The need for additional care in patients with classical galactosaemia

Purpose: Classical galactosaemia is an inborn error of galactose metabolism which may lead to impairments in body functions and accordingly, need for additional care. The primary aim of this study was to establish the type and intensity of this additional care. Materials and methods: Patients with classical galactosaemia aged >/=2 years were evaluated with the Capacity Profile, a standardised method to classify additional care needs according to type and intensity. Based on a semi-structured interview, current impairments in five domains of body functions were determined. The intensity of additional care was assessed (from 0, usual care, to 5, total dependence). Results: Forty-four patients with classical galactosaemia, 18 males and 26 females (median age 15 years, range 2-49 years), were included. There was a wide spectrum of impairments in mental functions. Motor function impairments were present in four patients, and mild speech impairments in eight patients. Additional care for sensory functions was uncommon. All patients needed a diet, which care is scored in the physical health domain. Conclusions: Apart from the diet all patients need, classical galactosaemia leads to the need for additional care mainly in the domains of mental functions and speech and voice functions. Implications for rehabilitation The Capacity Profile is a useful tool to demonstrate additional care needs in classical galactosaemia. In classical galactosaemia additional care is mostly indicated by mental impairments and speech and voice functions. One-fifth of patients have impairment of speech and voice functions at time of the study, and half of all patients had received speech therapy in childhood. Over 70% of patients need additional care/help due to impairment of mental functions, ranging from coaching due to social vulnerability to full day care

No association between DNA methylation and COPD in never and current smokers

Introduction: Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with cigarette smoke as the main risk factor for its development. Since not every smoker develops COPD, other factors likely underlie differences in susceptibility to develop COPD. Here, we tested if DNA methylation may be such a factor by assessing the association between DNA methylation levels and COPD in never and current smokers from the general population. Methods: For the current study, 1561 subjects were non-randomly selected from the LifeLines cohort study. We included 903 never smokers and 658 current smokers with and without COPD, defined as pre-bronchodilator forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <70%. Subsequently, we performed robust regression analysis on whole blood DNA methylation levels of 420 938 CpG sites with COPD as outcome. Results: None of the CpG sites in both the never and the current smokers were genome-wide significantly associated with COPD. CpG site cg14972228 annotated to SIPAL3 was most significant (p=5.66×10-6) in the never smokers, while CpG site cg08282037 annotated to EPS8L1 was most significant (p=1.45×10-5) in the current smokers. Conclusion: In contrast to a previous, smaller study, we did not observe any significant association between DNA methylation levels and the presence of COPD, independent of smoking status. Apparently, DNA methylation studies are highly variable

Risk of regional recurrence in triple-negative breast cancer patients: a Dutch cohort study

Triple-negative breast cancer is associated with early recurrence and low survival rates. Several trials investigate the safety of a more conservative approach of axillary treatment in clinically T1-2N0 breast cancer. Triple-negative breast cancer comprises only 15 % of newly diagnosed breast cancers, which might result in insufficient power for representative results for this subgroup. We aimed to provide a nationwide overview on the occurrence of (regional) recurrences in triple-negative breast cancer patients with a clinically T1-2N0 status. For this cohort study, 2548 women diagnosed between 2005 and 2008 with clinically T1-2N0 triple-negative breast cancer were selected from the Netherlands Cancer Registry. Follow-up data until 2014 were analyzed using Kaplan–Meier. Sentinel lymph node biopsy was performed in 2486 patients, and (completion) axillary lymph node dissection in 562 patients. Final pathologic nodal status was pN0 in 78.5 %, pN1mi in 4.5 %, pN1 in 12.3 %, pN2–3 in 3.6 %, and pNx in 1.1 %. During a follow-up of 5 years, regional recurrence occurred in 2.9 %, local recurrence in 4.2 % and distant recurrence in 12.2 %. Five-year disease-free survival was 78.7 %, distant disease-free survival 80.5 %, and 5-year overall survival 82.3 %. Triple-negative clinically T1-2N0 breast cancer patients rarely develop a regional recurrence. Their disease-free survival is more threatened by distant recurrence, affecting their overall survival. Consequently, it seems justified to include triple-negative breast cancer patients in randomized controlled trials investigating the safety of minimizing axillary staging and treatment

Does the 48-hour BH4 loading test miss responsive PKU patients?

