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Background: Viral infections are a major cause of morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Although immune suppression plays a central role, the literat...

BACKGROUND Patients with high-risk neuroblastoma (HR NBL) treated with myeloablative regimens are reported to be at risk for cardiovascular morbidity, and this risk may be increased by impaired renal function. PROCEDURE Long-term renal function was assessed in a national cohort of 18 (age 22.4 ± 4.9 years) HR NBL survivors by plasma creatinine (P-Cr), urea, and cystatin C (P-Cys C) concentrations, urine albumin/creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR). Ambulatory blood pressure was monitored, and common carotid intima-media thickness (CIMT) and left ventricular mass index (LVMI) were evaluated. RESULTS No significant difference in P-Cr, P-Cys C, or eGFR was found between the NBL survivors and the age- and sex-matched 20 controls. P-Cys C-based eGFR (eGFRcysc) was significantly lower than the P-Cr-based eGFRcr (97 ± 17 mL/min/1.73 m2 vs 111 ± 19 mL/min/1.73 m2 , P

High-dose therapy and hematopoietic stem cell transplantation (HSCT) have been shown to improve survival rates in high-risk neuroblastoma (HR-NBL), but may cause adverse effects on the growing skeleton. We studied skeletal health in a national cohort of long-term survivors of HR-NBL (n=21; age 16-30 years, median 22 years) and in 20 healthy age- and sex-matched controls. In addition to clinical evaluation and measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry, we performed spinal magnetic resonance imaging. Skeletal complications were categorized according to Common Terminology Criteria for Adverse Events (CTCAE). Altogether, 18/21 survivors presented with at least one skeletal adverse event according to CTCAE, the most common skeletal complications being short stature (n=14) and osteopenia (n=13). Altogether, 38% of the subjects had a severe complication (CTCAE score ⩾3) including bilateral slipped capital femoral epiphyseolysis in 3/21. Fracture rate was not increased. In spinal MRI, no vertebral fractures were found and degenerative intervertebral disc changes were equally prevalent in survivors and controls. BMD was lower in survivors than controls, but differences became non-significant when adjusted for bone size. In conclusion, skeletal late complications are common and can significantly impair the quality of life in young adult survivors of HR-NBL treated with high-dose protocols and HSCT.

Timely and reliable detection of viruses is of key importance in early diagnosis of infection(s) following allogeneic HSCT. Among the immunocompetent, infections with BKPyV and JCPyV are mostly subclinical, while post-HSCT, the former may cause HC and the latter PML. The epidemiology and clinical impact of the newly identified KIPyV, WUPyV, MCPyV, and TSPyV in this context remain to be defined. To assess the incidence and clinical impact of BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, and TSPyV infections, we performed longitudinal molecular surveillance for DNAemias of these HPyVs among 53 pediatric HSCT recipients. Surveillance pre-HSCT and for three months post-HSCT revealed BKPyV DNAemia in 20 (38%) patients. Our data demonstrate frequent BKPyV DNAemia among pediatric patients with HSCT and the confinement of clinical symptoms to high copy numbers alone. MCPyV and JCPyV viremias occurred at low and TSPyV viremia at very low prevalences. KIPyV or WUPyV viremias were not demonstrable in this group of immunocompromised patients.

BACKGROUND: Empagliflozin slowed the progression of CKD in patients with type 2 diabetes and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes.METHODS: Participants (n=7020) were randomized (1:1:1) to empagliflozin 10 mg/d, empagliflozin 25 mg/d, or placebo added to standard of care. We calculated eGFR slopes using random-intercept/random-coefficient models for prespecified study periods: treatment initiation (baseline to week 4), chronic maintenance treatment (week 4 to last value on treatment), and post-treatment (last value on treatment to follow-up).RESULTS: Compared with placebo, empagliflozin was associated with uniform shifts in individual eGFR slopes across all periods. On treatment initiation, adjusted mean slope (eGFR change per week, ml/min per 1.73 m2) decreased with empagliflozin (-0.77; 95% confidence interval, -0.83 to -0.71; placebo: 0.01; 95% confidence interval, -0.08 to 0.10; PCONCLUSIONS: The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function.

We evaluated the role of mismatched third-party hematopoietic stem cells (TPC) in shortening the neutropenia after umbilical cord blood transplantation (UCBT). A TPC graft was given to 7/37 children with UCBT to support engraftment due to anticipated increased risk of nonengraftment (N=6) or active infection (N=1). TPC grafts were collected with apheresis from haploidentical family members. The median UCB and CD34 cell counts were 5.10 (range, 4.13 to 9.98)×10/kg and 5.98 (range, 4.40 to 14.00)×10/kg, respectively. The median time to neutrophil engraftment was shorter in the patients with TPC (12 d; range, 9 to 24 d) than those without (23 d; range, 12 to 44 d) (P=0.010). TPC chimerism was lost in median at 28 (range, 24 to 103) days posttransplant. TPC grafts from mothers engrafted similarly as the grafts from other family members. UCB graft cell count and the use of methotrexate posttransplant strongly contributed to engraftment. TPC may form a valuable transient bridging graft over the neutropenia after UCBT in patients with anticipated high-risk of nonengraftment or toxicity due to pretransplant infections.

Objective We assessed the associations of energy, protein, carbohydrate and fat intake with weight status up to the age of 5.5 years in the prospective TEDDY study. Methods Food record data (3 days) and body mass index (BMI) measurements between 0.25 and 5.5 years were available from 5,563 children with increased genetic risk for type 1 diabetes followed from shortly after birth. We calculated odds ratios (ORs) for overweight and obesity by previous intake of energy, protein, carbohydrates and fat with adjustment for potential confounders. Results Overweight and obesity at the age of 5.5 years were positively associated with mean energy intake in previous age intervals (e.g. adjusted OR [95% confidence interval] for overweight: 1.06 [1.04, 1.09] per 100 kcal intake at the age of 4.5–5.0 years), and with protein intake after the age of 3.5 and 4.5 years, respectively (e. g. adjusted OR for overweight: 1.06 [1.03, 1.09] per 1 % of energy intake at the age of 4.5–5.0 years). The respective associations with carbohydrate and fat intake were less consistent. Conclusions These findings indicate that energy and protein intake are positively associated with increased risk for overweight in childhood, but yield no evidence for potential programming effects of protein intake in infancy.

Viral infections remain the cause of key complications following haematopoietic stem cell transplantation (HSCT). The impact of multiple, concurrent viral reactivations/infections remains to be delineated.The clinical correlates of single or multiple viremic infections following HSCT and especially the occurrence of respiratory viruses in the bloodstream were investigated. We retrospectively searched for 23 viruses in a total of 184 sera from 53 paediatric patients. The time-points of interest were pre-HSCT, one, two and three months post-HSCT, and at discharge or death. The viruses were analyzed by quantitative or qualitative PCR.Of the 53 patients, 13 (25%) had viraemias by multiple viruses and 27 (51%) by a single virus. Thirteen patients (25%) had no viruses detected by PCR during the study period. In the children with viremic co-infections, polyomaviruses predominated over herpes viruses. Nearly half the patients, 24/53 (45%) had a polyomavirus in their serum at one or more time-points. At 12/15 time-points and in 11/13 patients with co-infections polyomaviruses were involved, compared with 6/15 time-points and 6/13 patients for cytomegalovirus. Acute graft-versus-host disease (GvHD) and steroid use were significant risk factors for the viraemias caused by more than one virus.Viral co-detection is a common finding in children undergoing HSCT. With large-scale viral screening also viruses other than CMV could be found as potential pathogens. In this study, BKPyV predominated over CMV as a contributor in viraemias caused by multiple viruses in children receiving HSCT.

