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1.  Otocephaly-Dysgnathia Complex: Description of Four Cases and Confirmation of the Role of OTX2 
Molecular Syndromology  2013;4(6):302-305.
Otocephaly-dysgnathia complex is characterized by mandibular hypo- or aplasia, ear abnormalities, microstomia, and microglossia. Mutations in the orthodenticle homeobox 2 (OTX2) and paired related homeobox 1 (PRRX1) genes have recently been identified in some cases. We screened 4 otocephalic cases for these 2 genes and identified OTX2 mutations in 2 of them, thus confirming OTX2 is implicated in otocephaly. No PRRX1 mutation was identified. Interestingly, ocular involvement is not a constant feature in otocephalic cases with an OTX2 mutation. In one case, the mutation was inherited from a microphthalmic mother. The mechanism underlying this intrafamilial phenotypic variability remains unclear, but other genetic factors are likely to be necessary for the manifestation of the otocephalic phenotype.
doi:10.1159/000353727
PMCID: PMC3776467  PMID: 24167467
Agnathia; Microphthalmia; Otocephaly; OTX2; PRRX1
2.  More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated 
Molecular Syndromology  2013;4(5):235-245.
CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.
doi:10.1159/000351127
PMCID: PMC3711480  PMID: 23885230
CHARGE syndrome; CHD7; 22q11.2 deletion syndrome; TBX1

4.  Doctor's views on disclosing or withholding information on low risks of complication 
Journal of Medical Ethics  2007;33(2):67-70.
Background
More and more quantitative information is becoming available about the risks of complications arising from medical treatment. In everyday practice, this raises the question whether each and every risk, however low, should be disclosed to patients. What could be good reasons for doing or not doing so? This will increasingly become a dilemma for practitioners.
Objective
To report doctors' views on whether to disclose or withhold information on low risks of complications.
Methods
In a qualitative study design, 37 respondents (gastroenterologists and gynaecologists or obstetricians) were included. Focus group interviews were held with 22 respondents and individual in‐depth interviews with 15.
Results
Doctors have doubts about disclosing or withholding information on complication risk, especially in a risk range of 1 in 200 to 1 in 10 000. Their considerations on whether to disclose or to withhold information depend on a complicated mix of patient and doctor‐associated reasons; on medical and personal considerations; and on the kind and purpose of intervention.
Discussion
Even though the degree of a risk is important in a doctor's considerations, the severity of the possible complications and patients' wishes and competencies have an important role as well. Respondents said that low risks should always be communicated when there are alternatives for the intervention or when the patient may prevent or mitigate the risk. When the appropriateness of disclosing risks is doubtful, doctors should always tell their patients that no intervention is without risk, give them the opportunity to gather all the information they need or want, and enable them to detect a complication at an early stage.
doi:10.1136/jme.2005.014936
PMCID: PMC2598232  PMID: 17264190
5.  Diet and asthma in Dutch school children (ISAAC‐2) 
Thorax  2005;61(12):1048-1053.
Background
The rise in the prevalence of asthma in western societies may be related to changed dietary habits. Epidemiological studies in children have shown inverse associations of asthma related outcomes with intake of fruits, vegetables, dairy and whole grain products, and fish. In contrast to most previous studies, we used both questionnaire and clinical data to define asthma.
Methods
Intake of the abovementioned foods was studied in relation to asthma in 598 Dutch children aged 8–13 years. Dietary intake was estimated using a parent completed semi‐quantitative food frequency questionnaire. Current wheeze and current asthma were defined based on questionnaire data. More complex end points were defined using information on bronchial hyperresponsiveness (BHR) and atopic sensitisation as well. Linear associations were studied using logistic regression analysis and odds ratios presented for the highest versus the lowest tertile of intake. In the final models, adjustments were made for maternal educational level, foreign descent, and total energy intake.
Results
The intake of whole grain products and of fish was inversely associated with asthma. Adjusted odds ratios for the independent associations with whole grains and fish were 0.46 (95% CI 0.19 to 1.10) and 0.34 (95% CI 0.13 to 0.85) for current asthma and 0.28 (95% CI 0.08 to 0.99) and 0.12 (95% CI 0.02 to 0.66) for atopic asthma with BHR. Similar results were observed for current wheeze and atopic wheeze with BHR. Intake of (citrus) fruits, vegetables, and dairy products showed no clear associations with asthma end points.
Conclusions
Our findings suggest that a high intake of whole grain products and fish may have a protective effect against asthma in children.
doi:10.1136/thx.2005.043034
PMCID: PMC2117046  PMID: 16244092
diet; asthma; children; fish; whole grains
6.  Associations between ambient, personal, and indoor exposure to fine particulate matter constituents in Dutch and Finnish panels of cardiovascular patients 
Aims: To assess the relation between ambient, indoor, and personal levels of PM2.5 and its elemental composition for elderly subjects with cardiovascular disease.
