What does "Advanced" mean in 2023? reflecting on 10 years of the ESTRO advanced Skills in modern radiotherapy course.

The roles and responsibilities of radiation therapists (RTTs) are many and varied. Professional expectations are influenced by the technology available, as well as the level of autonomy RTTs have in their daily practice. This professional range requires RTTs to possess a unique set of ever evolving skills, posing challenges from an educational perspective. Teaching these "advanced skills" has been the ambition the ESTRO Advanced Skills in Modern Radiotherapy course. In the 10th year of this course, the Faculty look back and reflect on how our programme has evolved and what it has achieved.

[General practitioners' recognition and management of child abuse: what is going well and what could be improved?] / Kindermishandeling herkennen en aanpakken.

In the Netherlands, child abuse affects about 100.000 children resulting in at least 17 child fatalities a year. General practitioners' (GPs) health care position is of vital importance for recognising and managing child abuse. In this Clinical Lesson, using three illustrating cases, we discuss how GPs' suspicion of child abuse may arise including the role of gut feelings, and what the mandatory national guideline on child abuse means for the follow-up. We also clarify the role of the Dutch Child Abuse Counselling and Reporting Centre (CACRC) in the process. A first lesson is that any doubts about child abuse should lead to action because diagnostic failure has serious consequences for vulnerable children. A second lesson is that asking CACRC for anonymous advice how to deal with a situation may certainly have added value. Finally, we advise CACRC to invest in building a relationship of trust with the collaborating partners.

Delayed diagnosis of fetal and neonatal alloimmune thrombocytopenia: a cause of perinatal mortality and morbidity.

OBJECTIVE: To evaluate the rate and consequences of a late or missed diagnosis of fetal and neonatal alloimmune thrombocytopenia (FNAIT). DESIGN: Retrospective analysis of prospectively collected data of a national cohort. SETTING: National referral centre for fetal therapy in the Netherlands. POPULATION: Twenty-six women with pregnancies complicated by FNAIT and at least one previous pregnancy with a thrombocytopenic child. METHODS: Retrospective analysis of data from our electronic FNAIT database. In a consecutive cohort managed between July 2008 and July 2010, timing of first diagnosis of FNAIT was correlated to severity and outcome in the subsequent pregnancies. MAIN OUTCOME MEASURES: Occurrence of delayed diagnosis of FNAIT, and possibly associated intracranial haemorrhage (ICH). RESULTS: In four of 26 pregnancies, timely diagnostic testing for FNAIT was not performed despite fetal or neonatal thrombocytopenia or ICH. Down syndrome, dysmaturity and birth trauma were perceived to be the cause of the thrombocytopenia/ICH. In two of these four subsequent, untreated pregnancies, severe fetal ICH occurred. The other 22 women were treated for FNAIT using intravenous immunoglobulin, all children are alive and well. CONCLUSIONS: All neonates with thrombocytopenia at birth should be evaluated for FNAIT. Missing this diagnosis can have severe consequences for subsequent pregnancies.

Transmission of methicillin-resistant Staphylococcus pseudintermedius between infected dogs and cats and contact pets, humans and the environment in households and veterinary clinics.

The objective of this study was to investigate the prevalence of methicillin-resistant Staphylococcus pseudintermedius (MRSP) in people, pets and the environment in households with a pet with a clinical MRSP-infection within the past year. Personnel and the environment at veterinary clinics were also screened. Nasal swabs (humans), nasal and perineal swabs (pets) and environmental wipes were examined using selective culturing. Twenty households were enrolled; 10/20 index cases still had clinical signs of infection at the start of the study and all were MRSP-positive. Of the remaining 10 index cases five were MRSP-positive in nasal and/or perineal samples. Five of 14 (36%) contact dogs and four of 13 (31%) contact cats were found MRSP-positive. In the households with an index case with clinical signs of infection 6/7 (86%) contact animals were MRSP-positive. MRSP was cultured from 2/45 (4%) human nasal samples. Domestic contamination was widespread as positive samples were found in 70% of the households and 44% of all environmental samples were MRSP-positive. In all but one of these MRSP-positive households the index case was still MRSP positive. Among the personnel in veterinary clinics 4/141 (3%) were MRSP-positive. MRSP was cultured from 31/200 environmental samples in 7/13 clinics at the first sampling and in 3/6 clinics the environment remained MRSP-positive after cleaning and disinfection indicating that current cleaning procedures often were unable to eliminate MRSP. These results show that transmission of MRSP between infected or colonized dogs and cats and healthy people does occur but is relatively uncommon, while transmission to contact pets occurs frequently, especially when the index case still has clinical signs of MRSP-infection.