Portal vein thrombosis is a known risk among patients with cirrhosis, but the incidence of other thromboembolic events among patients with liver disease is inadequately delineated. This study examined the incidence of venous and arterial thromboembolic events in patients with cirrhosis and hepatitis C virus (HCV) infection and matched comparators. Patients diagnosed with HCV or cirrhosis of various etiologies were identified from a large medical claims database and matched by age and sex to comparator cohorts. New-onset diagnoses of venous and arterial thromboembolic events were determined. The incidence rate of each event was calculated and rate ratios computed using Poisson regression models, adjusting for baseline factors. The study included 22,733 HCV-infected patients and 68,198 comparators, and 15,158 cirrhosis patients and 45,473 comparators. The incidence of any thromboembolic event was 233.4 events per 10,000 person-years for the HCV cohort and 138.5 per 10,000 person-years for the comparators; the adjusted incidence rate ratio for any thromboembolic event was 1.62 (95% confidence interval [CI]: 1.48–1.77). For the cirrhosis patients and comparators, the crude rates of any thromboembolic event were 561.1 and 249.7 per 10,000 person-years, respectively. The adjusted incidence rate ratio was 2.28 (95% CI: 2.11–2.47). Arterial events, especially unstable angina and transient ischemic attack, were the most frequent events seen in both the HCV and cirrhosis cohorts, but venous events, especially portal vein thrombosis, showed a more pronounced elevation in patients with liver disease. Patients with HCV and cirrhosis of various etiologies are at increased risk of several types of thromboembolic events. Physicians should consider this increased risk when managing patients with liver disease.

Children with high-risk neuroblastoma (NBL) constitute a heterogenous group, but little attention has been paid to further subdivision of the high-risk group. Although the current therapies including multiple high-dose consolidations have neared their efficacy and tolerability limits, alternative therapies are needed. We wanted to define an ultrahigh-risk group among high-risk NBL patients, to be potential candidates for novel therapies given up-front. Children with high-risk NBL (n=59) treated at a single institution during 1987 to 2010 were evaluated for upfront prognostic factors at diagnosis and response to induction therapy. The overall outcome was not different during 1987 to 1994 versus 1995 to 2010. Therapy consisted of induction chemotherapy, surgery, and high dose-consolidation (single, tandem, or triple) with autologous stem cell rescue, followed by local irradiation and cis-retinoic acid. MYCN amplification and bone metastases were powerful upfront prognostic factors, and a combination of these determined an ultrahigh-risk group with a 5-year event-free survival of 0.125±0.083. The combination of MYCN amplification and bone metastases overruled the intensity of the therapy given and remained the only significant predictor (P

ADAM (a disintegrin and metalloproteinase) 12 is a metalloprotease implicated in cancer progression. ADAM12 can activate membrane-anchored proteins, such as sonic hedgehog, Delta-like 1 and certain epidermal growth factor receptor ligands, through a process called ectodomain shedding. We screened several membrane-anchored proteins to further dissect the substrate profile of ADAM12-mediated ectodomain shedding, and found shedding of five previously unreported substrates [Kitl1, VE-cadherin (vascular endothelial cadherin), Flk-1 (fetal liver kinase 1), Tie-2, and VCAM-1 (vascular cell adhesion molecule 1)], of which the latter four are specifically expressed by endothelial cells. We also observed that ADAM12 expression was increased in the tumour vasculature of infiltrating ductal carcinoma of the human breast as compared with little to no expression in normal breast tissue vasculature, suggesting a role for ADAM12 in tumour vessels. These results prompted us to further evaluate ADAM12-mediated shedding of two endothelial cell proteins, VE-cadherin and Tie-2. Endogenous ADAM12 expression was very low in cultured endothelial cells, but was significantly increased by cytokine stimulation. In parallel, the shed form of VE-cadherin was elevated in such cytokine-stimulated endothelial cells, and ADAM12 siRNA (small interfering RNA) knockdown reduced cytokine-induced shedding of VE-cadherin. In conclusion, the results of the present study demonstrate a role for ADAM12 in ectodomain shedding of several membrane-anchored endothelial proteins. We speculate that this process may have importance in tumour neovascularization or/and tumour cell extravasation.

Among the immunocompetent, infections with parvovirus B19 (B19V) and human bocavirus (HBoV) 1 range clinically from asymptomatic to severe, while following allogeneic hematopoietic SCT (HSCT) B19V can cause a persistent severe illness. The epidemiology and clinical impact of HBoV1 and the other emerging parvovirus 4 (PARV4) among immunocompromised patients have not been established. To determine the occurrence and clinical spectrum of B19V, PARV4 and HBoV1 infections, we performed a longitudinal molecular surveillance among 53 allogeneic HSCT recipients for pre- and post-HSCT DNAemias of these parvoviruses. Quantitative real-time PCR showed B19V DNA in sera of 16 (30%) patients, at mean levels of 4.6 × 10(3), 9.9 × 10(7), 1.1 × 10(10) and 1.6 × 10(2) B19V DNA copies/mL pre-HSCT (9/53), and at 1 (6/53), 2 (4/53) and 3 months (1/25) post HSCT, respectively. However, no clinical manifestation correlated with the presence of B19V viremia. All B19V sequences were of genotype 1. None of the sera investigated contained PARV4 or HBoV1 DNAs. Our data demonstrate B19V viremia to be frequent among pediatric allogeneic HSCT recipients, yet without apparent clinical correlates. PARV4 or HBoV1 viremias were not seen in these immunocompromised patients.

The aim of this study was to analyze the prevalence of frailty and physical health limitations among long-term survivors of high-risk neuroblastoma (HR NBL) and to investigate whether frail health is associated with variables of cardiovascular function, markers of inflammation and telomere length. A national study cohort of 19 (median age 22, range 16-30 years) long-term (>10 years) HR NBL survivors was studied and the findings were compared with 20 age- and sex-matched controls. Frailty was defined as ⩾3 of the following conditions: low muscle mass, low energy expenditure, slow running and weakness. The prevalence of frailty was significantly higher among the HR NBL survivors 9/19 (47%) than among the controls (0%). Thirteen (68%) of the survivors reported significant physical health limitations in vigorous activities, as opposed to none of the controls. The HR NBL survivors had significantly shorter telomere length and higher serum levels of high sensitivity C-reactive protein than did the controls. Frail health and poor physical functioning are prevalent among HR NBL survivors and suggest premature aging. Survivors with gonadal damage, very low fat mass percentage, low glycosylated hemoglobin A1c and increased common carotid artery intima-media thickness may be more prone to early aging after high dose therapy.

Left ventricular mass and ambulatory blood pressure are increased in long-term survivors of childhood cancer after autologous SCT

Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5 +/- 3.4%, but 44.7 +/- 3.2% (P

The roles of angiogenesis and angiogenic factors after allogenic hematopoietic SCT (HSCT) and during acute GVHD (aGVHD) are not known. Studies on pediatric patients are extremely scarce. Levels of angiopoietin-2 (Ang2) and vascular endothelial growth factor (VEGF) were analyzed from blood samples of 67 consecutive patients. The levels were correlated with aGVHD grades, routine laboratory parameters and outcome. Pre-transplant Ang2 values correlated with the occurrence of intestinal aGVHD (P=0.009), whereas post-transplant measurements correlated with the severity of skin and liver aGVHD (P=0.03, P=0.04, respectively). Pre-transplant levels of VEGF were associated with the occurrence of skin aGVHD (P=0.04), whereas post-transplant levels correlated to the severity of intestinal aGVHD (P=0.04). High Ang2 levels were associated with shorter EFS (P=0.039) and increased non-relapse mortality (NRM) (P=0.009). In conclusion, higher Ang2 levels predict higher NRM and, with coexisting high VEGF, also shorter EFS after pediatric HSCT. Our results suggest that both pre- and post-transplant levels of Ang2 and VEGF seem to correlate to the clinical state of the patient. However, the pathophysiology of this connection needs further studies.

