amsterdam (LASA). Lifestyle in old age (55-85 y) was assessed at baseline, while lifestyle in young age (around 25 y) and midlife (around 40 y) were assessed retrospectively. Lifestyle factors included physical activity, body mass index (BMI), number of alcohol drinks per week and smoking. Physical decline was calculated as change in physical performance score between baseline and six-year follow-up. Of the lifestyle factors present in old age, a BMI of 25-29 vs. BMI <25 kg/m2 (odds ratio (OR) 1.6; 95% confidence interval (CI) 1.1-2.2) and a BMI of > or =30 vs. BMI <25 kg/m2 (OR 1.8; 95% CI 1.2-2.7) were associated with physical decline in old age. Being physically inactive in old age was not significantly associated with an increased risk of physical decline, however, being physically inactive both in midlife and in old age increased the odds of physical decline in old age to 1.6 (95% CI 1.1-2.4) as compared to respondents who were physically inactive in midlife and physically active in old age. Being overweight in both age periods was associated with an OR of 1.5 (95% CI 1.1-2.2). These data suggest that overweight in old age, and chronic exposure to physical inactivity or overweight throughout life increases the risk of physical decline in old age. Therefore, physical activity and prevention of overweight at all ages should be stimulated to prevent physical decline in old age.

Background: Falls frequently occur in the elderly and are a major cause of morbidity and mortality., Objective: The objective of the study was to prospectively investigate the association between serum 25-hydroxyvitamin D [25(OH)D] levels and risk of recurrent falling in older men and women., Design: This was a prospective cohort study., Setting: An age- and sex-stratified random sample of the Dutch older population was determined., Subjects: Subjects included 1231 men and women (aged 65 yr and older) participating in the Longitudinal Aging Study Amsterdam., Measurements: Baseline serum 25(OH)D was determined by a competitive protein binding assay. During 1 yr, falls were prospectively recorded by means of a fall calendar., Results: Low 25(OH)D (<10 ng/ml) was associated with an increased risk of falling. After adjustment for age, sex, education level, region, season, physical activity, smoking, and alcohol intake, the odds ratios (95% confidence interval) were 1.78 (1.06-2.99) for subjects who experienced two falls or more as compared with those who did not fall or fell once and 2.23 (1.17-4.25) for subjects who fell three or more times as compared with those who fell two times or less. There was a statistically significant effect modification by age, and stratified analyses (<75 and > or = 75 yr) showed that the associations were particularly strong in the younger age group; the odds ratios (95% confidence interval) were 5.21 (2.03-13.40) for two falls or more and 4.96 (1.52-16.23) for three falls or more., Conclusions: Poor vitamin D status is independently associated with an increased risk of falling in the elderly, particularly in those aged 65-75 yr.

Purpose: The objective of this study was to investigate whether high levels of serum interleukin (IL)-6, C-reactive protein (CRP), and alpha1-antichymotrypsin (ACT) were associated with the loss of muscle strength or muscle mass (sarcopenia) in older persons., Subjects: The study included 986 men and women of the Longitudinal Aging Study Amsterdam, with a mean age of 74.6 years (standard deviation 6.2)., Methods: Grip strength (n = 986) and appendicular muscle mass (n = 328, using dual-energy x-ray absorptiometry) were obtained in 1995 and 1996 and repeated after a 3-year follow-up. Loss of muscle strength was defined as a loss of grip strength greater than 40%, and sarcopenia was defined as a loss of muscle mass greater than 3%, approximating the lowest 15% of the study sample., Results: Multiple linear and logistic regression analyses revealed that higher levels of IL-6 were associated with greater decline in muscle strength, which decreased by -3.21 kg (standard error 0.81) per standard deviation increase in log-transformed IL-6. After adjustment for confounders, including sociodemographic, health, and lifestyle factors, high IL-6 (>5 pg/mL) and high CRP (>6.1 mug/mL) were associated with a 2 to 3-fold greater risk of losing greater than 40% of muscle strength. Persons with high levels of ACT (>181% of the normal human pooled plasma) were 40% less likely to experience loss of muscle strength and tended (P = .07) to have a smaller decline in muscle mass compared with those in the lowest quartile of ACT. No consistent associations of IL-6 and CRP with sarcopenia were found., Conclusion: The findings of this prospective, population-based study suggest that higher levels of IL-6 and CRP increase the risk of muscle strength loss, whereas higher levels of ACT decrease the risk of muscle strength loss in older men and women.

Introduction: The aim of the prospective study reported here was to develop a risk profile that can be used to identify community-dwelling elderly at a high risk of recurrent falling., Materials and Methods: The study was designed as a 3-year prospective cohort study. A total of 1365 community-dwelling persons, aged 65 years and older, of the population-based Longitudinal Aging Study Amsterdam participated in the study. During an interview in 1995/1996, physical, cognitive, emotional and social aspects of functioning were assessed. A follow-up on the number of falls and fractures was conducted during a 3-year period using fall calendars that participants filled out weekly. Recurrent fallers were identified as those who fell at least twice within a 6-month period during the 3-year follow-up., Results: The incidence of recurrent falls at the 3-year follow-up point was 24.9% in women and 24.4% in men. Of the respondents, 5.5% reported a total of 87 fractures that resulted from a fall, including 20 hip fractures, 21 wrist fractures and seven humerus fractures. Recurrent fallers were more prone to have a fall-related fracture than those who were not defined as recurrent fallers (11.9% vs. 3.4%; OR: 3.8; 95% CI: 2.3-6.1). Backward logistic regression analysis identified the following predictors in the risk profile for recurrent falling: two or more previous falls, dizziness, functional limitations, weak grip strength, low body weight, fear of falling, the presence of dogs/cats in the household, a high educational level, drinking 18 or more alcoholic consumptions per week and two interaction terms (high education x 18 or more alcohol consumptions per week and two or more previous falls x fear of falling) (AUC=0.71)., Discussion: At a cut-off point of 5 on the total risk score (range 0-30), the model predicted recurrent falling with a sensitivity of 59% and a specificity of 71%. At a cut-off point of 10, the sensitivity and specificity were 31% and 92%, respectively. A risk profile including nine predictors that can easily be assessed seems to be a useful tool for the identification of community-dwelling elderly with a high risk of recurrent falling.

