Genome-wide analysis of rare copy number variations reveals PARK2 as a candidate gene for attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.

Increase in upper extremity fractures in young male soccer players in the Netherlands, 1998-2009.

Young male soccer players have been identified as a target group for injury prevention, but studies addressing trends and determinants of injuries within this group are scarce. The goal of this study was to analyze age-specific trends in hospital-treated upper extremity fractures (UEF) among boys playing soccer in the Netherlands and to explore associated soccer-related factors. Data were obtained from a national database for the period 1998-2009. Rates were expressed as the annual number of UEF per 1000 soccer players. Poisson's regression was used to explore the association of UEF with the number of artificial turf fields and the number of injuries by physical contact. UEF rates increased significantly by 19.4% in boys 5-10 years, 73.2% in boys 11-14 years, and 38.8% in boys 15-18 years old. The number of injuries by physical contact showed a significant univariate association with UEF in boys 15-18 years old. The number of artificial turf fields showed a significant univariate association with UEF in all age groups, and remained significant for boys aged 15-18 years in a multivariate model. This study showed an increase of UEF rates in boys playing soccer, and an independent association between artificial turf fields and UEF in the oldest boys.

Bipolar disorder risk alleles in children with ADHD.

Bipolar disorder (BD) and attention deficit/hyperactivity disorder (ADHD) may share common genetic risk factors as indicated by the high co-morbidity of BD and ADHD, their phenotypic overlap especially in pediatric populations, the high heritability of both disorders, and the co-occurrence in families. We therefore examined whether known polygenic BD risk alleles are associated with ADHD. We chose the eight best SNPs of the recent genome-wide association study (GWAS) of BD patients of German ancestry and the nine SNPs from international GWAS meeting a 'genome-wide significance' level of α = 5 × 10(-8). A GWAS was performed in 495 ADHD children and 1,300 population-based controls using HumanHap550v3 and Human660 W-Quadv1 BeadArrays. We found no significant association of childhood ADHD with single BD risk alleles surviving adjustment for multiple testing. Yet, risk alleles for BD and ADHD were directionally consistent at eight of nine loci with the strongest support for three SNPs in or near NCAN, BRE, and LMAN2L. The polygene analysis for the BP risk alleles at all 14 loci indicated a higher probability of being a BD risk allele carrier in the ADHD cases as compared to the controls. At a moderate power to detect association with ADHD, if true effects were close to estimates from GWAS for BD, our results suggest that the possible contribution of BD risk variants to childhood ADHD risk is considerably lower than for BD. Yet, our findings should encourage researchers to search for common genetic risk factors in BD and childhood ADHD in future studies.

Prognostic significance of chromosome 3 alterations determined by microsatellite analysis in uveal melanoma: a long-term follow-up study.

BACKGROUND: In uveal melanoma (UM), the most frequent primary intraocular tumour in adults, loss of one entire chromosome 3 (monosomy 3 (M3)) is observed in ~50% of tumours and is significantly associated with metastatic disease. The strong association of metastatic disease with M3 offers the opportunity for molecular prognostic testing of UM patients. METHODS: To re-evaluate M3 as prognostic marker in our clinical and laboratory setting and to determine the metastatic potential of rare tumours with partial M3, we performed a comprehensive study on 374 UM patients treated by enucleation in our clinic within 10 consecutive years, starting in 1998. Genotyping of all tumours was performed by microsatellite analysis. RESULTS: Median follow-up time was 5.2 years. The disease-specific mortality rates (death by UM metastases) for tumours with disomy 3 (D3) and M3 were 13.2% and 75.1%, respectively. The disease-specific survival was worse when M3 was observed together with chromosome 8 alterations (P=0.020). Death of UM metastases was also observed in 12 patients (9%) with D3 tumours. The metastasising D3 tumours showed a larger basal tumour diameter (P=0.007), and were more frequently of mixed or epitheloid cell type (P<0.0001) than D3 tumours that did not metastasise. Mortality rate of tumours showing partial M3 (8.3%) was as low as that for tumours with D3. CONCLUSION: This shows that large tumours with disomy 3 have an increased risk to develop metastases. On the basis of these results, our clinic offers routine prognostic testing of UM patients by chromosome 3 typing.

The fatty acid amide hydrolase (FAAH) gene variant rs324420 AA/AC is not associated with weight loss in a 1-year lifestyle intervention for obese children and adolescents.