Childhood acute lymphoblastic leukemia (ALL) is a genetically and prognostically heterogeneous malignancy with a mortality rate of 20% [1]. The identification of novel prognostic biomarkers is, the...

Background: The impact of breastfeeding on adult body composition is controversial. We evaluated effects of lifestyle and childhood-related factors, including infant feeding, on adult body composition. Methods: We determined total body and trunk fat and lean mass by densitometry in 158 adults who were born full-term and prospectively followed from birth to the age of 32 years. Data on various factors, extending from infancy to adulthood, with potential effect on body composition, were recorded. Results: Scapular skinfold thickness at 12 months correlated with adult trunk (R = 0.22, p = 0.005) and body fat percentage (R = 0.18, p = 0.023). In linear regression analysis, current physical activity (R = –0.33, p < 0.001) and maternal BMI (R = 0.28, p = 0.002) were associated with adult body fat percentage. Gender (R = 0.78, p < 0.001) and weight gain during infancy (R = 0.147, p = 0.008) were associated with adult lean mass. In the analysis of covariance, prolonged breastfeeding tended to lead to lower fat percentage in adulthood, but no direct association with the duration of breastfeeding and adult body composition was confirmed. Conclusions: Current physical activity, growth in infancy, gender and maternal BMI influence adult body composition. Breastfeeding has an indirect influence on adult body fat accumulation by affecting growth and body adiposity in infancy.

Background Public health policies aim to prevent suicide in the general population. Assessing their effectiveness is required to further guide public health policies. The present article focuses on the French paradox. The French health care system was classified as the best in the world according the World Health Organization (WHO). However, suicide rates in France remain high compared to other European countries. The aim of the present article was to analyze (i) the evolution of suicide Age-Standardized Death (ASDRs) in France during the last three decades and the associations with socio-economic parameters and (ii) to understand which populations may specifically benefit from further targeted suicide prevention policies. Methods The database of the World Health Organization (WHO), freely available, was explored in April 2015. ASDRs were calculated each year by ratio between the number of deaths by suicide and the total population (per 100,000 inhabitants). Number of deaths by gender and age were also analyzed. Results Overall, ASDR suicide has decreased since 1987 in France (−32.8% between 1987 and 2010). However, France kept the same rank (10/26) when compared to other European countries between 1987 and 2010. The relative burden of suicide in all-causes mortality increased during the same period (+28.2%) while the total number of deaths by suicide increased only slightly (+3.9%). More specifically, the number of deaths by suicide increased substantially in [35–54] years old (+40%) and 75+ years old (+27%) males, and in [35–54] (+41%) years old females. Between 2000 and 2010, suicide rates significantly decreased when yearly mean income increased, and when general and psychiatric care beds decreased. Conclusion Although ASDR suicide has decreased in France since 1987, this decline is quite modest when considering its universal access to care, the prevention of depression and suicide public policies. Suicide prevention public policies should focus on evaluation and improvement of prevention and care in the [35–54] years old population, and in the males aged 75+.

Aim Children with refractory or high-risk malignancies frequently suffer from poor quality of life during palliative care. This study explored the effect of metronomic drug administration on survival and quality of life in paediatric patients with various refractory or high-risk tumours. Methods We treated 17 patients with a maintenance therapy that consisted of metronomic thalidomide, etoposide and celecoxib. The endpoints of the study were overall and progression-free survival, changes in the Karnofsky–Lansky scores from baseline to the end of the study therapy and radiological responses. Results The median overall survival after the start of the study therapy was 6.2 months (range 2.0–57.7), and the six-, 12- and 24-month survival rates were 59%, 18% and 18%, respectively. The median progression-free survival was 3.2 months (range 0.3–17.8). The Karnofsky–Lansky scores increased significantly during the study therapy (p = 0.02), with 35% of the patients having a transient improvement in their clinical status. Radiologically, one partial response and two disease stabilisations were encountered. Grade III-V adverse events occurred in 76% of the patients. Conclusion Metronomic therapy may increase the quality of life during palliative care for childhood cancer, but requires careful patient selection to minimise the risk of serious adverse events.

Objectives To compare the effects of a combined oral contraceptive (COC) containing nomegestrol acetate and 17β-oestradiol (NOMAC/E2) on haemostasis, lipids, carbohydrate metabolism, C-reactive protein (CRP) and sex hormone-binding globulin (SHBG) with those of a COC containing levonorgestrel and ethinylestradiol (LNG/EE). Methods In a randomised, open-label study, 121 healthy women, 18-50 years of age, were randomly assigned to receive NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n = 61) for six cycles. The primary outcome was the change from baseline to cycle 6 for all indices. Results All parameters were similar at baseline between the two groups. Over six cycles, NOMAC/E2 had less effect on most haemostatic indices than LNG/EE. Lipids were essentially unchanged with NOMAC/E2, whereas with LNG/EE high-density lipoprotein cholesterol decreased and low-density lipoprotein cholesterol and triglycerides slightly increased. NOMAC/E2 induced negligible changes in glucose and insulin parameters, in contrast to LNG/EE. A much smaller increase in CRP was observed with NOMAC/E2 than with LNG/EE. NOMAC/E2 was associated with a greater increase in SHBG. Conclusions The monophasic COC NOMAC/E2 had less influence on haemostasis, lipids and carbohydrate metabolism than the COC LNG/EE.

Objectives To compare the effects of two monophasic combined oral contraceptives, containing either nomegestrol acetate/17β-oestradiol (NOMAC/E2) or levonorgestrel/ ethinylestradiol (LNG/EE) on endocrine function, androgens, and sex hormone-binding globulin (SHBG). Methods Randomised, open-label, multi-centre trial involving 121 healthy women, aged 18-50 years old. Participants received NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen (n = 60) or LNG/EE (150 μg/30 μg) in a 21/7-day regimen (n = 61) for six cycles. The primary outcome was the change from baseline to cycle 6 in markers of adrenal and thyroid function, androgens, and SHBG. Results Total cortisol, corticosteroid-binding globulin (CBG), and thyroxine-binding globulin (TBG) increased from baseline in both groups, with significantly greater increases in the LNG/EE group. No relevant changes from baseline or differences between the groups were observed for thyroid-stimulating hormone (TSH) and free thyroxine (T4). Androgens and androgen precursors decreased from baseline in both groups, with significantly greater decreases in the LNG/EE group (except for free testosterone). A greater increase in SHBG was observed with NOMAC/E2 than with LNG/EE. Conclusions NOMAC/E2 has significantly less influence on markers of adrenal and thyroid function and androgens than LNG/EE. The clinical relevance of these findings requires further study.

