Search for a genetic cause in children with unilateral isolated microtia and congenital aural atresia.

PURPOSE: Microtia describes a spectrum of auricular malformations ranging from mild dysplasia to anotia. A vast majority of microtia patients demonstrate congenital aural atresia (CAA). Isolated microtia has a right ear predominance (58-61%) and is more common in the male sex. Isolated microtia is a multifactorial condition involving genetic and environmental causes. The aim of this study is to describe the phenotype of children with unilateral isolated microtia and CAA, and to search for a common genetic cause trough DNA analysis. METHODS: Phenotyping included a complete clinical examination. Description on the degree of auricular malformation (Weerda classification-Weerda 1988), assessment for hemifacial microsomia and age-appropriate audiometric testing were documented. Computerized tomography of the temporal bone with 3-D rendering provided a histopathological classification (HEAR classification-Declau et al. 1999). Genetic testing was carried out by single nucleotide polymorphism (SNP) microarray. RESULTS: Complete data are available for 44 children (50% was younger than 33 days at presentation; 59.1% boys; 72.7% right ear). Type III microtia was present in 28 patients. Type 2b CAA existed in 32 patients. All patients had a normal hearing at the non-affected side. Genome wide deletion duplication analysis using microarray did not reveal any pathological copy number variant (CNV) that could explain the phenotype. CONCLUSIONS: Type III microtia (peanut-shell type) in combination with a type 2b CAA was the most common phenotype, present in 23 of 44 (52.3%) patients with isolated unilateral microtia. No abnormalities could be found by copy number variant (CNV) analysis. Whole exome sequencing in a larger sample with a similar phenotype may represent a future diagnostic approach.

The ACCEPT-study: design of an RCT with an active treatment control condition to study the effectiveness of the Dutch version of PEERS® for adolescents with autism spectrum disorder.

BACKGROUND: Social skills interventions are commonly deployed for adolescents with autism spectrum disorder (ASD). Because effective and appropriate social skills are determined by cultural factors that differ throughout the world, the effectiveness of these interventions relies on a good cultural fit. Therefore, the ACCEPT study examines the effectiveness of the Dutch Program for the Education and Enrichment of Relational Skills (PEERS®) social skills intervention. METHODS/DESIGN: This study is a two-arm parallel group randomized controlled trial (RCT) in which adolescents are randomly assigned (after baseline assessment) to one of two group interventions (PEERS® vs. active control condition). In total, 150 adolescents are to be included, with multi-informant involvement of their parents and teachers. The ACCEPT study uses an active control condition (puberty psychoeducation group training, focussing on social-emotional development) and explores possible moderators and mediators in improving social skills. The primary outcome measure is the Contextual Assessment of Social Skills (CASS). The CASS assesses social skills performance in a face to face social interaction with an unfamiliar, typically developing peer, making this a valuable instrument to assess the social conversational skills targeted in PEERS®. In addition, to obtain a complete picture of social skills, self-, parent- and teacher-reported social skills are assessed using the Social Skills improvement System (SSiS-RS) and Social Responsiveness Scale (SRS-2). Secondary outcome measures (i.e. explorative mediators) include social knowledge, social cognition, social anxiety, social contacts and feelings of parenting competency of caregivers. Moreover, demographic and diagnostic measures are assessed as potential moderators of treatment effectiveness. Assessments of adolescents, parents, and teachers take place at baseline (week 0), intermediate (week 7), post intervention (week 14), and at follow-up (week 28). CONCLUSION: This is the first RCT on the effectiveness of the PEERS® parent-assisted curriculum which includes an active control condition. The outcome of social skills is assessed using observational assessments and multi-informant questionnaires. Additionally, factors related to social learning are assessed at several time points, which will enable us to explore potential mediators and moderators of treatment effect. TRAIL REGISTRATION: Dutch trail register NTR6255 (NL6117). Registered February 8th, 2017 - retrospectively registered.

Urbanicity, hypothalamic-pituitary-adrenal axis functioning, and behavioral and emotional problems in children: a path analysis.

