To assess and compare the secular trend in age at menarche in Dutch girls (1955–2009) and girls from Turkish and Moroccan descent living in the Netherlands (1997–2009).
Data on growth and maturation were collected in 20,867 children of Dutch, Turkish and Moroccan descent in 2009 by trained health care professionals. Girls, 9 years and older, of Dutch (n = 2138), Turkish (n = 282), and Moroccan (n = 295) descent were asked whether they had experienced their first period. We compared median menarcheal age in 2009 with data from the previous Dutch Nationwide Growth Studies in 1955, 1965, 1980 and 1997. Age specific body mass index (BMI) z-scores were calculated to assess differences in BMI between pre- and postmenarcheal girls in different age groups.
Median age at menarche in Dutch girls, decreased significantly from 13.66 years in 1955 to 13.15 years in 1997 and 13.05 years in 2009. Compared to Dutch girls there is a larger decrease in median age of menarche in girls of Turkish and Moroccan descent between 1997 and 2009. In Turkish girls age at menarche decreased from 12.80 to 12.50 years and in Moroccan girls from 12.90 to 12.60 years. Thirty-three percent of Turkish girls younger than 12 years start menstruating in primary school. BMI-SDS is significantly higher in postmenarcheal girls than in premenarcheal girls irrespective of age.
There is a continuing secular trend in earlier age at menarche in Dutch girls. An even faster decrease in age at menarche is observed in girls of Turkish and Moroccan descent in the Netherlands.
We present an HOCM patient in whom marked regression of left ventricular hypertrophy occurred within two years following outflow desobliteration by percutaneous septal ablation. Maximum wall thickness (initially documented by both echo and MRI) decreased from 34 mm to 22 mm (followup by echo only due to presence of the ICD), crossing the threshold value of 30 mm which was one of the risk markers that had triggered the primary prophylactic ICD implantation in this case prior to septal ablation.
There is strong evidence that both adoptive T cell transfer and T cell checkpoint blockade can lead to regression of human melanoma. However, little data are available on the effect of these cancer therapies on the tumor-reactive T cell compartment. To address this issue we have profiled therapy-induced T cell reactivity against a panel of 145 melanoma-associated CD8+ T cell epitopes. Using this approach, we demonstrate that individual tumor-infiltrating lymphocyte cell products from melanoma patients contain unique patterns of reactivity against shared melanoma-associated antigens, and that the combined magnitude of these responses is surprisingly low. Importantly, TIL therapy increases the breadth of the tumor-reactive T cell compartment in vivo, and T cell reactivity observed post-therapy can almost in full be explained by the reactivity observed within the matched cell product. These results establish the value of high-throughput monitoring for the analysis of immuno-active therapeutics and suggest that the clinical efficacy of TIL therapy can be enhanced by the preparation of more defined tumor-reactive T cell products.
T-cell reactivity; TIL therapy; high throughput screening; pMHC multiplexing; tumor immunology
Occasionally patients undergoing resection for presumed malignancy of the pancreatic head are diagnosed postoperatively with benign disease. Autoimmune pancreatitis (AIP) is a rare disease that mimics pancreatic cancer. We aimed to determine the prevalence of benign disease and AIP in patients who underwent pancreatoduodenectomy (PD) over a 9-year period, and to explore if and how surgery could have been avoided.
All patients undergoing PD between 2000 and 2009 in a tertiary referral centre were analyzed retrospectively. In cancer-negative cases, postoperative diagnosis was reassessed. Preoperative index of suspicion of malignancy was scored as non-specific, suggestive, or high. In AIP patients, diagnostic criteria systems were checked.
A total of 274 PDs were performed for presumed malignancy. The prevalence of benign disease was 8.4 %, overall prevalence of AIP was 2.6 %. Based on preoperative index of suspicion of malignancy, surgery could have been avoided in 3 non-AIP patients. All AIP patients had sufficient index to justify surgery. If diagnostic criteria would have been checked; however, surgery could have been avoided in one to five AIP patients.