BACKGROUNDLDL cholesterol (LDL-C) is a modifiable cardiovascular disease risk factor. We used 3 LDL-C methods to study the agreement between fasting and postprandial LDL-C in type 2 diabetes (T2DM) patients.METHODSWe served 74 T2DM patients a standardized meal and sampled blood at fasting and 1.5, 3.0, 4.5, and 6.0 h postprandially. We measured LDL-C by use of modified β quantification (MBQ), the Friedewald equation (FE), and a direct homogeneous assay (DA). We evaluated agreement using 95% limits of agreement (LOA) within ±0.20 mmol/L (±7.7 mg/dL).RESULTSLDL-C concentrations at all postprandial times disagreed with those at fasting for all methods. In 66 patients who had complete measurements with all LDL-C methods, maximum mean differences (95% LOA) in postprandial vs fasting LDL-C were −0.16 mmol/L (−0.51; 0.19) [−6.2 mg/dL (−19.7; 7.3)] with MBQ at 3 h; −0.36 mmol/L (−0.89; 0.17) [−13.9 mg/dL (−34; 6.6)] with FE at 4.5 h; and −0.24 mmol/L (−0.62; 0.05) [−9.3 mg/dL (−24; 1.9)] with DA at 6.0 h. In postprandial samples, FE misclassified 38% of patients (two-thirds of statin users) into lower Adult Treatment Panel III (ATP III) risk categories. Greater disagreement between fasting and postprandial LDL-C was observed in individuals with postprandial triglyceride concentrations >2.08 mmol/L (>184 mg/dL) and in women (interactions: P ≤ 0.038).CONCLUSIONSDifferences up to 0.89 mmol/L (34 mg/dL) between fasting and postprandial LDL-C concentrations, with postprandial LDL-C concentrations usually being lower, were found in T2DM by 3 different LDL-C methods. Such differences are potentially relevant clinically and suggest that, irrespective of measurement method, postprandial LDL-C concentrations should not be used to assess cardiovascular disease risk.

Acoustic neuroma is a benign tumour accounting for approximately 6-10% of all intracranial tumours and occurs mainly in patients aged ≥50 years. Our aim was to investigate a wide range of occupational exposures, individual occupational titles and socioeconomic status (SES) as potential risk factors for acoustic neuroma.We conducted a population-based case-control study of 793 acoustic neuroma cases identified through the Swedish Cancer Registry and 101,762 randomly selected controls. Information on SES and occupation was obtained from censuses and linked to job-exposure matrices. Logistic regression was used to estimate ORs and calculate 95% CIs.An increased OR was seen for mercury exposure10 years before the reference year (OR 2.9; 95% CI 1.2 to 6.8), and a more modest association for benzene exposure (OR 1.8; 95% CI: 1.0 to 3.2) ≥10 years before the reference year. We observed a threefold increased risk for females working as tailors and dressmakers ≥10 years before the reference year, and a more than threefold significantly elevated OR for those working as truck and conveyor operators10 years before the reference year. We found no convincing evidence that SES is related to disease development.We observed an increased risk of acoustic neuroma associated with occupational exposure to mercury, benzene and textile dust. Men working as truck and conveyor operators10 years before the reference year had the highest increased risk of acoustic neuroma, but it is unclear what in those occupations might contribute to disease development. Our study also suggested an association between acoustic neuroma and being a class teacher or policeman. However, these findings should be further investigated to exclude the possibility of detection bias.

IFN-gammaR1 deficiency is a genetic etiology of Mendelian susceptibility to mycobacterial diseases, and includes two forms of complete recessive deficiency, with or without cell surface expression, and two forms of partial deficiency, dominant or recessive. We report here a novel form of partial and recessive Interferon gamma receptor 1 (IFN-gammaR1) deficiency, which is almost as severe as complete deficiency. The patient is homozygous for a mutation of the initiation codon (M1K). No detectable expression and function of IFN-gammaR1 were found in the patient's fibroblasts. However, IFN-gammaR1 expression was found to be impaired, but not abolished, on the EBV-transformed B cells, which could respond weakly to IFN-gamma. The mechanism underlying this weak expression involves leaky translation initiation at both non-AUG codons and the third AUG codon at position 19. It results in the residual expression of IFN-gammaR1 protein of normal molecular weight and function. The residual IFN-gamma signaling documented in this novel form of partial IFN-gammaR1 deficiency was not ubiquitous and was milder than that seen in other forms of partial IFN-gammaR1 deficiency, accounting for the more severe clinical phenotype of the patient, which was almost as severe as that of patients with complete deficiency.

Disinfection by-products in tap water have been found in some studies to be associated with adverse pregnancy outcomes, but little is known about how water use and consumption might change during early pregnancy. Estimating water-related activities only at one time during pregnancy could easily lead to exposure misclassification. To evaluate changes in water use among pregnant women, we used data from a large epidemiologic study in which 1990 women were interviewed around 9 and 20 weeks' gestation. The water variables that were examined included ingestion of cold and hot tap water as well as of bottled water, showering and bathing. Changes were detected between early and mid-pregnancy for ingested cold tap water and showering. Thirty-three percent of the subjects changed cold-water ingestion by > or =1.0 liters/day and 44% changed their time showering by > or =35 min per week during this period. Increases in cold tap water intake were associated with age >35 years, income < $40,000, and non-Hispanic white ethnicity. We also found that the proportion of the total variation due to within-subject variability was 62% for hot tap water ingestion but only 35% for showering and approximately 50% for cold tap water, bottled water and bathing. Limited resources in epidemiologic studies often require a decision between collecting data for a large number of people or collecting multiple measurements for a smaller number of people. The results in this study will be useful to researchers who need to determine where to invest their effort when assessing water-related exposures and should help in evaluation of previously performed studies.

Deletion in chromosome 9p involving the CDKN2A locus (9p21.3) is known in many malignancies. To detect this deletion in adolescent ALL patients we used oligo array CGH and studied 54 patients aged 10–25 years. Deletion rate was 25/54 (46%), of these 19/25 (76%) were homozygous. Small deletions (

ObjectiveNon-obese patients with type 2 diabetes (T2DM) are characterized by predominant defective insulin secretion. However, in non-obese T2DM patients, metformin, targeting insulin resistance, is non-inferior to the prandial insulin secretagogue, repaglinide, controlling overall glycaemia (HbA1c). Whether the same apply for postprandial glucose and lipid metabolism is unknown. Here, we compared the effect of metformin versus repaglinide on postprandial metabolism in non-obese T2DM patients.DesignSingle-centre, double-masked, double-dummy, crossover study during 2×4 months involving 96 non-obese (body mass index≤27 kg/m2) insulin-naïve T2DM patients. At enrolment, patients stopped prior oral hypoglycaemic agents therapies and after a 1-month run-in period on diet-only treatment, patients were randomized to repaglinide (2 mg) thrice daily followed by metformin (1 g) twice daily or vice versa each during 4 months with 1-month washout between interventions.MethodsPostprandial metabolism was evaluated by a standard test meal (3515 kJ; 54% fat, 13% protein and 33% carbohydrate) with blood sampling 0–6 h postprandially.ResultsFasting levels and total area under the curve (AUC) for plasma glucose, triglycerides and free fatty acids (FFA) changed equally between treatments. In contrast, fasting levels and AUC of total cholesterol, low-density lipoprotein (LDL) cholesterol, non-high-density lipoprotein (non-HDL) cholesterol and serum insulin were lower during metformin than repaglinide (mean (95% confidence intervals), LDL cholesterol difference metformin versus repaglinide: AUC: −0.17 mmol/l (−0.26; −0.08)). AUC differences remained significant after adjusting for fasting levels.ConclusionsIn non-obese T2DM patients, metformin reduced postprandial levels of glycaemia, triglycerides and FFA similarly compared to the prandial insulin secretagogue, repaglinide. Furthermore, metformin reduced fasting and postprandial cholesterolaemia and insulinaemia compared with repaglinide. These data support prescription of metformin as the preferred drug in non-obese patients with T2DM targeting fasting and postprandial glucose and lipid metabolism.