Screening in pregnancy for fetal or neonatal alloimmune thrombocytopenia: systematic review.

BACKGROUND: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a potentially devastating disease, which may lead to intracranial haemorrhage (ICH), with neurological damage as a consequence. In the absence of screening, FNAIT is only diagnosed after bleeding symptoms, with preventive options limited to a next pregnancy. OBJECTIVES: To estimate the population incidence of FNAIT and its consequences to prepare for study design of a screening programme. SEARCH STRATEGY: An electronic literature search using MEDLINE, EMBASE and Cochrane database, and references of retrieved articles. No language restrictions were applied. SELECTION CRITERIA: Prospective studies on screening for human platelet antigen 1a (HPA-1a) alloimmunisation in low-risk pregnant women. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for inclusion and extracted data. Main outcome data were prevalence of HPA-1a negativity, HPA-1a immunisation, platelet count at birth and perinatal ICH. We aimed to compare outcome with and without intervention. MAIN RESULTS: HPA-1a alloimmunisation occurred in 294/3028 (9.7%) pregnancies at risk. Severe FNAIT occurred in 71/227 (31%) immunised pregnancies, with perinatal ICH in 7/71 (10%). True natural history data were not found because interventions were performed in most screen-positive women. AUTHORS' CONCLUSIONS: Screening for HPA-1a alloimmunisation detects about two cases in 1000 pregnancies. The calculated risk for perinatal ICH of 10% in pregnancies with severe FNAIT is an underestimation because studies without interventions were lacking. Screening of all pregnancies together with effective antenatal treatment such as intravenous immunoglobulin may reduce the mortality and morbidity associated with FNAIT.

Effective seeding of smooth muscle cells into tubular poly(trimethylene carbonate) scaffolds for vascular tissue engineering.

Porous tubular poly(trimethylene carbonate) (PTMC) scaffolds for vascular tissue engineering, with an inner diameter of 3 mm and a wall thickness of 1 mm, were prepared by means of dip-coating and subsequent leaching of NaCl particles. The scaffolds, with an average pore size of 110 µm and a porosity of 85%, showed a smooth muscle cell (SMC) seeding efficiency of only 10%. To increase the efficiency of cell seeding, these scaffolds were coated with a microporous PTMC outer layer with a thickness of 0.1-0.4 mm, an average pore size of 28 µm, and a porosity of 65%. Coating of the scaffolds with the microporous outer layer did not influence the inner pore structure or the mechanical properties of the scaffolds to a significant extent. The intrinsic permeability of the scaffolds decreased from 60 × 10(-10) m(2) to approximately 5 × 10(-10) m(2) after coating with the microporous outer layer. The latter value is still relatively high indicating that these scaffolds may facilitate sufficient diffusion of nutrients and waste products during cell culturing. The efficiency of SMC seeding determined after 24 h cell adhesion in the scaffolds increased from less than 10% to 43% after coating with the microporous outer layer. The cells were homogeneously distributed in the scaffolds and cell numbers increased 60% during culturing for 7 days under stationary conditions. It is concluded that coating of porous tubular PTMC scaffolds with a microporous PTMC outer layer facilitates effective cell seeding in these scaffolds.

Flexible and elastic porous poly(trimethylene carbonate) structures for use in vascular tissue engineering.