The prevalence of benign disease in patients who underwent PD for presumed malignancy was 8.4 %, nearly one-third attributable to AIP. Although misdiagnosis of AIP as carcinoma is a problem of limited quantitative importance, every effort to establish the correct diagnosis should be undertaken considering the major therapeutic consequences. IgG4 measurement and systematic use of diagnostic criteria systems are recommended for every candidate patient for PD when there is no histological proof of malignancy.
Electronic supplementary material
The online version of this article (doi:10.1007/s10620-012-2191-7) contains supplementary material, which is available to authorized users.
Autoimmune pancreatitis; Autoimmune cholangitis; IgG4; Pancreatoduodenectomy; IgG4 related systemic disease
We report four patients with pneumothorax as a complication of ERCP with sphincterotomy. With conservative treatment all patients recovered. Previously, 16 comparable cases have been reported in the literature. The main risk factor for this rare complication seems (pre-cut) sphincterotomy. Pneumothorax is usually right-sided or bilateral and accompanied by pneumomediastinum, pneumoretroperitoneum and subcutaneous emphysema. The prognosis seems favourable with a non-surgical approach including intravenous antibiotics, fasting and when indicated chest tube drainage.
ERCP; Sphincterotomy; Pneumothorax; Complication
Quantitative coronary and vascular angiography (QCA resp., QVA) remains the current gold standard for evaluation of restenosis. Late loss as one of the most commonly accepted parameters to highlight efficacy of the various devices has shown high correlation to clinical parameters but, surprisingly, has no impact on the evaluation of the remaining amount of restenostic tissue. The current clinical practice leads to unrealistic late loss calculations. Smaller late loss differences are usually not greater than the inherited resolution limits of QCA, which is especially the case in small differences between the various stents in the drug-eluting stent era. Late loss include additional systematic and random errors, due to the fact that measurements were taken at two different time points including the inherited resolution and calibration limits of QCA on two occasions. Due to the limited value of late loss in discriminating the small differences between the one and other DES, late lumen area loss and clearly defined calculation algorithms (e.g., MLD-relocation) should be used in future DES studies also to fulfill the more stringent regulatory requirements.
In the treatment of homozygous and therapy-resistant hypercholesterolemia, lipid apheresis enables not only low density lipoprotein (LDL) cholesterol to be lowered by approximately 60%, but also oxidative stress factors to be influenced and adhesion molecules reduced. This was investigated in a group of 12 patients using the heparin-induced extracorporeal LDL precipitation (H.E.L.P.) procedure.
A significant lowering of LDL cholesterol and fibrinogen leads to an improvement in rheology and endothelial function, detectable and measurable within approximately 20 h by assessing minimum coronary resistance using positron emission tomography (PET) performed in 35 patients. This effect is detectable even after the first lipid apheresis session (H.E.L.P. procedure), documented in 12 patients.
Lipid apheresis appears to be the most effective procedure in the treatment of elevated lipoprotein(a) [Lp(a)]. A chosen group of nine patients with selective elevated Lp(a) illustrated both the influence on endothelial dysfunction, in the shape of sharply increased minimum coronary resistance, and the reduction through lipid apheresis, indicating that Lp(a) seems to exert a similar effect on the vascular wall and vascular function as LDL cholesterol.
Lipid apheresis; Hypercholesterolemia; Lipoprotein(a)
To provide cross-sectional height and head circumference (HC) references for healthy Dutch children with Down syndrome (DS), while considering the influence of concomitant disorders on their growth, and to compare growth between children with DS and children from the general population.
Longitudinal growth and medical data were retrospectively collected from medical records in 25 of the 30 regional hospital-based outpatient clinics for children with DS in the Netherlands. Children with Trisomy 21 karyotype of Dutch descent born after 1982 were included. The LMS method was applied to fit growth references.
We enrolled 1,596 children, and collected 10,558 measurements for height and 1,778 for HC. Children with DS without concomitant disorders (otherwise healthy children) and those suffering only from mild congenital heart defects showed similar growth patterns. The established growth charts, based on all measurements of these two groups, demonstrate the three age periods when height differences between children with and without DS increase: during pregnancy, during the first three years of life, and during puberty. This growth pattern results in a mean final height of 163.4 cm in boys and 151.8 cm in girls (−2.9 standard deviation (SD) and −3.0 SD on general Dutch charts, respectively). Mean HC (0 to 15 months) was 2 SD less than in the general Dutch population. The charts are available at www.tno.nl/growth.