Low density lipoprotein cholesterol (LDL-C) is an independent and modifiable risk factor for development of cardiovascular disease (CVD). Postprandial lipid metabolism has been linked to CVD, but little is known about the postprandial LDL-C profile in patients with type-2 diabetes (T2DM). We aimed to study the postprandial levels of LDL-C in T2DM patients.After an overnight fast, 74 T2DM patients, mean age approximately 60 years, were served a standard fat-rich meal of 3515 kJ containing 54% fat, 13 % protein and 33 % carbohydrates. Only drinking water was allowed postprandially. Blood samples were drawn at times 0 (fasting), 1.5, 3.0, 4.5 and 6.0 h (postprandial). In all samples, LDL-C was measured with modified beta quantification (separation by ultracentrifugation followed by measurement of infranate high density lipoprotein cholesterol (HLD-C) using a homogeneous assay).At all postprandial times, levels of LDL-C showed highly significant (p0.005) decreases compared to time 0 (mean [95% CI] maximum change in LDL-C levels at 3.0 h: -0.16 mmol/L [-0.12; -0.20]; p0.001). Independently of fasting LDL-C levels and ongoing statin therapy, LDL-C decreased significantly more in female compared to male patients postprandially (mean [95% CI] maximum unadjusted change versus time 0 in LDL-C for men [n=56] at 3.0 h: -0.14 mmol/L [-0.19; -0.10], p0.001; for women [n=18] at 4.5 h: -0.26 mmol/L [-0.35; -0.18], p0.001; -0.14 mmol/L [-0.24; -0.05], p = 0.005 between genders for the mean [95% CI] fasting adjusted difference at 4.5 h in the change versus time 0 in LDL-C; gender by time interaction: p = 0.007 (repeated measures mixed model)).In T2DM patients served a fat-rich meal, levels of LDL-C decreased significantly more in women compared to men postprandially, irrespective of fasting levels or ongoing statin therapy. This might have implications in the atherosclerotic process and on any difference in the risk of CVD between genders.

A small number of prior epidemiologic studies of occupational noise exposure based on self-report have suggested an association with acoustic neuroma. The goal of the present study was to further examine the association between noise exposure and acoustic neuroma by using an objective measure of exposure in the form of a job exposure matrix. A total of 793 acoustic neuroma cases aged 21–84 years were identified between 1987 and 1999 from the Swedish Cancer Registry. The 101,756 controls randomly selected from the study base were frequency matched to cases on age, sex, and calendar year of diagnosis. Occupational information, available for 599 of the cases and 73,432 of the controls, was obtained from censuses and was linked to a job exposure matrix based on actual noise measurements. All risk estimates were close to unity, regardless of noise exposure level or parameter. The overall odds ratio for exposure to � 85 dB of noise was 0.89 (95% confidence interval: 0.64, 1.23). Contrary to previous study results, the present findings did not demonstrate an increased acoustic neuroma risk related to occupational noise exposure even after allowing for a long latency period. The effect of nondifferential misclassification of exposure must be considered a potential cause of the negative findings. case-control studies; neuroma, acoustic; noise; risk factors

Background Recent data indicate a role for angiogenesis in hematologic malignancies. In addition to promoting new vessel growth in the bone marrow microenvironment, angiogenic factors are regulators of both hematopoietic and leukemic cells. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) and Tie1 tyrosine kinase receptor are known to promote leukemia cell survival. The details of this complex angiogenesis-related interaction are still uncertain. Procedure We studied bone marrow samples from 73 patients with acute lymphoblastic (ALL) or myelogenous (AML) leukemia by using immunological methods. Results Vascular endothelial growth factor receptor 3 expression was found in 15% of the samples, particularly in samples with pediatric lymphoblastic leukemias and monocytic AMLs. Tie1 protein expression was found in 11% of the samples, all of which were from adult AML patients. Conclusions Our findings suggest that there are angiogenesis-related differences between pediatric and adult lymphoblastic leukemias as well as between lymphoid and myeloid leukemias. Pediatr Blood Cancer © 2006 Wiley-Liss, Inc.

Delayed and/or insufficient T cell recovery post hematopoietic stem cell transplantation (HSCT) leads to an increased risk of morbidity and mortality. We evaluated thymic function and its association with T cell regeneration post HSCT and identified factors involved in the process among pediatric stem cell transplant recipients. T cell regeneration in 66 pediatric patients was prospectively followed by naive T cell phenotyping, measuring of T cell receptor excision circles (TRECs) and expression of Foxp3 by regulatory T cells for the first 18 months post HSCT. TRECs were lower pre-HSCT in children with a malignant than non-malignant primary disease or immunosuppressed controls (P=0.001). Naive T lymphocyte reconstitution and thymic recovery were slow in the recipients of allogeneic stem cell grafts post HSCT. Infections caused by herpesviruses had a prognostic impact on mortality. Children with low TRECs had a high mortality (P=0.05) and low TRECs were also associated with extensive chronic graft-versus-host disease from 6 months onwards. Low amount of Foxp3 pre-HSCT was associated with an increased mortality post HSCT (P=0.03). Our study indicates an association between impaired T cell regeneration and thymic dysfunction and the clinical post transplant complications in pediatric allogeneic stem cell transplantation.

Background A Disintegrin And Metalloprotease 12 (ADAM 12) is a glycoprotein synthesised by placenta and it has been shown to be a potential first-trimester maternal serum marker for Down syndrome (DS) in two small series. Here we analyse further, the potential of ADAM 12 as a marker for DS in a large collection of first-trimester serum samples. Materials and Methods The concentration of ADAM 12 was determined in 10–14-week pregnancy sera from 218 DS pregnancies and 389 gestational age-matched control pregnancies, which had been collected as part of routine prospective first-trimester screening programs (DS = 105) or as part of previous research studies (DS = 113). ADAM 12 was measured using a semi-automated time resolved immunofluorometric assay and median values for normal pregnancies were established by polynomial regression. These medians were then used to determine population distribution parameters for DS and normal pregnancy groups. Correlation with previously established PAPP-A and free β-hCG multiple of the medians (MoMs) and delta nuchal translucency (NT) were determined and used to model the performance of first-trimester screening with ADAM 12 in combination with other first-trimester markers at various time periods across the first trimester. The benefits of a contingent testing model incorporating early measurement of PAPP-A and ADAM 12 were also explored. Results The maternal serum concentration of ADAM 12 was significantly reduced (p = 0.0049) with an overall median MoM of 0.79 in the DS cases and a log10 MoM SD of 0.3734 in the DS cases and 0.3353 in the controls. There was a significant correlation of ADAM 12 MoM in DS cases with gestational age (r = 0.375) and the median MoM increased from 0.50 at 10–11 weeks to 1.38 at 13 weeks. ADAM 12 was correlated with maternal weight (r(controls) = 0.283), PAPP-A (r(controls) = 0.324, r(DS) = 0.251) but less so with free β-hCG (r(controls) = 0.062, r(DS) = 0.049) and delta NT (r(controls) = 0.110, r(DS) = 0.151). ADAM 12 was significantly (p = 0.026) lower in smokers (0.87 vs 1.00) and elevated in Afro-Caribbean women compared to Caucasian women (1.34 vs 1.00). Population modelling using parameters from this and an earlier study showed that a combination of ADAM 12 and PAPP-A measured at 8–9 weeks and combined with NT and free β-hCG measured at 12 weeks could achieve a detection rate of 97% at a 5% false-positive rate or 89% at a 1% false-positive rate. PAPP-A and ADAM 12 alone at 8–9 weeks could identify 91% of cases at a 5% false-positive rate. Using this as part of a contingent-screening model to select an intermediate risk group of women for NT and free β-hCG at 11–12 weeks would enable the detection of 92% of cases with a 1% false-positive rate at a cost of providing NT and free β-hCG for 6% of women with 94% of women having completed screening by the 10th week of pregnancy. Conclusion ADAM 12 in early first trimester is a very efficient marker of DS. In combination with existing markers, it offers enhanced screening efficiency in a two-stage sequential first-trimester screening program or in a contingent-screening model, which may have benefits in health economies where universal access to high quality ultrasound is difficult. More data on early first-trimester cases with DS are required to establish more secure population parameters by which to assess further the validity of these models. Copyright © 2006 John Wiley & Sons, Ltd.