Biocompatible and elastic porous tubular structures based on poly(1,3-trimethylene carbonate), PTMC, were developed as scaffolds for tissue engineering of small-diameter blood vessels. High-molecular-weight PTMC (M(n) = 4.37 x 10(5)) was cross-linked by gamma-irradiation in an inert nitrogen atmosphere. The resulting networks (50-70% gel content) were elastic and creep resistant. The PTMC materials were highly biocompatible as determined by cell adhesion and proliferation studies using various relevant cell types (human umbilical vein endothelial cells (HUVECs), smooth muscle cells (SMCs) and mesenchymal stem cells (MSCs)). Dimensionally stable tubular scaffolds with an interconnected pore network were prepared by particulate leaching. Different cross-linked porous PTMC specimens with average pore sizes ranging between 55 and 116 microm, and porosities ranging from 59% to 83% were prepared. These scaffolds were highly compliant and flexible, with high elongations at break. Furthermore, their resistance to creep was excellent and under cyclic loading conditions (20 deformation cycles to 30% elongation) no permanent deformation occurred. Seeding of SMCs into the wall of the tubular structures was done by carefully perfusing cell suspensions with syringes from the lumen through the wall. The cells were then cultured for 7 days. Upon proliferation of the SMCs, the formed blood vessel constructs had excellent mechanical properties. Their radial tensile strengths had increased from 0.23 to 0.78 MPa, which is close to those of natural blood vessels.

Lowering caveolin-1 expression in human vascular endothelial cells inhibits signal transduction in response to shear stress.

Vascular endothelial cells have an extensive response to physiological levels of shear stress. There is evidence that the protein caveolin-1 is involved in the early phase of this response. In this study, caveolin-1 was downregulated in human endothelial cells by RNAi. When these cells were subjected to a shear stress of 15 dyn/cm(2) for 10 minutes, activation of Akt and ERK1/2 was significantly lower than in control cells. Moreover, activation of Akt and ERK1/2 in response to vascular endothelial growth factor was significantly lower in cells with low levels of caveolin-1. However, activation of integrin-mediated signaling during cell adhesion onto fibronectin was not hampered by lowered caveolin-1 levels. In conclusion, caveolin-1 is an essential component in the response of endothelial cells to shear stress. Furthermore, the results suggest that the role of caveolin-1 in this process lies in facilitating efficient VEGFR2-mediated signaling.

Dietary intake of B(6-9-12) vitamins, serum homocysteine levels and their association with depressive symptoms: the Zutphen Elderly Study.

OBJECTIVE: Low B-vitamin status and high levels of serum homocysteine are found in depressed inpatients, but results of population-based studies of this association are inconclusive. We investigated whether a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are associated with depressive symptoms in elderly men. METHODS: The study sample included a total of 332 men aged 70-90 years who were free from cardiovascular diseases and diabetes at baseline in 1990. Depressive symptoms were measured with the Zung Self-rating Depression Scale at baseline in 1990 and dietary factors with the crosscheck dietary history method in 1985 and 1990. Serum levels of homocysteine were obtained in 1985. Multiple linear and logistic regression analyses were performed. RESULTS: Dietary intake of folate (-1.19, 95% CI -2.03; -0.36) and vitamin B(6) (-2.09, 95% CI -2.92; -1.26) per standard deviation increase was associated with lower levels of serum homocysteine, while vitamin B(12) was not associated with serum homocysteine. Intake of folate, vitamin B(6), vitamin B(12) and levels of serum homocysteine were not related to depressive symptoms. CONCLUSIONS: Our results do not support the hypothesis that a low dietary intake of B(6-9-12) vitamins and high levels of serum homocysteine are related to depression in healthy elderly men.

Secondary infertility as a late complication of vesico-amniotic shunt therapy.

OBJECTIVE: Vesico-amniotic shunting can be used for the treatment of fetal obstructive uropathy. However, the procedure is associated with a significant risk of complications. We report a case of a complicated vesico-amniotic placement, where a vesico-amniotic shunt ultimately resulted in, fortunately reversible, infertility. CASE: A 36-year-old multigravida was referred to our center at 13 weeks' gestation for the evaluation of fetal lower urinary obstruction. A vesico-amniotic shunt placement requiring several attempts was performed. A few weeks later premature rupture of the membranes occurred. At the request of the parents, the pregnancy was terminated at 22 weeks'gestation. The patient visited us again for secondary infertility, which turned out to be caused by a shunt left behind in the uterus, acting as an IUD. After hysteroscopic removal, she soon became pregnant again. CONCLUSION: This case illustrates the importance of careful documentation relating to each and every operation, of all materials used and what was retained in the patient. At delivery, obstetric staff should be completely aware of the prenatal treatment procedures performed, to ensure that no foreign objects are left by oversight, inside the patient's body.