Adult obese carriers of the A allele of SNP rs324420 in the fatty acid amide hydrolase (FAAH) gene lose more weight and improve associated phenotypes better than non-carriers during an intervention. We aimed to replicate this finding in obese children and adolescents undergoing a one year lifestyle intervention (Obeldicks program). A total of 453 overweight and obese children and adolescents (10.8±2.6 years, BMI-SDS 2.4±0.5; 55% girls) were genotyped for rs324420 (C/A) by restriction fragment length polymorphism (RFLP) analysis. Participants were prescribed a balanced diet, containing 55 En% carbohydrates, 30 En% fat, and 15 En% proteins. Moreover, they took part in an exercise therapy once a week. Blood was taken at baseline and after 1 year of intervention. Anthropometric (height, weight, BMI, and BMI-SDS) and plasma parameters (total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerides, glucose, insulin, and HOMA) as well as blood pressure were measured. Both mean BMI and BMI-SDS improved significantly. The mean systolic blood pressure was also lowered and concentrations of HDL-cholesterol increased significantly. However, none of the measured changes were associated with FAAH rs324420 AA/AC genotype. We did not detect evidence for an association of FAAH genotypes with weight reduction in overweight and obese children and adolescents. Hence, the previous finding in adults could not be confirmed. As the length (1 year as compared to 3 months) and mode of treatment (hypocaloric diet in adults vs. physical activity plus balanced meals) of the interventions varied, these parameters might have influenced the inconsistent results.

In vitro assessment of apheresis and pooled buffy coat platelet components suspended in plasma and SSP+ photochemically treated with amotosalen and UVA for pathogen inactivation (INTERCEPT Blood System™).

BACKGROUND AND OBJECTIVES: INTERCEPT Blood System™ is a pathogen inactivation system for blood components. The initial approval required a platelet component to be suspended in a combination of plasma and Platelet additive Solution/PAS-III. Improved platelet storage has been reported with Mg++ and K+ supplementation (PAS-IIIM). This study validated the use of INTERCEPT™/PAS-IIIM for apheresis and pooled buffy-coat platelet components. MATERIALS AND METHODS: The platelet dose and pH throughout 5 days of storage met the European and French requirements for quality standards. RESULTS AND CONCLUSION: Additional metabolic and activation assessments of the treated platelets confirmed the previously reported superiority of PAS-IIIM over PAS-III, but extended it to the INTERCEPT™ process.

Impact of immunosuppressive therapy on hepatitis C infection after renal transplantation.

BACKGROUND: Among patients after renal transplantation (NTx), hepatitis C virus (HCV) infection is a risk factor for graft loss and patient death caused by hepatic decompensation. Also, HCV has been implicated in the pathogenesis of glomerular diseases in native and transplanted kidneys. Therefore, the aim of this retrospective cohort study was to determine the effects of the widely used calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus (Tac) on hepatitis C virus replication, inflammatory activity, development of liver fibrosis, and long-term renal graft function. SUBJECTS AND METHODS: A cohort of 71 patients with HCV infection after kidney transplantation under immunosuppression with either CsA or Tac were analyzed for viral kinetics and serum transaminases. In addition, presence of liver fibrosis was detected by non-invasive measurements using the FibroScan. Graft function was determined biochemically. Patients with interferon therapy prior to transplantation were excluded from the study in order to avoid any impact of the antiviral therapy on outcomes. RESULTS: In the early period after transplantation, hepatitis C viral load was lower in patients treated with Tac as compared to CsA. This effect became negligible 3 months after transplantation. However, hepatic inflammatory activity was reduced in the CsA-treated group. Extent of liver fibrosis was similar in both groups of HCV-infected patients as well as in a control group of non-HCV-infected patients after renal transplantation (NTx), respectively. Renal function and glomerular filtration rate, as calculated by the modification of diet in renal disease (MDRD) formula, were significantly better in patients treated with Tac. CONCLUSIONS: During long-term immunosuppression, the CNIs cyclosporine A versus tacrolimus showed no significant differences in HCV-infected patients after renal transplantation with respect to viral replication and development of liver fibrosis. However, function of the renal graft is significantly better preserved in patients receiving tacrolimus.

Trends in wrist fractures in children and adolescents, 1997-2009.