High-dose therapy (HDTx) with autologous stem cell rescue has been widely applied in very-poor-risk pediatric solid tumors. Promising data have become available with the use of high-dose busulfan, whereas high-dose (HD) thiotepa is less commonly used. We report retrospectively our single-institution experience from 1986 to 2012 of single and tandem HDTx with special emphasis on HD-thiotepa as the backbone of HD regimen in Ewing family tumors, including all 24 patients in the Helsinki University Hospital referral area in population-based fashion (Ewing sarcoma 9, Askin tumor 9, peripheral neuroectodermal tumor 6). The 10-year overall survival for the entire cohort was 0.73±0.01. Thirteen out of the 24 underwent HDTx (10 single, 3 tandem). The HDTx regimen consisted of HD-thiotepa (900 mg/m), VP16, and carboplatin. Additional HD-melphalan and total body irradiation were used in the tandem regimens. There was no toxic mortality. The 5-year event-free survival was 0.73±0.16 for high-risk cases transplanted in 1CR. In the relapse group, 1 out of the 3 survived. Radiotherapy to axial sites was given safely in combination with HD-thiotepa in all 3 patients. Thiotepa-based HDTx approach resulted in an encouraging outcome without toxic mortality for high-risk patients. HD-thiotepa merits further studies in larger controlled series.

Deficient soluble fiber intake has been suggested to dysregulate the immune response either directly or through alterations of the microbial composition in the gut.We hypothesized that a high intake of dietary soluble fiber in early childhood decreases the risk of type 1 diabetes (T1D)-associated islet autoimmunity.We analyzed 17,620 food records collected between age 9 and 48 mo from 3358 children from the United States and Germany prospectively followed in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. HRs for the development of any/multiple islet autoantibodies (242 and 151 events, respectively) and T1D (71 events) by soluble fiber intake were calculated in Cox regression models and adjusted for potential confounders.There were no statistically significantly protective associations observed between a high intake of soluble fiber and islet autoimmunity or T1D. For example, the adjusted HRs (95% CIs) for high intake (highest compared with lowest quintile) at age 12 mo were 0.90 (0.55, 1.45) for any islet autoantibody, 1.20 (0.69, 2.11) for multiple islet autoantibodies, and 1.24 (0.57, 2.70) for T1D. In analyzing soluble fiber intake as a time-varying covariate, there were also no short-term associations between soluble fiber intake and islet autoimmunity development, with adjusted HRs of 0.85 (0.51, 1.42) for high intake and development of any islet autoantibody, for example.These results indicate that the intake level of dietary soluble fiber is not associated with islet autoimmunity or T1D in early life.

The aim of the study was to evaluate arterial morphology and function in a national cohort of long-term survivors of high-risk neuroblastoma (NBL) treated with high-dose chemotherapy and autologous hematopoietic stem cell transplantation with or without total body irradiation (TBI).Common carotid, femoral, brachial, and radial artery morphology were assessed with very-high-resolution vascular ultrasound (25-55 MHz), and carotid artery stiffness and brachial artery flow-mediated dilatation measured with conventional vascular ultrasound in 19 adult or pubertal (age 22.7 ± 4.9 years, range 16-30) NBL survivors transplanted during 1984-1999 at the mean age of 2.5 ± 1.0 years. Results were compared with 20 age- and sex-matched healthy controls. The cardiovascular risk assessment included history, body mass index, fasting plasma lipids, glucose, and 24-h ambulatory blood pressure (BP). The survivors had consistently smaller arterial lumens, increased carotid intima-media thickness (IMT), plaque formation (N = 3), and stiffness, as well as increased radial artery intima thickness (N = 5) compared with the control group. Survivors displayed higher plasma triglyceride and cholesterol levels, and increased heart rate, as well as increased systolic and diastolic BPs. TBI (N = 10) and a low body surface area were independent predictors for decreased arterial lumen size and increased IMT. Three out of five survivors with subclinical intima thickening had arterial plaques. Plaques occurred only among TBI-treated survivors.Long-term childhood cancer survivors treated with TBI during early childhood display significant signs of premature arterial aging during young adulthood.

Disinfection by-products (DBPs) in drinking water may be associated with adverse pregnancy outcomes. However, the results from previous epidemiological studies are not consistent, perhaps in part due to individual variation in water use and consumption. This study was performed to evaluate and describe demographic and behavioral characteristics as predictors of ingested water, showering, bathing, and swimming among pregnant women. Water use and consumption data were collected through telephone interviews with 2297 pregnant women from three geographical sites in the southern United States. The data were analyzed according to demographic, health, and behavioral variables expected to be predictors of water use and thus potential confounding factors relating water use to pregnancy outcome. The candidate predictors were evaluated using backward elimination in regression models. Demographic variables tended to be more strongly predictive of the use and consumption of water than health and behavior-related factors. Non-Hispanic white women drank 0.4 (95% confidence interval (CI) 0.2; 0.7) liters more cold tap water per day than Hispanic women and 0.3 (95% CI 0.1; 0.4) liters more than non-Hispanic black women. Non-Hispanic white women also reported drinking a higher proportion of filtered tap water, whereas Hispanic women replaced more of their tap water with bottled water. Lower socioeconomic groups reported spending a longer time showering and bathing, but were less likely to use swimming pools. The results of this study should help researchers to anticipate and better control for confounding and misclassification in studies of exposure to DBPs and pregnancy outcomes.

The possibility that long term exposure to relatively weak power frequency electromagnetic fields (EMF) could increase the risk of breast cancer has been investigated during the past decade. The hypothesis is based on the assumption that magnetic field exposures suppress melatonin production and that melatonin is protective against breast cancer. Most epidemiological studies have indicated little or no overall effect of EMF exposure, but some early studies suggested effects among premenopausal women, particularly for estrogen receptor positive breast tumors. The early studies were often limited by small numbers, crude exposure information and lack of information on confounding factors. In more recent occupational studies, again no overall risk increases were reported, but some studies found increased risks in certain subgroups, although with no consistent pattern across studies. A recent very large occupational study with improved exposure assessment and enough statistical power also for subgroup analyses found no indications of increased risks in any subgroups. Most of the recent well-designed residential studies report no increased risks, and similar findings are reported in the majority of studies of bed heating devices. Overall, the weight of the evidence available today does not suggest an increased risk of breast cancer related to EMF exposure.