[The Dutch Child Health Care guideline 'early detection of congenital heart disease in the age group 0-19 years']. / De standaard 'Vroegtijdige opsporing van aangeboren hartafwijkingen 0-19 jaar' van de jeugdgezondheidszorg.

The Dutch Child Health Care guideline on the early detection of congenital heart disease was developed according to the principles for evidence-based guideline development and contains recommendations for the conduct of the examination during routine check-ups and for referral criteria. Most congenital heart diseases can be detected in the first year of life if physicians and nurses work according to this guideline. Important early times for screening are the home visit to infants at the age of two weeks by the child health nurse and the routine check-up of infants at the age of four weeks by the child health care physician. A routine cardiac screening is carried out in every child by the nurse and the physician at times specified in the basic list of professional responsibilities. A more extensive examination is carried out when indicated. Routine cardiac check-ups are recommended until the age of four, after which they should be done only when indicated on medical grounds. A feasibility study showed that physicians and nurses can apply the guideline effectively, provided that they take part in prior specific training.

Workload and stress in horses: comparison in horses ridden deep and round ('rollkur') with a draw rein and horses ridden in a natural frame with only light rein contact.

'Rollkur' or 'overbending' is the low and deep riding of a dressage horse during training or warming up. Lately, this technique has been criticized, and not necessarily objectively, on welfare grounds. To be able to evaluate these criticisms, more needs to be known about the workload and stress of horses being ridden 'rollkur'. The aim of the present study was to compare the workload of eight riding-school horses when being ridden deep and round with a draw rein ('rollkur') and when being ridden in a natural frame with only light rein contact ('free'). Workload (as measured by heart rate and blood lactate concentration) was slightly higher when horses were ridden 'rollkur' than when they were ridden 'free'. There were no differences in packed cell volume, or glucose and cortisol concentrations. No signs of uneasiness or stress could be determined when the horses were ridden 'rollkur'. Subjectively, all horses improved their way of moving during 'rollkur' and were more responsive to their rider.

A novel time resolved fluorometric assay of anoikis using Europium-labelled Annexin V in cultured adherent cells.

BACKGROUND: Adherent cells undergo apoptosis when detached from their home ground, a process called anoikis (homelessness). METHODS: We developed a new and sensitive method to analyse apoptosis and anoikis of adherent cell types using a time resolved fluorometric assay with Europium-labelled Annexin V. Anoikis was induced with tumor necrosis factor-alpha/cycloheximide and three cell fractions of the cell cultures were prepared and analysed. Fraction 1 consisted of adherent cells, analysed while growing on their support (without detachment by trypsinisation). Fraction 2 contained detached cells due to anoikis (floating cells) and fraction 3 contained apoptotic bodies. Both fractions 2 and 3 were present in the culture medium and were isolated by differential centrifugation. RESULTS: TNF-alpha treatment of three different types of adherent cell cultures induced a significant increase of the amount of floating cells (anoikis) and apoptotic bodies compared to control cell cultures. Also in the adherent cell fractions a small amount of apoptosis was observed. CONCLUSIONS: The novel time resolved assay provides the ability to analyse the cell death cascade in adherent cell cultures of the same sample at the same time in a sensitive and reproducible way.

A cardiac-specific health-related quality of life module for young adults with congenital heart disease: development and validation.