BACKGROUND: Urbanization is steadily increasing worldwide. Previous research indicated a higher incidence of mental health problems in more urban areas, however, very little is known regarding potential mechanisms underlying this association. We examined whether urbanicity was associated with mental health problems in children directly, and indirectly via hypothalamic-pituitary-adrenal (HPA)-axis functioning. METHODS: Utilizing data from two independent samples of children we examined the effects of current urbanicity (n = 306, ages seven to 12 years) and early childhood urbanicity (n = 141, followed from birth through age 7 years). Children's mothers reported on their mental health problems and their family's socioeconomic status. Salivary cortisol samples were collected during a psychosocial stress procedure to assess HPA axis reactivity to stress, and at home to assess basal HPA axis functioning. Neighborhood-level urbanicity and socioeconomic conditions were extracted from Statistics Netherlands. Path models were estimated using a bootstrapping procedure to detect indirect effects. RESULTS: We found no evidence for a direct effect of urbanicity on mental health problems, nor were there indirect effects of urbanicity through HPA axis functioning. Furthermore, we did not find evidence for an effect of urbanicity on HPA axis functioning or effects of HPA axis functioning on mental health problems. CONCLUSIONS: Possibly, the effects of urbanicity on HPA axis functioning and mental health do not manifest until adolescence. An alternative explanation is a buffering effect of high family socioeconomic status as the majority of children were from families with an average or high socioeconomic status. Further studies remain necessary to conclude that urbanicity does not affect children's mental health via HPA axis functioning.

The Stability of Comorbid Psychiatric Disorders: A 7 Year Follow Up of Children with Pervasive Developmental Disorder-Not Otherwise Specified.

The current study was a 7-year follow-up of 74 6-12 year old children with Pervasive Developmental Disorder-Not Otherwise Specified. We examined the rates and 7 year stability of comorbid psychiatric diagnoses as ascertained with the Diagnostic Interview Schedule for Children: Parent version at ages 6-12 and again at ages 12-20. Also, we examined childhood factors that predicted the stability of comorbid psychiatric disorders. The rate of comorbid psychiatric disorders dropped significantly from childhood (81 %) to adolescence (61 %). Higher levels of parent reported stereotyped behaviors and reduced social interest in childhood significantly predicted the stability of psychiatric comorbidity. Re-evaluation of psychiatric comorbidity should be considered in clinical practice, since several individuals shifted in comorbid diagnoses.

ASD Symptom Severity in Adolescence of Individuals Diagnosed with PDD-NOS in Childhood: Stability and the Relation with Psychiatric Comorbidity and Societal Participation.

The current 7-year follow-up study investigated: (1) the stability of ASD severity, and (2) associations of ASD severity in adolescence with (a) childhood and concurrent psychiatric comorbidity, and (b) concurrent societal functioning. The Autism Diagnostic Observation Schedule (ADOS) and the Diagnostic Interview Schedule for Children were administered in childhood (ages 6-12) and in adolescence (ages 12-20) to 72 individuals with a pervasive developmental disorder-not otherwise specified (PDD-NOS). ADOS calibrated severity scores showed a large stability (r = .51). Psychiatric comorbidity in childhood and adolescence were not associated with ASD severity in adolescence. Mental health care use (87 %) and special education needs were high (71 %). Reevaluation of ASD severity and psychiatric comorbidity later in life seem useful when PDD-NOS is diagnosed in childhood.

Teacher characteristics, social classroom relationships, and children's social, emotional, and behavioral classroom adjustment in special education.

The goal of this study was to explore relations between teacher characteristics (i.e., competence and wellbeing); social classroom relationships (i.e., teacher-child and peer interactions); and children's social, emotional, and behavioral classroom adjustment. These relations were explored at both the individual and classroom levels among 414 children with emotional and behavioral disorders placed in special education. Two models were specified. In the first model, children's classroom adjustment was regressed on social relationships and teacher characteristics. In the second model, reversed links were examined by regressing teacher characteristics on social relationships and children's adjustment. Results of model 1 showed that, at the individual level, better social and emotional adjustment of children was predicted by higher levels of teacher-child closeness and better behavioral adjustment was predicted by both positive teacher-child and peer interactions. At the classroom level, positive social relationships were predicted by higher levels of teacher competence, which in turn were associated with lower classroom levels of social problems. Higher levels of teacher wellbeing were directly associated with classroom adaptive and maladaptive child outcomes. Results of model 2 showed that, at the individual and classroom levels, only the emotional and behavioral problems of children predicted social classroom relationships. At the classroom level, teacher competence was best predicted by positive teacher-child relationships and teacher wellbeing was best predicted by classroom levels of prosocial behavior. We discuss the importance of positive teacher-child and peer interactions for children placed in special education and suggest ways of improving classroom processes by targeting teacher competence.