Height and HC references showed that growth retardation in otherwise healthy children with DS meanly occurs in three critical periods of growth, resulting in shorter final stature and smaller HC than the general Dutch population shows. With these references, health care professionals can optimize their preventive care: monitoring growth of individual children with DS optimal, so that growth retarding comorbidities can be identified early, and focusing on the critical age periods to establish ways to optimize growth.
To assess the prevalence of overweight and obesity among Dutch children and adolescents, to examine the 30-years trend, and to create new body mass index reference charts.
Nationwide cross-sectional data collection by trained health care professionals.
Participants: 10,129 children of Dutch origin aged 0–21 years.
Main Outcome Measures
Overweight (including obesity) and obesity prevalences for Dutch children, defined by the cut-off values on body mass index references according to the International Obesity Task Force.
In 2009, 12.8% of the Dutch boys and 14.8% of the Dutch girls aged 2–21 years were overweight and 1.8% of the boys and 2.2% of the girls were classified as obese. This is a two to three fold higher prevalence in overweight and four to six fold increase in obesity since 1980. Since 1997, a substantial rise took place, especially in obesity, which increased 1.4 times in girls and doubled in boys. There was no increase in mean BMI SDS in the major cities since 1997.
Overweight and obesity prevalences in 2009 were substantially higher than in 1980 and 1997. However, the overweight prevalence stabilized in the major cities. This might be an indication that the rising trend in overweight in the Netherlands is starting to turn.
Genetic manipulation of poxvirus genomes through attenuation, or insertion of therapeutic genes has led to a number of vector candidates for the treatment of a variety of human diseases. The development of recombinant poxviruses often involves the genomic insertion of a selectable marker for purification and selection purposes. The use of marker genes however inevitably results in a vector that contains unwanted genetic information of no therapeutic value.
Here we describe an improved strategy that allows for the creation of marker-free recombinant poxviruses of any species. The Selectable and Excisable Marker (SEM) system incorporates a unique fusion marker gene for the efficient selection of poxvirus recombinants and the Cre/loxP system to facilitate the subsequent removal of the marker. We have defined and characterized this new methodological tool by insertion of a foreign gene into vaccinia virus, with the subsequent removal of the selectable marker. We then analyzed the importance of loxP orientation during Cre recombination, and show that the SEM system can be used to introduce site-specific deletions or inversions into the viral genome. Finally, we demonstrate that the SEM strategy is amenable to other poxviruses, as demonstrated here with the creation of an ectromelia virus recombinant lacking the EVM002 gene.
The system described here thus provides a faster, simpler and more efficient means to create clinic-ready recombinant poxviruses for therapeutic gene therapy applications.
Breastfeeding (BF) is protective against overweight and is associated with dietary behaviour. The aims of our study were to assess the relationship between exclusive BF duration and BMI, waist circumference (WC) and waist-hip ratio (WHR) at adulthood, and to study whether dietary behaviour could explain the relationship between BF duration and the proxies of fat mass.
In 2004-2005, 822 subjects from the Terneuzen Birth Cohort (n = 2,604), aged 18-28 years, filled in postal questionnaires including sociodemographic factors and aspects of dietary behaviour (dietary pattern, and consumption of fruit and vegetables, snacks, sweetened beverages and alcohol); 737 subjects also underwent anthropometric measurements of weight, height, and waist and hip circumference. The relationship between exclusive BF duration and dietary outcomes was investigated by logistic regression analysis. The relationships of BF duration with the anthropometric measures were investigated by linear regression analyses. All results were corrected for age, gender and possible confounders. Finally, regression analyses were performed to investigate if diet factors had a mediating effect on the relationship between BF duration and fat mass.