PURPOSE: Distal radius and carpal fractures in children and adolescents represent approximately 25% of all pediatric fractures. Incidence rates and causes of these fractures change over time owing to changes in activities and risk factors. The purpose of this study was to examine recent population-based trends in incidence and causes of wrist fractures in children and adolescents. METHODS: We obtained data from the Dutch Injury Surveillance System of emergency department visits of 15 geographically distributed hospitals, and from the National Hospital Discharge Registry. This included a representative sample of outpatients and inpatients, respectively. We calculated incidence rates of wrist fractures per 100,000 person-years for each year between 1997 and 2009. Using Poisson's regression, we analyzed trends for children and adolescents 5 to 9, 10 to 14, and 15 to 19 years of age separately for boys and girls. RESULTS: During the study period, incidence rates increased significantly in boys and girls 5 to 9 and 10 to 14 years of age, with the strongest increase in the age group 10 to 14 years. The observed increases were mainly due to increased incidence rates during soccer and gymnastics at school. CONCLUSIONS: This population-based study revealed a substantial sports-related increase in the incidence rate of wrist fractures in boys and girls aged 5 to 9 and 10 to 14 years in the period 1997 to 2009. CLINICAL RELEVANCE: With knowledge of the epidemiology of wrist fractures, prevention programs can be improved. From this study, we know that the incidence rate of wrist fractures in childhood is increasing, mainly as a result of soccer and gymnastics at school. Future sport injury research and surveillance data are necessary to develop new prevention programs based on identifying and addressing specific risk factors, especially in young athletes.

[Maintenance for implant-retained overdentures. An inventory of long-term costs]. / Nazorg aan overkappingsprothesen op implantaten. Een inventarisatie van de kosten op de lange termijn.

The maintenance costs for implant-retained overdentures are the subject of this study. A Pubmed Medline search was performed on the basis of the combination of the mesh terms 'maintenance', 'implant' and 'overdenture'. Eventually 85 publications were identified that met the initial selection criteria. For a subsequent selection, maintenance had to be the primary outcome measure, an observation period of 5 year or more was required and it had to be possible to capitalise the maintenance costs. Four articles remained as a result of this filtering procedure, 2 of which came from Dutch institutes. The findings were reasonably consistent. The structural costs for maintenance of implant-retained overdentures during the first 10 years was estimated at 1,400 Euro. It is expected that an overdenture on implants in the mandible will be replaced after a mean period of 12 years. For both outcome measures considerable individual variance applies.

[A description of a population with severe oligodontia]. / Beschrijving van een populatie met ernstige oligodontie.

The dentition of 116 patients with a non-syndromic form of oligodontia was characterized. For this purpose use was made of the so-called Tooth Agenesis Code (TAC), with which the various patterns of missing teeth can be indicated with a unique number. Oligodontia can present itself in very diverse ways. Only 3 patterns were seen (2 times) among these 116 patients. Considered per quadrant, in the upper jaw, on the one hand, agenesis of both premolars and the lateral incisor was most common and, on the other, the absence of all teeth except the central incisor and the first molar. In the lower jaw, agenesis of the second or of both premolars was most common. Evaluating treatments and formulating standards of restoration in the treatment of patients with severe oligodontia are methodological challenges. Homogeneous, comparable sub-groups of patients of any size are difficult to construct due to the low prevalence of severe oligodontia and the diversity of patterns of agenesis when the whole mouth is taken into consideration.

[Prosthetic dilemmas. Connecting natural teeth and implants]. / Prothetische dilemma's. Het verbinden van natuurlijke gebitselementen en implantaten.

In clinical practice, the prognosis seems, with some reservations, to be comparable for tooth-implant and implant-implant supported bridges in the middle-long term.This conclusion seems particularly valid for tooth-implant bridges in free-end situations, where a single implant is connected with a tooth. Prerequisites are a healthy tooth abutment, a pontic length not exceeding the width of a bicuspid, a rigid connection between implant and tooth and the use of strong cement.

Healthcare costs and productivity costs of hand and wrist injuries by external cause: A population-based study in working-age adults in the period 2008-2012.

BACKGROUND: Hand and wrist injuries are very common at the Emergency Departments (ED), and among the most costly injury types in the working population. The purpose of this study was to explore the causes of non-trivial hand and wrist injuries (i.e., hand fractures, wrist fractures and complex soft-tissue injuries) in working-age adults in order to identify target areas for prevention. METHODS: Data were extracted from the Dutch Injury Surveillance System, from the National Hospital Discharge Registry and from a patient follow-up survey in working-age adults (aged 20-64 years) in the period 2008-2012. An incidence-based cost model was used to estimate healthcare costs, and an absenteeism model for estimating the productivity costs. Total costs were calculated by external cause, subdivided in their main categories (home, sports, work, traffic and violence) and their most important subclasses. RESULTS: Total costs of these injuries in The Netherlands were US $410 million per year, of which 75% (US $307 million) productivity costs. Males represented 66% (US $271 million) of the total costs. Within the male group, the group 35-49 years had the highest contribution to total costs (US $112 million), as well as the highest costs per case (US $10,675). Work-related injuries showed the highest costs per case (US $11,797), however, only 25% of the total costs were work-related. The top five causes in terms of total costs were: accidents at home (falls 23%, contact with an object 17%), traffic (cycling 9%) and work (industrial work 4%, and construction work 4%). CONCLUSION: Hand and wrist injuries are a major cause of healthcare and productivity costs in working-age adults. To reduce the costs to society, prevention initiatives should be targeted at major contributing causes, that are mainly related to activities at home (falls, contact with an object) and accidents at the road (cycling).