Contains fulltext : 217632.pdf (Publisher’s version ) (Open Access

Innate responses induced by whole inactivated virus or subunit influenza vaccines in cultured dendritic cells correlate with immune responses in vivo

Vaccine development involves time-consuming and expensive evaluation of candidate vaccines in animal models. As mediators of both innate and adaptive immune responses dendritic cells (DCs) are considered to be highly important for vaccine performance. Here we evaluated how far the response of DCs to a vaccine in vitro is in line with the immune response the vaccine evokes in vivo. To this end, we investigated the response of murine bone marrow-derived DCs to whole inactivated virus (WIV) and subunit (SU) influenza vaccine preparations. These vaccine preparations were chosen because they differ in the immune response they evoke in mice with WIV being superior to SU vaccine through induction of higher virus-neutralizing antibody titers and a more favorable Th1-skewed response phenotype. Stimulation of DCs with WIV, but not SU vaccine, resulted in a cytokine response that was comparable to that of DCs stimulated with live virus. Similarly, the gene expression profiles of DCs treated with WIV or live virus were similar and differed from that of SU vaccine-treated DCs. More specifically, exposure of DCs to WIV resulted in differential expression of genes in known antiviral pathways, whereas SU vaccine did not. The stronger antiviral and more Th1-related response of DCs to WIV as compared to SU vaccine correlates well with the superior immune response found in mice. These results indicate that in vitro stimulation of DCs with novel vaccine candidates combined with the assessment of multiple parameters, including gene signatures, may be a valuable tool for the selection of vaccine candidates

Classical galactosemia: neuropsychological and psychosocial functioning beyond intellectual abilities

BACKGROUND: Despite early diagnosis and treatment, Classical Galactosemia (CG) patients frequently develop long-term complications, such as cognitive impairment. Available literature primarily reports on general intellectual abilities and shows a substantially lower Full Scale Intelligence Quotient (FSIQ) in CG patients than in the general population. Both problems in social functioning as well as internalizing problems are often reported in CG patients. The combination of intelligence, cognitive functioning, beh

Early motor outcomes in infants with critical congenital heart disease are related to neonatal brain development and brain injury

Aim To assess the relationship between neonatal brain development and injury with early motor outcomes in infants with critical congenital heart disease (CCHD). Method Neonatal brain magnetic resonance imaging was performed after open-heart surgery with cardiopulmonary bypass. Cortical grey matter (CGM), unmyelinated white matter, and cerebellar volumes, as well as white matter motor tract fractional anisotropy and mean diffusivity were assessed. White matter injury (WMI) and arterial ischaemic stroke (AIS) with corticospinal tract (CST) involvement were scored. Associations with motor outcomes at 3, 9, and 18 months were corrected for repeated cardiac surgery. Results Fifty-one infants (31 males, 20 females) were included prospectively. Median age at neonatal surgery and postoperative brain magnetic resonance imaging was 7 days (interquartile range [IQR] 5-11d) and 15 days (IQR 12-21d) respectively. Smaller CGM and cerebellar volumes were associated with lower fine motor scores at 9 months (CGM regression coefficient=0.51, 95% confidence interval [CI]=0.15-0.86; cerebellum regression coefficient=3.08, 95% CI=1.07-5.09) and 18 months (cerebellum regression coefficient=2.08, 95% CI=0.47-5.12). The fractional anisotropy and mean diffusivity of white matter motor tracts were not related with motor scores. WMI was related to lower gross motor scores at 9 months (mean difference -0.8SD, 95% CI=-1.5 to -0.2). AIS with CST involvement increased the risk of gross motor problems and muscle tone abnormalities. Cerebral palsy (n=3) was preceded by severe ischaemic brain injury. Interpretation Neonatal brain development and injury are associated with fewer favourable early motor outcomes in infants with CCHD

Social-cognitive functioning and social skills in patients with early treated phenylketonuria:a PKU-COBESO study

OBJECTIVE: Early treatment of phenylketonuria (ET-PKU) prevents mental retardation, but many patients still show cognitive and mood problems. In this study, it was investigated whether ET-PKU-patients have specific phenylalanine (Phe-)related problems with respect to social-cognitive functioning and social skills. METHODS: Ninety five PKU-patients (mean age 21.6 ± 10.2 years) and 95 healthy controls (mean age 19.6 ± 8.7 years) were compared on performance of computerized and paper-and-pencil tasks measuring social-cognitive abilities and on parent- and self-reported social skills, using multivariate analyses of variance, and controlling for general cognitive ability (IQ-estimate). Further comparisons were made between patients using tetrahydrobiopterin (BH4, N = 30) and patients not using BH4. Associations with Phe-levels on the day of testing, during childhood, during adolescence and throughout life were examined. RESULTS: PKU-patients showed poorer social-cognitive functioning and reportedly had poorer social skills than controls (regardless of general cognitive abilities). Quality of social-cognitive functioning was negatively related to recent Phe-levels and Phe-levels between 8 and 12 years for adolescents with PKU. Quality of social skills was negatively related to lifetime phenylalanine levels in adult patients, and specifically to Phe-levels between 0 and 7, and between 8 and 12 years. There were no differences with respect to social outcome measures between the BH4 and non-BH4 groups. CONCLUSION: PKU-patients have Phe-related difficulties with social-cognitive functioning and social skills. Problems seem to be more evident among adolescents and adults with PKU. High Phe-levels during childhood and early adolescence seem to be of greater influence than current and recent Phe-levels for these patients

Rituximab in early systemic sclerosis

Objectives (1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc). Methods A small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated. Results In total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SS