Developmental links between disobedient behavior and social classroom relationships in boys with psychiatric disorders in special education.

In mainstream education, positive relationships with teachers and peers have been found to positively influence children's behavioral development. However, high levels of classroom behavior problems may hinder the formation of such positive relationships. Therefore, findings from mainstream education cannot be generalized to special education. The present study investigated the developmental links between disobedience and positive as well as negative relationships with teachers and peers among boys in restrictive special educational settings. At three assessment waves across one school year, teacher-reports of teacher-child closeness and conflict, and peer-reports of peer acceptance, rejection and disobedience were collected among 340 boys (mean age = 10.1 years, SD = 1.58, range = 5-13) with psychiatric disorders receiving special education. Autoregressive cross-lagged models were fitted to explore the nature of these developmental links. The impact of boys' age was examined using multiple group analyses. Findings supported the importance of teacher-child conflict, but not closeness, and positive and negative peer relationships for the development of boys' disobedience, with a stronger effect of negative than positive relationships. However, teacher-child and peer relationships were not longitudinally related and the effect of boys' age was minimal. This study extends prior research by suggesting that, despite differences in educational setting and severity of behavior problems between children in mainstream and special education, reducing negative classroom interactional patterns is most important in preventing the development of problematic classroom behavior in boys with severe social-emotional and behavioral difficulties.

Disclosure pattern and follow-up after the molecular diagnosis of BRCA/CHEK2 mutations.

Five to 10% of all breast cancer cases are due to mutations of high penetrance susceptibility genes, especially BRCA1 and BRCA2. In families with known BRCA mutations, disclosure of genetic test results could induce relatives to undergo genetic testing themselves and adopt cancer risk management strategies, if necessary. This study examines disclosure patterns of individuals tested for mutations in the BRCA1, BRCA2 and CHEK2 genes to first-degree relatives with emphasis on a possible gender difference. It also assesses which management strategy is preferred by mutation-positive women in Belgium and the influence of psychological characteristics on communication and choice of management strategy. Ninety-nine adults from BRCA/CHEK2 families, selected from the Centre of Medical Genetics of Antwerp, were included in the study. They were provided with medical and psychological questionnaires, the latter being the Self-Assessment Questionnaire, which is the Dutch version of the Spielberger State-Trait Anxiety Inventory and the Dutch version of the Coping Inventory for Stressful Situations (CISS-NL). The survey focused on disclosure, coping and management strategies with special attention on possible gender differences. The influence of socio-demographic and medical data on disclosure and cancer risk management as well as the influence of psychological features were examined by means of various statistical analyses. Ninety-nine patients were included, of whom 25 (25 %) were male. Eighty-seven percent of the participants informed all of their adult first-degree relatives about their mutation status without any gender discrimination. Seventy-eight percent of highly-educated participants informed all of their adult first-degree relatives, compared to 98 % of less formally-educated participants (p = 0.006). The majority of mutation-positive women preferred prophylactic surgery to surveillance. Psychological differences appeared to have little influence on disclosure patterns and management strategies. The gender difference seems to be less pronounced than previously assumed. A striking observation, however, is the fact that significantly more participants who were less formally-educated informed all of their adult first-degree relatives, compared to participants who were highly-educated. In our study population, most female mutation carriers opted for prophylactic surgery. Since the study population is small, further studies are needed to enhance the generalizability of these results.

Left ventricular longitudinal strain measured by speckle tracking as a predictor of the decrease in left ventricular deformation in children with congenital stenosis of the aorta or coarctation of the aorta.

Children born with a left ventricular outflow tract obstruction (LVOTO) can present with symptoms of left ventricular (LV) failure while ejection fraction (EF) is normal. A more sensitive parameter of systolic function might be obtained with speckle tracking echocardiography, which describes ventricular longitudinal deformation in strain values. It is presumed that despite a normal or only slight decrease in ejection fraction, patients with a LVOTO demonstrate aberrations in the longitudinal deformation of the left ventricle. In addition, it is expected that after a successful intervention, longitudinal deformation returns to normal values. Standard trans-thoracic echocardiography was performed on 33 consecutive patients with a LVOTO, either an isolated aortic coarctation (AoCo) or an isolated aortic stenosis (AoSt). Before intervention a significant decrease in strain values was observed compared with the control group (N = 40), with an additional decrease in strain values in the first week after intervention (N = 16). Strain values recovered after a mean follow-up period of 42 wk (N = 9), though normal values were never reached. In addition, patients with an AoCo had a smaller decrease in strain values compared with patients with AoSt. All strain values were measured with a concomitant ejection fraction between normal limits. It is concluded that patients with a congenital LVOTO have decreased ventricular systolic function measured as strain values, whereas their ejection fraction is within the normal range. Therefore, as ejection fraction may not be an accurate measure, speckle tracking-based strain may be significant in the identification of subtle changes in longitudinal deformation and may create opportunities for patients to benefit from early treatment for heart failure.