A significant inverse dose-response relationship of BF duration was found for BMI (β-0.13, SE 0.06), WC (β-0.39, SE 0.18) and WHR (β-0.003, SE 0.001), after correction for age, gender and confounders. The odds ratio (OR) of exclusive BF duration in months for a breakfast frequency of at least 5 times a week was 1.16 (95%CI 1.06-1.27), and for snack consumption of less than twice a week was 1.15 (95%CI 1.06-1.25). Both ORs were corrected for age, gender and confounders. For other dietary outcomes, the results point in the same direction, i.e. a positive relationship with BF duration, but these were not statistically significant. A mediating effect of the diet factors on the association between BF and anthropometric outcomes was not shown.
Exclusive BF duration had a significant inverse dose-response relationship with BMI, WC and WHR at young adulthood. BF duration was positively related to a healthier diet at adulthood, but this did not explain the protective effect of BF against body fat. Our results underline the recommendation of the WHO to exclusively breastfeed for 6 months or longer.
Bile duct injury (BDI) is a dreaded complication of cholecystectomy, often caused by misinterpretation of biliary anatomy. To prevent BDI, techniques have been developed for intraoperative assessment of bile duct anatomy. This article reviews the evidence for the different techniques and discusses their strengths and weaknesses in terms of efficacy, ease, and cost-effectiveness.
PubMed was searched from January 1980 through December 2009 for articles concerning bile duct visualization techniques for prevention of BDI during laparoscopic cholecystectomy.
Nine techniques were identified. The critical-view-of-safety approach, indirectly establishing biliary anatomy, is accepted by most guidelines and commentaries as the surgical technique of choice to minimize BDI risk. Intraoperative cholangiography is associated with lower BDI risk (OR 0.67, CI 0.61–0.75). However, it incurs extra costs, prolongs the operative procedure, and may be experienced as cumbersome. An established reliable alternative is laparoscopic ultrasound, but its longer learning curve limits widespread implementation. Easier to perform are cholecystocholangiography and dye cholangiography, but these yield poor-quality images. Light cholangiography, requiring retrograde insertion of an optical fiber into the common bile duct, is too unwieldy for routine use. Experimental techniques are passive infrared cholangiography, hyperspectral cholangiography, and near-infrared fluorescence cholangiography. The latter two are performed noninvasively and provide real-time images. Quantitative data in patients are necessary to further evaluate these techniques.
The critical-view-of-safety approach should be used during laparoscopic cholecystectomy. Intraoperative cholangiography or laparoscopic ultrasound is recommended to be performed routinely. Hyperspectral cholangiography and near-infrared fluorescence cholangiography are promising novel techniques to prevent BDI and thus increase patient safety.
Cholecystectomy; CBD; Common bile duct; Complications
Building on previous research with disaster-exposed children and adolescents, a randomised clinical trial was performed in the treatment of trauma-related symptoms. In the current study two active treatments were compared among children in a broad age range and from a wide diversity of ethnic populations.
The primary aim was to compare the effectiveness and efficiency of Cognitive Behavioural Therapy (CBT) and Eye Movement Desensitisation and Reprocessing (EMDR).
Children (n=52, aged 4–18) were randomly allocated to either CBT (n=26) or EMDR (n=26) in a disaster mental health after-care setting after an explosion of a fireworks factory. All children received up to four individual treatment sessions over a 4–8 week period along with up to four sessions of parent guidance. Blind assessment took place pre- and post-treatment and at 3 months follow-up on a variety of parent-rated and self-report measures of post-traumatic stress disorder symptomatology, depression, anxiety, and behaviour problems. Analyses of variance (general linear model repeated measures) were conducted on the intention-to-treat sample and the completers.
Both treatment approaches produced significant reductions on all measures and results were maintained at follow-up. Treatment gains of EMDR were reached in fewer sessions.
Standardised CBT and EMDR interventions can significantly improve functioning of disaster-exposed children.
Randomised controlled trial; eye movement desensitisation and reprocessing (EMDR); cognitive behavioural therapy (CBT); post-traumatic stress disorder (PTSD); disaster
Insights into the effects of energy balance-related parenting practices on children's diet and activity behavior at an early age is warranted to determine which practices should be recommended and to whom. The purpose of this study was to examine child and parent background correlates of energy balance-related parenting practices at age 5, as well as the associations of these practices with children's diet, activity behavior, and body mass index (BMI) development.