Objective: To describe the lifestyle of men and women aged 55-64 years in The Netherlands in 2002/'03 and compare it with the lifestyle of people of the same age in 1992/'93., Design: Descriptive., Method: Data were used from the Longitudinal Aging Study Amsterdam. The study comprised two randomly selected samples from local municipal registers in 1992/'93 (n = 966) and 2002/'03 (n = 1002), stratified according to sex, age and expected 5-year survival. Participants were from 11 municipalities in the west, northeast and south of The Netherlands. Data were collected from interviews, measurements and a written questionnaire. The response was 62% in 1992/'93 and 57% in 2002/'03., Results: In 1992/'93, 9.5% of the men and 20.5% of the women were obese. Ten years later these percentages were 18.4 and 27.5. The percentage of current smokers was stable over time and included one-third of men and one-quarter of women. More people used alcohol in 2002/'03; excessive alcohol use was found in 15.7% of the men (11.7% in 1992/'93) and 19.5% of the women (11.1% in 1992/'93). The energy expended through walking, bicycling, household activities and sports was one-fifth less in 2002/'03., Conclusion: The lifestyle of people aged 55-64 years in The Netherlands was less healthy in 2002/'03 than in 1992/'93. Because positive changes in lifestyle can reduce the risk of chronic diseases, functional limitations and early death, more attention to healthy living is necessary in this age group.

Objectives: To examine whether anemia is associated with a higher incidence of recurrent falls., Design: Prospective cohort study., Setting: Community-dwelling sample in The Netherlands., Participants: Three hundred ninety-four participants aged 65 to 88 from the Longitudinal Aging Study Amsterdam., Measurements: Anemia was defined according to World Health Organization criteria as a hemoglobin concentration less than 12 g/dL in women and less than 13 g/dL in men. Falls were prospectively determined using fall calendars that participants filled out weekly for 3 years. Recurrent fallers were identified as those who fell at least two times within 6 months during the 3-year follow-up., Results: Of the 394 persons, 11.9% (18 women and 29 men) had anemia. The incidence of recurrent falls was 38.3% of anemic persons versus 19.6% of nonanemic persons (P=.004). After adjustment for sex, age, body mass index, and diseases, anemia was significantly associated with a 1.91 times greater risk for recurrent falls (95% confidence interval=1.09-3.36). Poor physical function (indicated by muscle strength, physical performance, and limitations) partly mediated the association between anemia and incidence of recurrent falls., Conclusion: Late-life anemia is common and associated with twice the risk of recurrent falls. Muscle weakness and poor physical performance appear to partly mediate this association.

Background and Objectives: Our aim was to construct a harmonized measure of activities of daily living (ADL) across six countries, and to evaluate the reliability and validity of this measure., Methods: A population of 9,297 persons, aged 65-89 years, was drawn from the Comparison of Longitudinal European Studies on Aging (CLESA) study, which includes data from five European countries and Israel. Because the number, type, and response format of the ADL items differed across the six studies, a four-item scale was constructed to harmonize the data, using items common to most countries. A procedure was devised to substitute or construct items that were not available in two of the countries., Results: Cronbach's alpha for the four-item ADL measure varied from 0.81 in Spain to 0.92 in Finland, and was similar to the alpha of scales including five or six items. Kappa scores between substituted or constructed items and the actual items varied from 0.50 to 0.78. In all countries, the percentage of persons with ADL disability differed significantly across age and was associated with chronic diseases, poor self-rated health, global disability, and home help utilization., Conclusion: The harmonized four-item ADL measure seems a reliable and valid instrument for comparing ADL disability in older people across countries.

Objective: The objective of this study was to examine whether low levels of oestradiol and testosterone are associated with impaired mobility, low muscle strength and the incidence of falls in a population-based sample of older men and women., Design: Cross-sectional population-based study, based on data of the Longitudinal Ageing Study Amsterdam (LASA), including 623 men and 663 women, aged 65-88 years., Measurements: Serum levels of oestradiol, testosterone, albumin and sex hormone-binding globulin (SHBG) were measured. Physical performance, functional limitations and muscle strength were assessed, and a follow-up on falls was performed prospectively within 3 years., Results: After adjustment for age, level of education, alcohol use, physical activity, chronic disease and body mass index (BMI), men in the highest quartile of the oestradiol/SHBG ratio had significantly higher physical performance scores than men in the lowest quartile (beta = 0.103). Serum levels of total testosterone were positively associated with muscle strength (beta = 0.085). Calculated bioavailable testosterone levels were positively associated with physical performance and muscle strength (beta = 0.128 and 0.109 respectively). No associations of oestradiol levels with mobility were seen in women. Levels of oestradiol and testosterone were not associated with falls., Conclusions: It can be concluded that low levels of sex hormones were associated with impaired mobility and low muscle strength in men, but not in women. Levels of sex hormones were not associated with the incidence of falls neither in men, nor in women.