Bone healing and mannose-binding lectin.

Non-union of a fracture is a phenomenon that may complicate bone healing. Consolidation of a fracture can be divided into three phases: inflammation, reconstruction, and remodeling. Both the complement system and the coagulation cascade interact at various steps throughout these phases. Several complement components are specifically associated with the inflammation phase of bone healing. However, in which way complement components influence the remodeling phase has not been established yet. Mannose-Binding Lectin (MBL) and its associated serine protease MASP-2 (Mannanbinding lectin serine protease-2) are important initiating proteins of the complement system and have also been implicated in coagulation. With respect to the characteristics and interactions of MBL, it is likely to assume a considerable influence of MBL in the remodeling phase of bone healing. A deficiency in MBL then, caused by a genetic variation, may disturb this particular process during bone healing, due to either an accumulation of apoptotic cells or to a diminished scaffold of fibrin molecules. The next step would be early identification of patients with a deficiency of MBL, allowing for early therapeutic intervention or even non-union preventive measures. This review aims to discuss the true and hypothesized role of MBL in bone healing and the consequences of a depletion of the protein in the etiology of fracture non-union.

Auditory neuropathy: a challenge for diagnosis and treatment.

In current terminology, auditory neuropathy spectrum disorder (ANSD) is a disease involving the disruption of the temporal coding of acoustic signals in auditory nerve fibres, resulting in the impairment of auditory perceptions that rely on temporal cues. There is debate about almost every aspect of the disorder, including aetiology, lesion sites, and the terminology used to describe it. ANSD is a heterogeneous disease despite similar audiological findings. The absence of an auditory brainstem response (ABR) and the presence of otoacoustic emissions (OAE) suggest an ANSD profile. However, to determine the exact anatomical site of the disorder, more in-depth audiological and electrophysiological tests must be combined with imaging, genetics and neurological examinations. Greater diagnostic specificity is therefore needed to provide these patients with more adequate treatment.

Inhaled corticosteroids in persons with HIV infection: not that harmless.

There is a growing group of HIV-seropositive patients at risk for chronic lung disease due to their life style and age. The interaction between certain antiretroviral drugs and corticosteroid inhalation therapy is potentially dangerous but often unrecognised. We present three cases from our HIV-clinic of whom two developed full blown Cushing's syndrome over a short period of time and one presented with asymptomatic hypocortisolaemia due to serious drug interactions between HIV-drugs and inhaled corticosteroids. General practitioners, HIV and chest physicians should all be aware of this potentially life-threatening interaction and the combination of those products should be avoided where possible.

Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing.

Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron-exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted.

Epidemiology and outcome of Shigella, Salmonella and Campylobacter infections in travellers returning from the tropics with fever and diarrhoea.

INTRODUCTION: During a study on fever after a stay in the tropics, we aimed at investigating the epidemiology and outcome of invasive bacterial enteritis due to Shigella, Salmonella or Campylobacter spp. in patients diagnosed with febrile traveller's diarrhoea. METHODS: From April 2000 to September 2006, we evaluated prospectively 594 travellers presenting with fever and diarrhoea within a month after a stay in the tropics. Patients not found with a systemic infection were assumed to have febrile traveller's diarrhoea (TD). Invasive bacterial enteritis was confirmed by isolation of Shigella, Campylobacter or nontyphoidal Salmonella in stool cultures. RESULTS: Systemic infections (mainly malaria) were diagnosed in 259 (44%) evaluated travellers. Invasive bacterial enteritis, either alone or with another infection, was confirmed in 114 (34%) of the 335 remaining patients with febrile TD. Aetiologies were distributed between Campylobacter jejuni (47, 41%), Shigella spp. (43, 38%), Salmonella spp. (22, 19%) and mixed Campylobacter-Salmonella infection (2, 2%). Invasive bacterial enteritis accounted for about a third of febrile TD cases occurring after a stay in sub-Saharan Africa, North Africa/Middle East or Latin America, and for half of those occurring after a travel to southern Asia (including 33% only due to C. jejuni). Resistance to fluoroquinolones was exclusively observed in C. jejuni isolates, but at an overall rate of 53%. Clinical failure occurred in 33% of the patients with C. jejuni infection empirically treated with a fluoroquinolone. CONCLUSION: Invasive bacterial enteritis was a frequent aetiology of febrile TD. C. jejuni was the leading pathogen after a travel to southern Asia, and was associated with high rate of resistance to fluoroquinolones and of clinical failure.