Reaction of surrounding gingiva to permucosal implants of dense hydroxyapatite in dogs.

Experimental and histological studies on the reaction of surrounding gingiva to permucosal implants of dense calcium hydroxyapatite were carried out in dogs. Epithelial attachment and connection of supra-alveolar collagen fibres to the implant surface seemed to form a biological seal around implants similar to that around natural teeth. However, excellent oral hygiene is very important for the maintenance of this biological seal.

A clinical, radiographic, and histological evaluation of permucosal dental implants of dense hydroxylapatite in dogs.

A clinical, histological, and radiographic examination was performed on 77 permucosal dental implants, made of dense sintered hydroxylapatite: 34 solid cylinders and 43 hollow cylinders. The hollow cylinders were pre-compressed between two titanium caps. The implants were placed in partly edentulous mandibles of dogs, and were physiologically loaded. Healing was clinically and radiographically evaluated during a six-month to five-year period. At various times, implants with their surrounding tissues were removed and prepared for light and electron microscopy. All implants showed a good initial fit and were maintained in place without undercut or mechanical stabilization. After 18 months, 76% of the solid cylinders had fractured at the implant/bone junction due to fatigue. However, the submerged portions of the solid cylinders were preserved without clinical problems, and became entirely embedded in bone. The pre-stressed implants did not fracture, and 91% were functioning 24 months after placement. The average scores of pocket depths and gingival bleeding showed no significant differences between implants and surrounding natural teeth. Bone deposition occurred on the entire surface of the implant below the crest of the alveolar bone, and intimate bone contact was confirmed by electron microscopy. It was also observed that a layer of bone tissue was deposited on the implant surface in the permucosal area just above the alveolar bone level. Embedding of gingival fibers in this layer resulted in gingival attachment to the implant, comparable with that of natural teeth.

Characteristics of 5410 edentulous implant candidates and the treatment they receive.

Since 1989 implant dentistry in the Netherlands is a National Dental Insurance (NDI) benefit, thus reducing out-of-pocket expenditures for implant candidates considerably. A nationwide investigation was set up in order to evaluate quantitative, qualitative and financial effects of this new provision. The patient and treatment characteristics of 5410 edentulous implant candidates are discussed. Intensive monitoring of the usage of these new regulations facilitates health care policy making, including future planning. Over a 3 1/2 yr period, two out of every thousand totally edentulous NDI patients were treated in combination with dental implants. This number is being considered small, bearing in mind the number of edentulous patients in the Netherlands and the proportion of dissatisfied denture wearers. Demographic data, prosthetic and pre-prosthetic surgical history reveal that these patients, mostly female and middle-aged, experience severe denture-related problems. In the majority of cases the implants are placed by an oral surgeon and the suprastructure is made by a general dentist or at a centre for special dental care. The treatment itself mostly consists of an implant retained overdenture on two or four permucosal implants and a bar-construction.

A nationwide evaluative study on implant-retained overdentures.

OBJECTIVES: In the Netherlands, dental implants have been included in the National Dental Insurance Scheme (NDIS) since 1989. Nowadays, out-of-pocket expenditure is low, making implant treatment financially feasible for a large group of edentulous, potential implant candidates. Treatment can be performed by both oral surgeons and general dentists. Results of implant treatment in the literature are usually obtained in academic and specialized centers. In contrast to this, the present study evaluates the quantitative and qualitative aspects of rehabilitation with oral implants in combination with an overdenture when applied on a nationwide scale. METHODS: For this purpose all patients (n = 5410) treated between January 1989 and July 1992 were extensively documented pre-operatively, implant patients (n = 429) were clinically investigated by two independent observers and the effect of treatment on denture complaints was assessed by means of a questionnaire (n = 460). RESULTS: Only a small proportion of the potential pool of implant candidates is actually being treated, to a constant number of approximately 2000 patients a year. The selected patients have major denture problems and have received relatively high levels of prosthetic care during the last decade. Clinical results are comparable to those reported in the literature, implant survival after 3 years for the lower jaw being 96.3% and for the upper jaw 70.4%. Oral hygiene was frequently considered suboptimal and seen in conjunction with marginal inflammation of the peri-implant mucosa. Subjective results were excellent, patients were quite satisfied with the improvements in the comfort and esthetics of their lower denture. CONCLUSIONS: Implant-overdenture treatment, within the guidelines and regulations set by the Dutch NDIS, is a safe and effective treatment alternative, in particular for the rehabilitation of the lower jaw.