This study represents the development and validation of a cardiac-specific module of the generic health-related quality of life (HRQoL) instrument, the TAAQOL (TNO/AZL Adult Quality Of Life), for young adults with congenital heart disease (CHD). Items were selected based on literature, an explorative previous study in CHD patients, interviews with patients, and the advice of experts. The newly developed Congenital Heart Disease-TNO/AZL Adult Quality of Life (CHD-TAAQOL) was tested in 156 patients with mild or complex CHD and consisted of three hypothesised subject scales: 'Symptoms' (9 items), 'Impact Cardiac Surveillance' (7 items), and 'Worries' (10 items). Cronbach's alpha for the three scales were 0.77, 0.78, and 0.82, respectively. Scale structure was confirmed by Principal Component Analysis, corrected item-scale and interscale correlations. Overall, 55% of reported health status problems were associated with negative emotions, which is an argument for assessing HRQoL as a concept distinct from health status. Convergent validity with validated generic instruments (TAAQOL and Short Form-36, SF-36) showed satisfactory coefficients. Discriminant validity was proven by significantly higher scores for mild CHD patients compared with those with complex CHD. In conclusion, the CHD-TAAQOL module together with the generic TAAQOL can be used to assess group differences for cardiac-specific HRQoL in young adults with CHD. Testing psychometric properties of the CHD-TAAQOL shows satisfactory results. However, to detect changes in HRQoL over time, further research is needed.

Effect of conjugated linoleic acid supplementation after weight loss on appetite and food intake in overweight subjects.

OBJECTIVE: To study the effects of 13 weeks conjugated linoleic acid (CLA) supplementation in overweight subjects on body-weight maintenance, parameters of appetite and energy intake (EI) at breakfast after weight loss. DESIGN: This study had a double-blind, placebo-controlled randomized design. SUBJECTS: A total of 26 men and 28 women (age 37.8+/-7.7 y; body mass index 27.8+/-1.5 kg/m(2)). INTERVENTIONS: Subjects were first submitted to a very-low-calorie diet (VLCD; 2.1 MJ/day) for 3 weeks after which they started with the 13-week intervention period. They either received 1.8 g CLA or placebo per day or 3.6 g CLA or placebo per day. Additionally, subjects of the high dosage intervention replaced their habitual lunch by one meal of a protein-rich, low-energy supplement. EI was measured at breakfast and appetite profile after an overnight fast. RESULTS: The mean body weight loss was 6.9+/-1.7% of their original body weight. Multiple regression analysis showed that at the end of the 13-week intervention, CLA did not have an effect on body weight regain. Feelings of fullness and satiety were increased and feelings of hunger were decreased after 13 weeks intervention by CLA compared to placebo, independent of %body weight regain. However, EI measured at breakfast was not affected by CLA. CONCLUSION: Appetite (hunger, satiety and fullness) was favorably, dose-independently affected by a 13-week consumption of 1.8 or 3.6 g CLA/day. This did not result in a lower EI at breakfast or an improved body-weight maintenance after weight loss.

The effect of conjugated linoleic acid supplementation after weight loss on body weight regain, body composition, and resting metabolic rate in overweight subjects.

OBJECTIVE: To study the effects of 13 weeks conjugated linoleic acid (CLA) supplementation in overweight subjects after weight loss on weight regain, body composition, resting metabolic rate, substrate oxidation, and blood plasma parameters. DESIGN: This study had a double-blind, placebo-controlled randomized design. Subjects were first submitted to a very-low-calorie diet (VLCD 2.1 MJ/d) for 3 weeks after which they started with the 13-week intervention period. They either received 1.8 g CLA or placebo per day (low dosage, LD) or 3.6 g CLA or placebo per day (high dosage, HD). SUBJECTS: A total of 26 men and 28 women (age 37.8+/-7.7 y; body mass index (BMI) 27.8+/-1.5 kg/m(2)). MEASUREMENTS: Before VLCD (t=-3), after VLCD but before CLA or placebo intervention (t=0) and after 13-week CLA or placebo intervention (t=13), body weight, body composition (hydrodensitometry and deuterium dilution), resting metabolic rate, substrate oxidation, physical activity, and blood plasma parameters (glucose, insulin, triacylglycerol, free fatty acids, glycerol and beta-hydroxy butyrate) were measured. RESULTS: The VLCD significantly lowered body weight (6.9+/-1.7%), %body fat, fat mass, fat-free mass, resting metabolic rate, respiratory quotient and plasma glucose, insulin, and triacylglycerol concentrations, while free fatty acids, glycerol and beta-hydroxy butyrate concentrations were increased. Multiple regression analysis showed that at the end of the 13-week intervention, CLA did not affect %body weight regain (CLA LD 47.9+/-88.2%, CLA HD 27.4+/-29.8%, Placebo LD 32.0+/-42.8%, Placebo HD 22.5+/-37.9%). The regain of fat-free mass was increased by CLA (LD 6.2+/-3.9, HD 4.6+/-2.4%) compared to placebo (LD 2.8+/-3.2%, HD 3.4+/-3.6%), independent of %body weight regain and physical activity. As a consequence of an increased regain of fat-free mass by CLA, resting metabolic rate was increased by CLA (LD 12.0+/-11.4%, HD 13.7+/-14.4%) compared to placebo (LD 9.1+/-11.0%, HD 8.6+/-8.5%). Substrate oxidation and blood plasma parameters were not affected by CLA. CONCLUSION: In conclusion, the regain of fat-free mass was favorably, dose-independently affected by a 13-week consumption of 1.8 or 3.6 g CLA/day and consequently increased the resting metabolic rate. However, it did not result in improved body weight maintenance after weight loss.