Time delays in diagnosis of pulmonary tuberculosis: a systematic review of literature.

BACKGROUND: Delay in diagnosis of pulmonary tuberculosis results in increasing severity, mortality and transmission. Various investigators have reported about delays in diagnosis of tuberculosis. We aimed at summarizing the data on these delays in diagnosis of tuberculosis. METHODS: A systematic review of literature was carried out. Literature search was done in Medline and EMBASE from 1990 to 2008. We used the following search terms: delay, tuberculosis, diagnosis, and help-seeking/health-seeking behavior without language restrictions. In addition, indices of four major tuberculosis journals were hand-searched. Subject experts in tuberculosis and authors of primary studies were contacted. Reference lists, review articles and text book chapters were also searched. All the studies were assessed for methodological quality. Only studies carried out on smear/culture-positive tuberculosis patients and reporting about total, patient and health-care system delays were included. RESULTS: A total of 419 potential studies were identified by the search. Fifty two studies qualified for the review. The reported ranges of average (median or mean) total delay, patient delay, health system delay were 25-185 days, 4.9-162 days and 2-87 days respectively for both low and high income countries. Average patient delay was similar to health system delay (28.7 versus 25 days). Both patient delay and health system delay in low income countries (31.7 days and 28.5 days) were similar to those reported in high income countries (25.8 days and 21.5 days). CONCLUSION: The results of this review suggest that there is a need for revising case-finding strategies. The reported high treatment success rate of directly observed treatment may be supplemented by measures to shorten the delay in diagnosis. This may result in reduction of infectious cases and better tuberculosis control.

Child to adult continuities of psychopathology: a 24-year follow-up.

OBJECTIVE: To determine continuities of mental health problems of children across a 24-year follow-up period. METHOD: In 1983, parent ratings of emotional and behavioral problems were collected with the Child Behavior Checklist (CBCL) in a general population sample of 2076 children. Twenty-four years later, 1365 participants completed Adult Self-Reports (ASR) to assess emotional and behavioral problems. RESULTS: Of the participants who were classified as deviant in childhood, 22.2% were also classified as deviant in adulthood. Both homotypic and heterotypic continuity was found. Childhood aggressive, delinquent, and anxious/depressed problems were associated with most adult psychopathology. Attention problems did not predict later problems independently. CONCLUSION: Even though assessed with parent-reports in childhood and analogous self-reports in adulthood, and over a large period of 24 years, continuity of psychopathology was found from childhood into adulthood. Anxious/depressed problems, delinquent behavior and aggressive behavior in childhood are core predictors for adult psychopathology.

Molecular diagnostics of intestinal parasites in returning travellers.

A new diagnostic strategy was assessed for the routine diagnosis of intestinal parasites in returning travellers and immigrants. Over a period of 13 months, unpreserved stool samples, patient characteristics and clinical data were collected from those attending a travel clinic. Stool samples were analysed on a daily basis by microscopic examination and antigen detection (i.e. care as usual), and compared with a weekly performed multiplex real-time polymerase chain reaction (PCR) analysis on Entamoeba histolytica, Giardia lamblia, Cryptosporidium and Strongyloides stercoralis. Microscopy and antigen assays of 2,591 stool samples showed E. histolytica, G. lamblia, Cryptosporidium and S. stercoralis in 0.3, 4.7, 0.5 and 0.1% of the cases, respectively. These detection rates were increased using real-time PCR to 0.5, 6.0, 1.3 and 0.8%, respectively. The prevalence of ten additional pathogenic parasite species identified with microscopy was, at most, 0.5%. A pre-selective decision tree based on travel history or gastro-intestinal complaints could not be made. With increased detection rates at a lower workload and the potential to extend with additional parasite targets combined with fully automated DNA isolation, molecular high-throughput screening could eventually replace microscopy to a large extent.