Methods: In the framework of a European Union funded study, panel studies were conducted in Amsterdam, the Netherlands and Helsinki, Finland. Outdoor PM2.5 concentrations were measured at a fixed site. Each subject's indoor and personal PM2.5 exposure was measured biweekly for six months, during the 24 hour period preceding intensive health measurements. The absorbance of PM2.5 filters was measured as a marker for diesel exhaust. The elemental content of more than 50% of the personal and indoor samples and all corresponding outdoor samples was measured using energy dispersive x ray fluorescence.
Results: For Amsterdam and Helsinki respectively, a total of 225 and 238 personal, and 220 and 233 indoor measurements, were analysed from 36 and 46 subjects. For most elements, personal and indoor concentrations were lower than and highly correlated with outdoor concentrations. The highest correlations (median r>0.9) were found for sulfur and particle absorbance, which both represent fine mode particles from outdoor origin. Low correlations were observed for elements that represent the coarser part of the PM2.5 particles (Ca, Cu, Si, Cl).
Conclusions: The findings of this study provide support for using fixed site measurements as a measure of exposure to particulate matter in time series studies linking the day to day variation in particulate matter to the day to day variation in health endpoints, especially for components of particulate matter that are generally associated with fine particles and have few indoor sources. The high correlation for absorbance of PM2.5 documents that this applies to particulate matter from combustion sources, such as diesel vehicles, as well.
doi:10.1136/oem.2004.016618
PMCID: PMC1740941  PMID: 16299096
7.  Fatigue as a predictor of sickness absence: results from the Maastricht cohort study on fatigue at work 
Occupational and Environmental Medicine  2003;60(Suppl 1):i71-i76.
Objectives: To investigate whether there is a relationship between fatigue and sickness absence. Two additional hypotheses were based on the theoretical distinction between involuntary, health related absence and voluntary, attitudinal absence. In the literature, the former term is usually used to describe long term sickness absence, the latter relates to short term sickness absence. In line with this, the first additional hypothesis was that higher fatigue would correspond with a higher risk of long term, primarily health related absence. The second additional hypothesis was that higher fatigue would correspond with a higher risk of short term, primarily motivational absence.
Methods: A multidimensional fatigue measure, as well as potential sociodemographic and work related confounders were assessed in the baseline questionnaire of the Maastricht cohort study on fatigue at work. Sickness absence was objectively assessed on the basis of organisational absence records and measured over the six months immediately following the baseline questionnaire. In the first, general hypothesis the effect of fatigue on time-to-onset of first sickness absence spell during follow up was investigated. For this purpose, a survival analysis was performed. The effect of fatigue on long term sickness absence was tested by a logistic regression analysis. The effect of fatigue on short term sickness absence was investigated by performing a survival analysis with time-to-onset of first short absence spell as an outcome.
Results: It was found that higher fatigue decreased the time-to-onset of the first sickness absence spell. Additional analyses showed that fatigue was related to long term as well as to short term sickness absence. The effect of fatigue on the first mentioned outcome was stronger than the effect on the latter outcome. Potential confounders only weakened the effect of fatigue on long term absence.
Conclusions: Fatigue was associated with short term but particularly with long term sickness absence. The relation between fatigue and future sickness absence holds when controlling for work related and sociodemographic confounders. Fatigue as measured with the Checklist Individual Strength can be used as a screening instrument to assess the likelihood of sickness absence in the short term.
doi:10.1136/oem.60.suppl_1.i71
PMCID: PMC1765725  PMID: 12782750
8.  Relationship between exhaled NO, respiratory symptoms, lung function, bronchial hyperresponsiveness, and blood eosinophilia in school children 
Thorax  2003;58(3):242-245.
Methods: Levels of eNO in a sample of 450 children aged 7–12 years out of a total sample of 2504 school children living in different urban areas near motorways were determined. The aim of this cross-sectional study was to explore the relationship between eNO, impairment of lung function (PEF, FVC, FEV1 and MMEF), bronchial hyperresponsiveness (BHR), and blood eosinophilia in children with and without atopy as assessed by skin prick testing.
Results: Regression analysis showed that wheezing and nasal discharge and conjunctivitis that had occurred during the previous 12 months were positively associated with eNO levels in atopic children (relative increase of 1.48 and 1.41, respectively; p<0.05) but not in non-atopic children. Similarly, BHR and the number of blood eosinophils per ml were positively associated with eNO levels in atopic children (relative increase of 1.55 and 2.29, respectively; p<0.05) but not in non-atopic children. The lung function indices PEF, FVC, FEV1 and MMEF were not associated with eNO levels.