Questionnaire data originated from the KOALA Birth Cohort Study for ages 5 (N = 2026) and 7 (N = 1819). Linear regression analyses were used to examine the association of child and parent background characteristics with parenting practices (i.e., diet- and activity-related restriction, monitoring and stimulation), and to examine the associations between these parenting practices and children's diet (in terms of energy intake, dietary fiber intake, and added sugar intake) and activity behavior (i.e., physical activity and sedentary time) at age 5, as well as BMI development from age 5 to age 7. Moderation analyses were used to examine whether the associations between the parenting practices and child behavior depended on child characteristics.
Several child and parent background characteristics were associated with the parenting practices. Dietary monitoring, stimulation of healthy intake and stimulation of physical activity were associated with desirable energy balance-related behaviors (i.e., dietary intake and/or activity behavior) and desirable BMI development, whereas restriction of sedentary time showed associations with undesirable behaviors and BMI development. Child eating style and weight status, but not child gender or activity style, moderated the associations between parenting practices and behavior. Dietary restriction and monitoring showed weaker, or even undesirable associations for children with a deviant eating style, whereas these practices showed associations with desirable behavior for normal eaters. By contrast, stimulation to eat healthy worked particularly well for children with a deviant eating style or a high BMI.
Although most energy balance-related parenting practices were associated with desirable behaviors, some practices showed associations with undesirable child behavior and weight outcomes. Only parental stimulation showed desirable associations with regard to both diet and activity behavior. The interaction between parenting and child characteristics in the association with behavior calls for parenting that is tailored to the individual child.
A decrease in the need for liver transplantations (LTX) in Primary Biliary Cirrhosis (PBC), possibly related to treatment with ursodeoxycholic acid (UDCA), has been reported in the USA and UK. The aim of this study was to assess LTX requirements in PBC over the past 20 years in the Netherlands.
Analysis of PBC transplant data of the Dutch Organ Transplant Registry during the period 1988-2008, including both absolute and proportional numbers. The indication for LTX was categorized as liver failure, hepatocellular carcinoma or poor quality of life (severe fatigue or pruritus). Data were analysed for two decades: 1.1.1988-31.12.1997 (1st) and 1.1.1998-31.12.2007 (2nd). The severity of disease was quantified using MELD scores. To fit lines which show trends over time we applied a linear regression model.
A total of 110 patients (87% women) was placed on the waiting list. 105 patients were transplanted (1st: 61, 2nd: 44), 5 (5%) died while listed. The absolute annual number of LTX for PBC slightly decreased during the 20 year period, the proportional number decreased significantly. At the time of LTX the mean age was 53.6 yrs. (1st: 53.4, 2nd: 53.8), the mean MELD score 13.9 (1st:14.5, 2nd:13.0). The median interval from diagnosis to LTX was 90.5 months (1st:86.5, 2nd: 93.5). 69% of patients was treated with UDCA (1st 38%, 2nd 82%).
Over the past 20 years the absolute number of LTX for PBC in the Netherlands showed a tendency to decrease whereas the proportional decrease was significant. There was a trend over time toward earlier transplantation.
We recently reported the age interval 2–6y being the earliest and most critical for adult overweight. We now aim to determine which age intervals are predictive of cardiometabolic risk at young adulthood.
Methods and Findings
We analyzed data from 642 18–28 years olds from the Terneuzen Birth Cohort. Individual BMI SDS trajectories were fitted by a piecewise linear model. By multiple regression analyses relationships were assessed between subsequent conditional BMI SDS changes and components of the metabolic syndrome (MetS), skinfold thickness and hsCRP at young adulthood. Results were adjusted for gender and age, and other confounders. Gender was studied as an effect modifier. All BMI SDS changes throughout childhood were related to waist circumference and skinfold thickness. No other significant relationship was found before the age of 2 years, except between the BMI SDS change 0–1y and hsCRP. Fasting blood glucose was not predicted by any BMI SDS change. BMI SDS change 2–6y was strongly related to most outcome variables, especially to waist circumference (ß 0.47, SE 0.02), systolic and diastolic blood pressure (ß 0.20 SE 0.04 and ß 0.19 SE 0.03), and hsCRP (ß 0.16 SE 0.04). The BMI SDS change 10–18y was most strongly related to HDL cholesterol (ß -0.10, SE 0.03), and triglycerides (ß 0.21, SE 0.03). To a lesser degree, the BMI SDS change 6–10y was related to most outcome variables. BMI SDS changes 2–6y and 10–18y were significantly related to MetS: the OR was respectively 3.39 (95%CI 2.33–4.94) and 2.84 (95%CI 1.94–4.15).