Flexible (Polyactive) versus rigid (hydroxyapatite) dental implants.

In a beagle dog study, the peri-implant bone changes around flexible (Polyactive) and rigid hydroxyapatite (HA) implants were investigated radiographically by quantitative digital subtraction analysis and by assessment of marginal bone height, with the aid of a computerized method. A loss of approximately 1 mm of marginal bone height was observed for both the dense Polyactive and the HA implants, after 6 months of loading. This value appeared to be stable from 12 weeks of loading onward. Along the total length of the implant during the first 6 weeks of loading, both the flexible (dense Polyactive) and the rigid (HA) implants showed a decrease in density. However, after this 6-week period, the bone density around the implants increased, and after 18 weeks the original bone density was reached. The flexible Polyactive implants provoked less decrease in density than the rigid HA implants, although not to a statistically significant level. This finding sustains the hypothesis that flexible implant materials may transfer stresses to the surrounding bone more favorably.

The combined use of endosteal implants and iliac crest onlay grafts in the severely atrophic mandible: a longitudinal study.

Thirteen patients, who received an onlay bone graft augmentation to their severely atrophic mandible in combination with a simultaneous implant insertion, were studied prospectively. A reproducible method that allowed for accurate assessment of graft resorption, consisting of lateral and oblique-lateral cephalometric radiographs in combination with an image analysis system, was used to assess the resorption rate in all patients and between subgroups of patients, according to selected patient and treatment characteristics. Thirty implants were placed, none of which were lost, and all patients expressed satisfaction after a mean observation period of 877 days. A mean resorption rate of 36% of the grafted bone height occurred, mainly during the first year and with some degree of individual variance. After three years the resorption had virtually stopped. No statistically significant differences between any of the subgroups of patients could be distinguished. Peri-implantitis was found around eight implants in seven patients. It is concluded that the described surgical technique should be used only if there are stringent indications.

Polyactive as a bone-filler in a beagle dog model.

Calcification is a crucial step in the bone-bonding mechanism of PEO/PBT hydrogel copolymers (Polyactive, a new generation of bone-fillers. A beagle dog study was conducted to determine whether the preoperative presence of a calcium phosphate layer (precalcification) on a PEO/PBT 80/20 copolymer would further increase the bone-bonding rate. Standard bone cavities were filled with either precalcified or nonprecalcified porous cylindric PEO/PBT 80/20 implants, or hydroxyapatite granules held together with PEO/PBT 70/30, or were left unfilled. A significantly higher percentage of mineralized component was present in the cavities filled with the precalcified PEO/PBT 80/20 copolymer than in the control defects. As a result of swelling by fluid-uptake, the press-fit inserted copolymer implants showed a significant reduction in pore size, thus preventing optimal bone ingrowth. Both precalcification of the copolymer and underfilling of the defect, to create space for the copolymer to increase in diameter, stimulate postoperative calcification and bone ingrowth in PEO/PBT 80/20 copolymers.

[Dental implants under overlay dentures: an assessment]. / Tandheelkundige implantaten onder overkappingsprotheses: een evaluatie.

In the treatment of edentulous patients endosseous implants play an increasingly important role. This paper discusses treatment and treatment results from a nationwide study among 429 edentulous patients who received implant-retained complete overdentures. In this particular treatment concept the denture derives retention and support from the implants that are placed in the edentulous part of the jaw. In terms of implant survival and patient satisfaction treatment results can be considered satisfactory, especially for the mandible. Of those patients who had an implant supported denture in the mandible, 95% considered the new mandibular denture to function better than the previously constructed denture. The chance on implant survival, three years postoperatively, is approximately 97%. It is concluded that oral rehabilitation in the mandible by means of endosseous implants in combination with a complete overdenture is a reliable and effective treatment alternative.