Slightly, but significantly, reduced bone mineral density (BMD) has been detected as a late effect after stem cell transplantation (SCT) performed in childhood. The aim of the study was to evaluate the risk factors of reduced BMD after SCT in childhood. We evaluated areal BMD of 16 young adults (six males, 10 females), aged 21 yr (range 15-34) by dual-energy X-ray absorptiometry at the lumbar spine, at the femoral neck, in the total hip, and in the total body. Bone turnover rate was evaluated by markers of bone formation and resorption. Six of the 16 patients had reduced BMD with a Z-score of < or = -1 at least at one measurement site. Factors associated with reduced BMD were prepubertal status at transplant (p = 0.03), delayed pubertal growth (p = 0.03), pubertal onset gonadal hormone insufficiency (p = 0.02), and female sex (p = 0.02). Surprisingly, height in SDs and lumbar spine BMD correlated negatively (p = 0.008) in those with reduced bone mass, indicating that low areal density could not be due the small size of the vertebrae. Bone turnover markers were similar for those with normal and reduced BMD. In conclusion, 38% of the SCT long-term survivors had reduced areal BMD. Prepubertal status at transplant with pubertal onset gonadal hormone insufficiency and female sex predisposed to reduced bone mass after SCT performed in childhood.

BACKGROUND: The occurrence of invasive fungal infection (IFIs) in a pediatric hematology/oncology unit after renovation of the ventilation system, and initiating routine azole antifungal prophylaxis was monitored. In addition, the value of serial screening for Aspergillus galactomannan (GM) for diagnosing invasive aspergillosis was assessed. PROCEDURE: A total of 98 consecutive high-risk pediatric patients were prospectively surveyed for signs of IFI and weekly monitored for serum GM. The data was not made available to treating physicians. RESULTS: Only 2 patients had proven and 27 possible IFI based on the European Organization for Research and Treatment of Cancer/Mycoses Study Group definitions. The incidence of proven IFI was 1/31 (3.2%) in the allogeneic stem cell transplant (SCT) (Aspergillus spp), 0/26 in the autologous SCT, and 1/60 (1.6%) in the induction therapy group (C. krusei). GM was detected at least in one tested sample in 12/98 patients (12.2%), in five patients in two or more sequential samples. In the latter group, IFI was proven in one patient and could not be excluded in the others. Four of the five patients belonged to the 31 allogeneic and one to the 26 autologous SCT patients. In patients with only one positive GM test none developed signs of IFI and only one received empirical amphotericin B. CONCLUSIONS: With the currently used preventative and prophylactic measures, IFI is uncommon in children with high-risk for infection. Regular screening for GM could be useful among allogeneic SCT patients and two positive samples should prompt further investigative procedures and pre-emptive antifungal therapy.

Several recent epidemiologic studies on occupational magnetic field exposure have suggested an association with female breast cancer. The purpose of this study was to test this hypothesis by using the extensive Swedish population registers in combination with improved exposure assessment. The study base consisted of all women between 1976 and 1999 gainfully employed in Stockholm or Gotland County in Sweden. A total of 20,400 cases of breast cancer were identified from the cancer registry, and 116,227 controls were selected randomly from the study base. Information was available on estrogen receptor status, occupation, socioeconomic status, and age. Parity was available for a subset. The exposure was assessed by linkage to a newly developed job-exposure matrix based on personal magnetic field measurements on women. All risk estimates were close to unity regardless of exposure cutpoint or choice of exposure parameter. The overall odds ratio for women exposed to 0.30 microT or more was 1.01 (95% confidence interval: 0.93, 1.10). The size of the study allowed for estimates with good precision also in subgroups where previous studies have suggested increased risk, but the findings do not support the hypothesis that magnetic fields influence the risk of female breast cancer.

We examined the recovery of circulating monocytoid (Lin- CD11+ HLA-DR+) and plasmacytoid (Lin- CD123+ HLA-DR+) precursor (pre) dendritic cell (DC) subsets after allogeneic stem cell transplantation (SCT) in 39 children, using age-matched healthy children as controls. The frequencies of DCs in peripheral blood samples were determined by flow cytometry. The initial recovery of DC occurred simultaneously with myeloid engraftment. However, with time, DC subset values declined, being very low 40-50 days after SCT. Low monocytoid and plasmacytoid DC values were associated significantly with the development of severe acute graft-versus-host disease (aGVHD) (P=0.042 and 0.017, respectively). Plasmacytoid DC values were lower than in the age-matched controls for the entire follow-up period (range 102-2569 days), although, with time, values approached normal levels. Normal monocytoid DC numbers were observed within 300-400 days post SCT. The severity of chronic GVHD did not correlate with quantitative recovery of DC. We conclude that in pediatric SCT, initial recovery of DC production is concurrent with that of myelopoiesis, yet with time, DC subset values decline and low counts are associated with severe aGVHD. Monocytoid DC numbers approach normal levels within a year of SCT, but plasmacytoid DC counts recover very slowly.

Background Human herpesvirus-6 (HHV-6) and -7 (HHV-7) may reactivate with immunosuppression and cause symptoms varying from subclinical to severe organ manifestations. The presence of HHV-6 and -7 and their possible association with clinical problems among pediatric recipients of stem cell grafts was studied in a single institution setting between November 1999 and December 2001. Procedure A total of 60 patients, mean age 8.5 years, were transplanted: 2/3 received allogeneic grafts and 1/3 autologous stem cell rescue. The presence of HHV-6 and -7 was studied in blood by polymerase chain reaction (PCR) (HHV-6) and antigenemia (HHV-6 and -7). Results Both HHV-6 and -7 were frequently present in the blood of stem cell graft recipients. No significant difference in the incidence of HHV-6 or -7 reactivations between the allogeneic and autologous patients nor recipients of sibling or unrelated donor (URD) grafts was observed. HHV-6 antigenemia was associated with fever, rash, and delayed engraftment. Among symptomatic patients two cases of encephalitis were encountered with both having HHV-6 detectable in their cerebrospinal fluid (CSF) by PCR. Conclusions HHV-6 and -7 seem to be common in blood both pre- and post-transplant among pediatric recipients of stem cell grafts. Prolonged reactivations appear to correlate with clinical symptoms such as fever, rash, and bone marrow suppression in the post-stem cell transplant setting (SCT), but severe complications are rare. Transient reactivations appear to be of very limited clinical significance. © 2005 Wiley-Liss, Inc.

Aims : Since hyaluronan (HA) metabolism is disturbed in some malignant tumours and in inflammatory diseases, we analysed HA and its receptor CD44 as well as the expression of the Ki67 nuclear protein, a marker of cell proliferation, in histological sections of duodenal biopsies of coeliac disease patients and controls. Methods and results : The study group consisted of 52 patients with coeliac disease in remission, 40 patients with newly diagnosed disease and 10 healthy control subjects. HA was detected with a specific biotinylated probe prepared from cartilage aggrecan and link protein, and CD44 with an antibody recognizing all forms of CD44 and another specific for its v6 variant. For the expression of the nuclear protein, monoclonal antibody MIB-1 was used. The percentage of HA-positive cells in surface epithelium was higher in newly diagnosed patients (13%) compared with patients in remission (11%) and controls (2%). In addition, HA intensity in the lamina propria was decreased in the newly diagnosed patients. In patients with active disease, 22–26% of the surface epithelium was CD44+, whereas the corresponding figure in patients in remission was 5%, and that of controls 1%. The more intensive MIB-1 labelling in the duodenal epithelium of coeliac patients without treatment was normalized after gluten-free diet. Conclusions : The HA-positive coat on surface epithelium seen even in patients in remission suggests persistent or even permanent changes in the epithelial permeability barrier in coeliac disease.