BMI SDS changes from 2y onwards were related to cardiometabolic risk at young adulthood, the age interval 2–6y being the most predictive. Monitoring and stabilizing the BMI SDS of children as young as 2–6y may not only reverse the progression towards adult overweight, but it may also safeguard cardiometabolic status.
To assess the prevalence of overweight and obesity in children living in the Netherlands and compare the findings with the Third and Fourth National Growth Studies carried out in 1980 and 1997, respectively.
Design and methods
Data were obtained from the child health care system. International cut‐off points for body mass index (BMI) were used to determine overweight and obesity. Cases were weighted for ethnicity and municipality size in such a way that the sample matched the distribution in the general population. The LMS method was used to calculate the age‐related distribution of BMI, and the prevalence was calculated from the fitted distribution.
Data on 90 071 children aged 4–16 years were routinely collected by 11 community health services during 2002–2004.
On average, 14.5% of the boys and 17.5% of the girls were overweight (including obesity), which is a substantial increase since 1980 (boys 3.9%, girls 6.9%) and 1997 (boys 9.7%, girls 13.0%). Similarly, 2.6% of the boys and 3.3% of the girls aged 4–16 years were obese, which is much higher than in 1980 (boys 0.2%, girls 0.5%) and 1997 (boys 1.2%, girls 2.0%). At the age of 4, 12.3% of the boys and 16.2% of the girls were already overweight.
The prevalence of overweight and obesity in the Netherlands is still rising, and at an even faster rate than before. Evidence‐based interventions are needed to counter the obesity epidemic, and there is an urgent need for pre‐school intervention programmes.
overweight; obesity; children; body mass index; prevalence
Ubiquitination plays a critical role in many cellular processes. A growing number of viruses have evolved strategies to exploit the ubiquitin-proteasome system, including members of the Poxviridae family. Members of the poxvirus family have recently been shown to encode BTB/kelch and ankyrin/F-box proteins that interact with cullin-3 and cullin-1 based ubiquitin ligases, respectively. Multiple members of the poxvirus family also encode ubiquitin ligases with intrinsic activity. This review describes the numerous mechanisms that poxviruses employ to manipulate the ubiquitin-proteasome system.
poxvirus; ubiquitin; F-box; BTB/kelch; RING finger
The validity of the rule of thumb that infants may have a weight loss of 10% in the first days after birth is unknown. We assessed the validity of this and other rules to detect breast‐fed infants with hypernatraemic dehydration.
A reference chart for relative weight change was constructed by the LMS method. The reference group was obtained by a retrospective cohort study.
1544 healthy, exclusively breast‐fed infants with 3075 weight measurements born in the Netherlands and 83 cases of breast‐fed infants with hypernatraemic dehydration obtained from literature.
The rule of thumb had a sensitivity of 90.4%, a specificity of 98.3% and a positive predictive value of 3.7%. Referring infants if their weight change is below −2.5 SDS (0.6th centile) in the reference chart in the first week of life and using the rule of thumb in the second week had a sensitivity of 85.5%, a specificity of 99.4% and a positive predictive value of 9.2%.
The rule of thumb is likely to produce too many false positive results, assuming that for screening purposes the specificity needs to be high. A chart for relative weight change can be helpful to detect infants with hypernatraemic dehydration.
breast feeding; weight loss; growth monitoring; infancy; hypernatraemic dehydration
Complications of overweight amplify with age, and irreversible damage already exists in young persons. Identifying the most sensitive age interval(s) for adult overweight is relevant for primary prevention. The aim of the study was to assess the relative contribution of body mass index (BMI) changes between 0 and 18 years to adult overweight, and to identify the earliest critical growth period.