Conclusions: In addition to conventional lung function tests and symptom questionnaires, eNO is a suitable measure of airway inflammation and its application may reinforce the power of epidemiological surveys on respiratory health.
doi:10.1136/thorax.58.3.242
PMCID: PMC1746591  PMID: 12612304
10.  Mass concentration and elemental composition of PM10 in classrooms 
OBJECTIVES: To investigate the sources of high concentrations of particles of < 10 microns diameter (PM10) in classrooms, observed in a previous study on childhood exposure to PM10, and to study the correlation between classroom and outdoor concentrations of mass and elements of PM10. METHODS: Measurements of PM10 were conducted in two schools and outdoors in Amsterdam, the Netherlands. Averaging time was 24 hours for the outdoor measurements and both 8 hours (school time) and 24 hours for the classroom measurements. Analysis by x ray fluorescence was used to measure the elemental composition of 55 samples from the 11 days when measurements were conducted simultaneously in both classrooms and outdoors. RESULTS: For most elements, classroom concentrations were considerably higher than outdoor concentrations, especially during school hours. The highest classroom/outdoor ratios were found for the elements from soils Si, Ca, and Ti. The only measured elements that were not increased were S, Br, Pb, and Cl, which are dominated by non-crustal sources. For S, Br, and Pb, which are generally associated with particles < 1 micron, significant correlations between classroom and outdoor concentrations and between the two classrooms were found. The other elements generally had low correlations. CONCLUSIONS: The results show that the high PM10 concentrations found in our classrooms are probably due to resuspension of coarse particles or suspension of soil material. Due to these excess coarse particles, the correlation between classroom and outdoor concentrations is lower for elements associated with coarse particles than for elements associated with fine particles. As the general composition of PM10 in classrooms differs from the composition of PM10 in ambient air, the high PM10 mass concentrations in classrooms can probably not be directly compared with ambient air quality guidelines.
 
PMCID: PMC1757765  PMID: 10472320
11.  Personal and outdoor nitrogen dioxide concentrations in relation to degree of urbanization and traffic density. 
Environmental Health Perspectives  2001;109(Suppl 3):411-417.
To assess differences in exposure to air pollution from traffic in relation to degree of urbanization and traffic density, we measured personal and home outdoor nitrogen dioxide (NO(2)) concentrations for 241 children from six different primary schools in the Netherlands. Three schools were situated in areas with varying degrees of urbanization (very urban, fairly urban, and nonurban) and three other schools were located near highways with varying traffic density (very busy, fairly busy, and not busy). Weekly averaged measurements were conducted during four different seasons. Simultaneously, indoor and outdoor measurements were conducted at the schools. Personal and outdoor NO(2) concentrations differed significantly among children attending schools in areas with different degrees of urbanization and among children attending schools in areas close to highways with different traffic densities. For the children living near highways, personal and outdoor NO(2) concentrations also significantly decreased with increasing distance of the home address to the highway. Differences in personal exposures between children from the different schools remained present and significant after adjusting for indoor sources of NO(2). This study has shown that personal and outdoor NO(2) concentrations are influenced significantly by the degree of urbanization of the city district and by the traffic density of and distance to a nearby highway. Because NO(2) can be considered a marker for air pollution from traffic, the more easily measured variables degree of urbanization, traffic density, and distance to a nearby highway can all be used to estimate exposure to traffic-related air pollution.
PMCID: PMC1240559  PMID: 11429326
12.  Airborne concentrations of PM(2.5) and diesel exhaust particles on Harlem sidewalks: a community-based pilot study. 
Environmental Health Perspectives  2000;108(3):213-218.
Residents of the dense urban core neighborhoods of New York City (NYC) have expressed increasing concern about the potential human health impacts of diesel vehicle emissions. We measured concentrations of particulate matter [less than/equal to] 2.5 micro in aerodynamic diameter (PM(2.5)) and diesel exhaust particles (DEP) on sidewalks in Harlem, NYC, and tested whether spatial variations in concentrations were related to local diesel traffic density. Eight-hour (1000-1800 hr) air samples for PM(2.5 )and elemental carbon (EC) were collected for 5 days in July 1996 on sidewalks adjacent to four geographically distinct Harlem intersections. Samples were taken using portable monitors worn by study staff. Simultaneous traffic counts for diesel trucks, buses, cars, and pedestrians were carried out at each intersection on [Greater/equal to] 2 of the 5 sampling days. Eight-hour diesel vehicle counts ranged from 61 to 2,467 across the four sites. Mean concentrations of PM(2.5) exhibited only modest site-to-site variation (37-47 microg/m(3)), reflecting the importance of broader regional sources of PM(2.5). In contrast, EC concentrations varied 4-fold across sites (from 1.5 to 6 microg/m(3)), and were associated with bus and truck counts on adjacent streets and, at one site, with the presence of a bus depot. A high correlation (r = 0.95) was observed between EC concentrations measured analytically and a blackness measurement based on PM(2.5) filter reflectance, suggesting the utility of the latter as a surrogate measure of DEP in future community-based studies. These results show that local diesel sources in Harlem create spatial variations in sidewalk concentrations of DEP. The study also demonstrates the feasibility of a new paradigm for community-based research involving full and active partnership between academic scientists and community-based organizations.