Intestinal immunopathology was studied after allogeneic stem cell transplantation (SCT) in a common clinical setup in 20 children with malignant (n=17) or nonmalignant diseases (n=3) receiving grafts from siblings (7) and unrelated donors (13). In all, 19 had total body irradiation. Duodenal biopsies at 6 and 12 weeks post transplant were evaluated by histology, immunohistochemistry, and ISEL for the detection of T-lymphocytes, inflammatory cytokines, proliferation, and apoptosis. The controls were 12 healthy children and three patients with proven intestinal graft-versus-host disease. An increased rate of apoptosis and proliferation with upregulated expression of HLA-DR antigen was detected up to 3 months post transplant in the SCT patients, even in those with a histologically normal small intestine. A low level of IFNgamma and TNFalpha was observed in the lamina propria. The initial low density of gammadelta-positive T cells had recovered to normal by the time of the second endoscopy at 12 weeks post transplant. We conclude that inflammatory activity and T cell infiltration detected by immunohistochemistry may not belong to the 'normal' recovery of the small intestine after SCT. Increased cell turnover in the intestinal crypts continues until 3 months after SCT, suggesting either an unexpectedly long-lasting effect of transplant-related toxicity or, preferably, an ongoing subclinical alloreactive process, also present in the patients without intestinal symptoms.

Escitalopram was compared to placebo in moderately to severely depressed patients in primary care with citalopram as the active reference. Patients were randomized to receive flexible doses of 10-20 mg/day escitalopram (n=155), 20-40 mg/day citalopram (n=160), or placebo (n=154) over an 8-week double-blind period. The primary efficacy parameter was the change from baseline to last assessment in the Montgomery-Asberg Depression Rating Scale total score. Escitalopram produced a statistically significant therapeutic difference of 2.9 points (P=0.002) compared to placebo, and escitalopram was consistently and statistically significantly more efficacious than placebo from week 1 onwards. Analysis of Clinical Global Impression-Severity and Clinical Global Impression-Improvement confirmed the primary efficacy results. By week 8, significantly more patients had responded to treatment with escitalopram than with citalopram (P=0.021) or placebo (P=0.009). Escitalopram was as well tolerated as citalopram and had a similar adverse event profile. Both escitalopram- and citalopram-treated patients had placebo-level adverse event withdrawal rates (3% and 4%, respectively). This study demonstrates the consistent antidepressant efficacy and excellent tolerability of escitalopram 10-20 mg/day in primary care patients with major depressive disorder.

Aim: To evaluate ovarian function after modern intensive multi-agent chemotherapy for osteosarcoma given during childhood or adolescence. Methods: After discontinuation of treatment, 10 female osteosarcoma survivors were followed up for 1.5–14 (median 4.6) years. Their age at diagnosis was a median of 12.9 (range 6–15) years and at the last follow up 18.6 (range 16–22). The main follow up included recording of their pubertal and menstrual status and of sex hormone determinations. Results: Prior to diagnosis, 5/10 had had their menarche, and one had it while on therapy. At discontinuation of chemotherapy, ovarian function had severely deteriorated; none of the girls experienced regular menstrual cycles. However, during follow up, significant restoration of ovarian function was evident. At the last follow up, 9/10 patients were menstruating spontaneously. During follow up, four patients, three of whom had received high doses of alkylating agents, presented with clear hypergonadotrophism with high FSH levels (14.4–132 IU/l). Three of these four patients initiated menstruation after their gonadotrophin levels normalised. Conclusions: The modern multi-agent chemotherapy applied for osteosarcoma impairs ovarian function. Normalisation of ovarian function is common, even in cases with severe hypergonadotrophic hypogonadism, but may only occur after several years off chemotherapy. Regular assessment of ovarian function and cautious use of hormone replacement therapy are important in patients with chemotherapy induced gonadal damage.

In acute myeloblastic leukemia (AML) the follow-up of minimal residual disease (MRD) has focused on specific chromosomal aberrations (e.g. t(15;17), t(8;21), inv16/t(16;16)) mostly employing reverse transcriptase-PCR. High or increasing levels of MRD are associated with an increased risk of relapse but low levels may persist in patients with prolonged or even durable remission. In adult patients with AML the increased risk of relapse has also been demonstrated using flow cytometry and fluorescence in situ hybridization (FISH). We evaluated the presence of MRD among pediatric patients with AML during and after the cessation of therapy. We were able to establish a clonal marker for the follow-up in 80% of our cases; 11 of the 15 with a clonal marker had detectable MRD at some point during follow-up while 4/15 relapsed 12-14 months after diagnosis. In two there was hematological relapse preceded by an increase in their FISH-detectable number of clonal cells. In 7 of the 11 remaining in CR1 there were small (1%) numbers of clonal cells detectable at one or more time-points. Out of the group of 15 pediatric patients with AML, 12 are currently alive in CCR with a median follow-up of 44 months (range 7-63 months). Our data establish the role of metaphase-FISH in the follow-up of AML in children and emphasize the importance of an increasing level of MRD in predicting a relapse. Yet, low and stable levels of marrow MRD a ppear compatible with CCR.

Relatively little is known concerning the magnitude of alterations of platelet activation and secretion markers of patients with major depression when compared to patients at increased risk for, or with current, clinically significant atherosclerosis. Markers of in vivo platelet stimulation and secretion were measured under basal conditions in normal comparison subjects (n = 12) and three patient groups: patients diagnosed with DSM-IV major depression (n = 15), dialysis-dependent patients (n = 12), and patients with severe thoracic aortic atherosclerosis (n = 10). In comparison to normal comparison subjects, depressed patients and patients with thoracic aortic atherosclerosis exhibited the greatest platelet stimulation as detected by increased anti-LIBS platelet binding. Dialysis-dependent patients exhibited the highest plasma concentrations of the renally-excreted platelet-specific secretion protein, beta-thromboglobulin. This study extends previous observations of increased platelet activation in patients with major depression and documents similar alterations in patients with transesophageal echocardiography (TEE)-documented thoracic aortic atherosclerosis. Future studies will determine whether the magnitude of platelet stimulation and secretion in patients with comorbid depression and atherosclerotic aortic disease is greater than that observed in nondepressed patients with atherosclerotic aortic disease or major depression alone. These findings provide further evidence for either increased platelet activation and/or intrinsic heightened platelet reactivity as one of the biological substrates underlying the increased risk of depressed patients for cardiovascular disease.

Treatment-related late toxicities after pediatric allogeneic hematopoietic SCT (allo-HSCT) are increasingly important as long-term survival has become an expected outcome for many transplanted children and adolescents. In a retrospective cohort study, we assessed long-term health outcomes in 204 allo-HSCT survivors transplanted in childhood or adolescence (20 years) between 1978 through 2000 after a median follow-up time of 12 (range 4-28) years. Data on conditioning regimen, adverse health events (AE) and growth and hormonal substitutions (hormone replacement therapies (HRTs)) were obtained from medical records. AEs were graded retrospectively according to Common Terminology Criteria for Adverse Events v3.0. Late deaths (⩾48 months after allo-HSCT) were evaluated separately. Multivariate analysis demonstrated that chronic GVHD (P0.000) and longer follow-up time (P0.05) correlated with AEs, whereas CY-based conditioning was inversely correlated (P0.002). TBI and longer follow-up duration predicted more severe AEs (P0.001 and P0.001, respectively). HRTs were more frequent after TBI. Diabetes type II, dyslipidemia and hypertension were detected in 9, 7 and 7% of the survivors, respectively. Late deaths (n=22) were most frequently due to pulmonary failure (n=7), followed by secondary malignancy (n=5). The occurrence of AEs after pediatric allo-HSCT is high and likely to increase during extended follow-up, particularly in patients who have received TBI.