Methods and Findings
Data from 762 subjects in the Terneuzen Birth Cohort with an average of 21 growth measurements per subject from birth until 18 years were used. The main outcome measure was the BMI standard deviation score (SDS) at young adulthood. For each subject BMI SDS was fitted by a piecewise linear model at eight different ages and correlated to adult BMI SDS. The age intervals in between are considered critical according to three criteria, tested by respectively Students' t-tests, multiple linear regression analyses and Pearson's correlation tests. In the age intervals 4 months(m) -1 year(y), 2–6 y, 6–10 y and 10–18 y the BMI SDS change differs between adults with and without overweight (P≤0.001). The age intervals 2–6 y and 10–18 y also meet the second criterion, implying that the BMI change during this period has a predictive value for adult BMI SDS in addition to BMI SDS at the end of the period. The largest rise in correlation between estimated BMI SDS and measured adult BMI SDS occurs during the period 2–6 y (from 0.36 to 0.63), which results in a high sensitivity (0.6) and specificity (0.8) by the age of 6 y.
The age interval from 2 y to 6 y is the earliest and most critical growth period for adult overweight. Therefore, primary prevention of adult overweight seems most likely to be successful if targeted at this specific age interval. By identifying those with an upwards centile crossing between 2 and 6 years, the development towards adult overweight might be reversed.
Hemangiomas of the heart are extremely rare. The prognosis is quite variable, because this benign tumor may grow, involute, or stop growing; therefore, resection is usually the treatment of choice. In patients with tumors of the left atrium, percutaneous balloon mitral valvulotomy is generally contraindicated. Yet for patients with moderate-to-severe mitral valve stenosis, balloon valvulotomy is an established therapy.
Herein, we present the case of a 73-year-old woman who was referred to our department in 1995 with severe mitral valve stenosis. Echocardiography showed a valve orifice area of 0.9 cm2, according to Gorlin's formula, and a mean pressure gradient of 11 mmHg. Surgical therapy was declined by the patient. There were no signs of coronary artery disease. The injection of contrast medium into the left coronary artery showed a hemangioma at the posterior wall of the left atrium. Magnetic resonance imaging and transesophageal echocardiography confirmed the diagnosis. Despite the increased risk posed by the hemangioma, we performed successful percutaneous balloon mitral valvulotomy with an Inoue balloon.
We saw the patient in 2001, and again in 2008 when she was 86 years of age. She was in excellent condition, with no signs of relevant dyspnea. Magnetic resonance imaging showed the size of the hemangioma to be stable. By use of echocardiography, we were able to confirm a good long-term result of the balloon valvulotomy. In this patient, a nonsurgical approach was adequate because of the lack of growth of the hemangioma in the left atrium.
Balloon dilatation/methods; echocardiography; heart neoplasms; hemangioma, left atrial/diagnosis; long-term outcome; magnetic resonance imaging; mitral valve stenosis/complications/treatment; percutaneous balloon mitral valvulotomy
Cellular homeostasis depends on an intricate balance of protein expression and degradation. The ubiquitin-proteasome pathway plays a crucial role in specifically targeting proteins tagged with ubiquitin for destruction. This degradation can be effectively blocked by both chemically synthesized and natural proteasome inhibitors. Poxviruses encode a number of proteins that exploit the ubiquitin-proteasome system, including virally encoded ubiquitin molecules and ubiquitin ligases, as well as BTB/kelch proteins and F-box proteins, which interact with cellular ubiquitin ligases. Here we show that poxvirus infection was dramatically affected by a range of proteasome inhibitors, including MG132, MG115, lactacystin, and bortezomib (Velcade). Confocal microscopy demonstrated that infected cells treated with MG132 or bortezomib lacked viral replication factories within the cytoplasm. This was accompanied by the absence of late gene expression and DNA replication; however, early gene expression occurred unabated. Proteasomal inhibition with MG132 or bortezomib also had dramatic effects on viral titers, severely blocking viral replication and propagation. The effects of MG132 on poxvirus infection were reversible upon washout, resulting in the production of late genes and viral replication factories. Significantly, the addition of an ubiquitin-activating enzyme (E1) inhibitor had a similar affect on late and early protein expression. Together, our data suggests that a functional ubiquitin-proteasome system is required during poxvirus infection.