Chemosensitization of myeloma plasma cells by an antisense-mediated downregulation of Bcl-2 protein.

An antisense oligodeoxynucleotide (ODN) complementary to the first six codons of the Bcl-2 mRNA, G3139 (oblimersen sodium; Genasense), has been shown to downregulate Bcl-2 and produce responses in a variety of malignancies including drug-resistant lymphoma. Incubation of ex vivo purified plasma cells from patients with multiple myeloma (MM) with carboxyfluorescein (FAM)-labeled antisense ODNs resulted in a time- and dose-dependent uptake in the cytoplasm and nucleus. No major differences in uptake of Bcl-2 antisense ODNs were observed among patients' samples. Incubation of purified myeloma plasma cells with G3139, but not solvent or reverse polarity control ODNs, resulted in a reduction (>75%) of Bcl-2 mRNA levels after 2 and 4 days, as measured by Real-Time PCR. Treatment with G3139 led to a sequence-specific reduction of Bcl-2 protein levels within 4 days of exposure in 10 out of 11 clinical samples from patients with chemosensitive and multidrug-resistant disease, without significant reduction of alpha-Actin, Bax, Bcl-XL, or Mcl-1 proteins. This resulted in a significantly enhanced sensitivity of the myeloma tumor cells to dexamethasone or doxorubicin-induced apoptosis. G3139 can consistently enter myeloma cells, downregulate the expression of Bcl-2, and enhance the efficacy of myeloma therapy. These data support further clinical evaluation of G3139 therapy in multiple myeloma.

The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells.

Lovastatin is an irreversible inhibitor of HMG-CoA reductase and blocks the production of mevalonate, a critical compound in the production of cholesterol and isoprenoids. Isoprenylation of target proteins, like the GTP-binding protein Ras, is essential for their membrane localization and subsequent participation in intracellular signaling cascades. Lovastatin effectively decreased the viability of plasma cells from cell lines (n = 10) and myeloma patients' samples (n = 8) in a dose- and time-dependent way. Importantly, co-incubation of lovastatin with dexamethasone had a synergistic effect in inducing plasma cell cytotoxity. This effect was not the consequence of a change in the protein expression levels of Bcl-2 or Bax induced by lovastatin. The decrease in plasma cell viability was the result of induction of apoptosis and inhibition of proliferation. Mevalonate effectively reversed the cytotoxic and cytostatic effects of lovastatin in plasma cells. The cytotoxic activity of lovastatin was higher in Pgp expressing cell lines, but did not correlate with the multidrug resistance (MDR)-related proteins LRP, Bcl-2 and Bax. Lovastatin treatment resulted in a shift of Ras localization from the membrane to the cytosol that was reversed by mevalonate. The data presented in this paper warrant study of lovastatin alone or in combination with therapeutic drugs, in the treatment of myeloma patients.