Images
PMCID: PMC1637978  PMID: 10706526
13.  Childhood exposure to PM10: relation between personal, classroom, and outdoor concentrations. 
OBJECTIVES: To investigate the validity of outdoor concentrations of particulate matter < 10 microns diameter (PM10) as a measure of exposure in time series studies, and to study the extent to which differences between personal and outdoor PM10 concentrations can be explained. METHODS: Four to eight repeated measurements of personal and outdoor PM10 concentrations were conducted for 45 children, aged 10-12 years, from four schools in Wageningen and Amsterdam, The Netherlands. Repeated PM10 measurements in the classrooms were conducted in three of the schools. Averaging time was 24 hours for the personal and outdoor measurements, and eight hours (daytime) and 24 hours for the classroom measurements. For each child separately, personal exposures were related to outdoor concentrations in a regression analysis. The distribution of the individual correlation and regression coefficients was investigated. Information about factors that might influence personal exposures was obtained by questionnaire. RESULTS: Median Pearson's correlations between personal and outdoor concentrations were 0.63 for children with parents who did not smoke and 0.59 for children with parents who smoked. For children with parents who did not smoke, excluding days with exposure to environmental tobacco smoke (ETS) improved the correlation to a median R of 0.73. The mean personal PM10 concentration was 105 micrograms/m3; on average 67 micrograms/m3 higher than the corresponding outdoor concentrations. The main part of this difference could be attributed to exposure to ETS, to high PM10 concentrations in the classrooms, and to (indoor) physical activity. CONCLUSIONS: The results show a reasonably high correlation between repeated personal and outdoor PM10 measurements within children, providing support for the use of fixed site measurements as a measure of exposure to PM10 in epidemiological time series studies. The large differences between personal and outdoor PM10 concentrations probably result from a child's proximity to particle generating sources and particles resuspended by personal activities.
PMCID: PMC1128970  PMID: 9470897
14.  Successful paediatric HIV treatment in rural primary care in Africa 
Archives of Disease in Childhood  2009;95(6):414-421.
Objective
Clinical outcomes of HIV-infected children on antiretroviral treatment (ART) in a decentralised, nurse/counsellor-led programme.
Design
Clinical cohort.
Setting
KwaZulu-Natal, South Africa.
Patients
HIV-infected children aged ≤15 years on ART, June 2004–2008.
Main outcome measures
Survival according to baseline characteristics including age, WHO clinical stage, haemoglobin and CD4%, was assessed in Kaplan–Meier analyses. Hazard ratios for mortality were estimated using Cox proportional hazards regression and changes in laboratory parameters and weight-for-age z scores after 6–12 months' treatment were calculated.
Results
477 HIV-infected children began ART at a median age of 74 months (range 4–180), median CD4 count (CD4%) of 433 cells/mm3 (17%) and median HIV viral load of log 4.2 copies/ml; 105 (22%) were on treatment for tuberculosis and 317 (76.6%) were WHO stage 3/4. There were significant increases after ART initiation in CD4% (17% vs 22%; p<0.001), haemoglobin (9.9 vs 11.7 g/l; p≤0.001) and albumin (30 vs 36 g/l; p≤0.001). 32 (6.7%) children died over 732 child-years of follow-up (43.7 deaths/1000 child-years; 95% CI 32.7 to 58.2), 17 (53.1%) within 90 days of treatment initiation; median age of death was 84 (IQR 10–181) months. Children with baseline haemoglobin ≤8 g/l were more likely to die (adjusted HR 4.5; 95% CI 1.6 to 12.3), as were those aged <18 months compared with >60 months (adjusted HR 3.2; 95% CI 1.2 to 9.1).
Conclusions
Good clinical outcomes in HIV-infected children on ART are possible in a rural, decentralised service. Few young children are on ART, highlighting the urgent need to identify HIV-exposed infants.
doi:10.1136/adc.2009.169367
PMCID: PMC3181433  PMID: 19880392

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