Cellular proteins containing BTB and kelch domains have been shown to function as adapters for the recruitment of substrates to cullin-3-based ubiquitin ligases. Poxviruses are the only family of viruses known to encode multiple BTB/kelch proteins, suggesting that poxviruses may modulate the ubiquitin pathway through interaction with cullin-3. Ectromelia virus encodes four BTB/kelch proteins and one BTB-only protein. Here we demonstrate that two of the ectromelia virus encoded BTB/kelch proteins, EVM150 and EVM167, interacted with cullin-3. Similar to cellular BTB proteins, the BTB domain of EVM150 and EVM167 was necessary and sufficient for cullin-3 interaction. During infection, EVM150 and EVM167 localized to discrete cytoplasmic regions, which co-localized with cullin-3. Furthermore, EVM150 and EVM167 co-localized and interacted with conjugated ubiquitin, as demonstrated by confocal microscopy and co-immunoprecipitation. Our findings suggest that the ectromelia virus encoded BTB/kelch proteins, EVM150 and EVM167, interact with cullin-3 potentially functioning to recruit unidentified substrates for ubiquitination.
poxvirus; ectromelia; cullin-3; ubiquitination; BTB/kelch
Poxviruses are notorious for encoding multiple proteins that regulate cellular signaling pathways, including the ubiquitin-proteasome system. Bioinformatics indicated that ectromelia virus, the causative agent of lethal mousepox, encoded four proteins, EVM002, EVM005, EVM154, and EVM165, containing putative F-box domains. In contrast to cellular F-box proteins, the ectromelia virus proteins contain C-terminal F-box domains in conjunction with N-terminal ankyrin repeats, a combination that has not been previously reported for cellular proteins. These observations suggested that the ectromelia virus F-box proteins interact with SCF (Skp1, cullin-1, and F-box) ubiquitin ligases. We focused our studies on EVM005, since this protein had only one ortholog in cowpox virus. Using mass spectrometry, we identified cullin-1 as a binding partner for EVM005, and this interaction was confirmed by overexpression of hemagglutinin (HA)-cullin-1. During infection, Flag-EVM005 and HA-cullin-1 colocalized to distinct cellular bodies. Significantly, EVM005 coprecipitated with endogenous Skp1, cullin-1, and Roc1 and associated with conjugated ubiquitin, suggesting that EVM005 interacted with the components of a functional ubiquitin ligase. Interaction of EVM005 with cullin-1 and Skp1 was abolished upon deletion of the F-box, indicating that the F-box played a crucial role in interaction with the SCF complex. Additionally, EVM002 and EVM154 interacted with Skp1 and conjugated ubiquitin, suggesting that ectromelia virus encodes multiple F-box-containing proteins that regulate the SCF complex. Our results indicate that ectromelia virus has evolved multiple proteins that interact with the SCF complex.
It is generally assumed that most patients with celiac disease (CD) have a slowed growth in terms of length (or height) and weight. However, the effectiveness of slowed growth as a tool for identifying children with CD is unknown. Our aim is to study the diagnostic efficiency of several growth criteria used to detect CD children.
A case-control simulation study was carried out. Longitudinal length and weight measurements from birth to 2.5 years of age were used from three groups of CD patients (n = 134) (one group diagnosed by screening, two groups with clinical manifestations), and a reference group obtained from the Social Medical Survey of Children Attending Child Health Clinics (SMOCC) cohort (n = 2,151) in The Netherlands. The main outcome measures were sensitivity, specificity and positive predictive value (PPV) for each criterion.
Body mass index (BMI) performed best for the groups with clinical manifestations. Thirty percent of the CD children with clinical manifestations and two percent of the reference children had a BMI Standard Deviation Score (SDS) less than -1.5 and a decrease in BMI SDS of at least -2.5 (PPV = 0.85%). The growth criteria did not discriminate between the screened CD group and the reference group.
For the CD children with clinical manifestations, the most sensitive growth parameter is a decrease in BMI SDS. BMI is a better predictor than weight, and much better than length or height. Toddlers with CD detected by screening grow normally at this stage of the disease.