Beam characterization and feasibility study for a small animal irradiation platform at clinical proton therapy facilities.

A deeper understanding of biological mechanisms to promote more efficient treatment strategies in proton therapy demands advances in preclinical radiation research. However this is often limited by insufficient availability of adequate infrastructures for precision image guided small animal proton irradiation. The project SIRMIO aims at filling this gap by developing a portable image-guided research platform for small animal irradiation, to be used at clinical facilities and allowing for a precision similar to a clinical treatment, when scaled down to the small animal size. This work investigates the achievable dosimetric properties of different lowest energy clinical proton therapy beams, manipulated by a dedicated portable beamline including active focusing after initial beam energy degradation and collimation. By measuring the lateral beam size in air close to the beam nozzle exit and the laterally integrated depth dose in water, an analytical beam model based on the beam parameters of the clinical beam at the Rinecker Proton Therapy Center was created for the lowest available clinical beam energy. The same approach was then applied to estimate the lowest energy beam model of different proton therapy facilities, Paul Scherrer Institute, Centre Antoine Lacassagne, Trento Proton Therapy Centre and the Danish Centre for Particle Therapy, based on their available beam commissioning data. This comparison indicated similar beam properties for all investigated sites, with emittance values of a few tens of mm·mrad. Finally, starting from these beam models, we simulated propagation through a novel beamline designed to manipulate the beam energy and size for precise small animal irradiation, and evaluated the resulting dosimetric properties in water. For all investigated initial clinical beams, similar dosimetric results suitable for small animal irradiation were found. This work supports the feasibility of the proposed SIRMIO beamline, promising suitable beam characteristics to allow for precise preclinical irradiation at clinical treatment facilities.

Dwell time verification in brachytherapy based on time resolved in vivo dosimetry.

PURPOSE: This paper presents a method to verify dwell times during High Dose Rate (HDR) Brachytherapy (BT) by means of in vivo dosimetry (IVD), and reports on an afterloader's stability in dwell time control. METHODS: In vivo dosimetry was performed during 20 HDR prostate cancer treatments using a point detector based on a radio-luminescence crystal (Al2O3:C) coupled to a fiber-optic cable. The dose rate was recorded at either 10 Hz or 20 Hz during the treatments. The "time of transit" when the source moved between two dwell positions was identified using the difference in count rate between two measurements. The dwell times were then determined by subtracting two adjacent times of transit. The measured dwell times were matched with the planned dwell times and categorised into two groups: Dwell times matching a single dwell position (identified) and dwell times matching the sum of multiple dwell positions (unidentified). Deviations between measured and planned dwell times were calculated for the identified dwell positions. RESULTS: A total of 3518 dwell positions were analysed. The amount of identified dwell positions were 82%, which increased to 89% if the short dwell times (<1 s) were omitted in the analysis. The largest deviation was -0.4 s seen for a single dwell position, and in 97.1% of the cases, the deviations were <0.15 s. CONCLUSION: The dwell times in BT are well controlled by the afterloader. It is shown that IVD facilitates the detection of dwell time offsets that could have a clinical impact.

Changes in the vesicular zinc pattern following traumatic brain injury.

The present study aims at evaluating the significance of zinc ions on the development of brain damage in a model of traumatic brain injury (TBI). The zinc ion specific autometallographic technique, the ZnSe(AMG) method, using silver enhancement of in vivo-captured zinc ions bound in zinc-selenium nanocrystals was applied to follow changes in the vesicular zinc pattern. Balb/c mice, ZnT3 knockout (ZnT3-Ko) mice, a mouse genetically knocked out for the protein ZnT3 responsible for sequestering zinc into synaptic vesicles, and littermates from the genetically un-manipulated mother type mice, wild type (Wt), were used. The Wt and the Balb/c mice exhibited instantaneously a boost in the zinc staining adjacent to the lesion involving all six neocortical layers. Ultra-structural analyses revealed that the in vivo created ZnSe nanocrystals were still confined to the vesicles of the zinc-enriched (ZEN) neurons in the neuropil. No differences between the Balb/c and Wt mice were seen at any time points. In the ZnT3-Ko mice the ZEN terminals stayed void of AMG grains, but a number of neuronal somata around the lesion became loaded with ZnSe nanocrystals. These silver-enhanced ZnSe nanocrystals were confined to the cytoplasm of the somata and their proximal dendrites. No such soma staining was seen in the Wt or Balb/c mice. We speculate that vesicular zinc may not contribute to neuronal damage following TBI.

Immersion autometallographic tracing of zinc ions in Alzheimer beta-amyloid plaques.

An easy to perform autometallographic technique (AMG) for capturing zinc ions in Alzheimer plaques is presented. The possibility of visualizing loosely bound or free zinc ions in tissue by immersion autometallography (iZnS(AMG)) is a relatively recent development. The iZnS(AMG) staining is caused by zinc-sulphur nanocrystals created in 1-2 mm thick brain slices that are immersed in a 0.1% sodium sulphide, 3% glutaraldehyde phosphate buffered solution, the NeoTimm Solution (NTS), for 3 days. When the zinc-sulphur nanocrystals are subsequently silver-enhanced by autometallography, the plaques are readily identified as spheres of dark interlacing strands of different sizes, embedded in the pattern of zinc-enriched terminals. The zinc specificity of the iZnS(AMG) technique was tested by immersion of brain slides in the chelator DEDTC prior to the NTS immersion. The iZnS(AMG) detection of zinc ions is easily standardized and can be used in the quantification of plaques with stereological methods. This technique is the first to detect zinc in plaques in the cerebellum of transgenic PS1/APP mice and the first to detect zinc ions in plaques and dystrophic neurites at electron microscopical levels.

Psychosocial distress during pregnancy and the risk of infantile colic: a follow-up study.

AIM: To examine the association between psychosocial exposures during pregnancy and the risk of infantile colic. METHODS: The study included 378 infants and was conducted as a substudy of the Danish National Birth Cohort from 1997 to 1999, with prenatal data collected twice during pregnancy. A diary with a record for postpartum weeks 4-8 was used to quantify the amount of the infants' crying and fussing. RESULTS: The cumulative incidence proportion of infantile colic was 8.2%. A threefold increased risk of infantile colic (OR = 3.7; 95% CI: 1.1-13.2) was found for mothers who reported distress during pregnancy. Close to a twofold increased risk of IC was found for the women who scored higher than 8 on the psychological distress scale (adjusted OR = 1.9; 95% CI: 0.5-7.2). CONCLUSION: The results indicate that general distress during pregnancy influences the risk of infantile colic. Whether or not this relationship is causal requires further investigations.

[Infantile colic--an assessment of possible risk factors]. / Tremånederskolik--en vurdering af mulige risikofaktorer.

Infantile colic is defined as crying or fussing for more than three hours a day for more than three days a week. The aetiology is unknown, although many hypotheses have been examined: allergy, type of feeding, the development of the gastrointestinal tract, the development of the central nervous system, and the mother/infant relationship. The frequency varies between 8% and 40% in industrialised countries. We found that education, parity, age, obstetric factors, and gender were not important risk factors. There are no unambiguous results on psychosocial risk factors and infantile colic. Giving parents advice and education in parenting were more effective than changing diets. Elimination of cow's milk or the diet of the mother had some effect. This review comprises studies where infantile colic is defined quantitatively. Despite this, no unambiguous results, which are consistent with a multifactorial aetiology were found.

Do pregnant women report use of dispensed medications?

Surveillance of drug safety in pregnancy often draws on administrative prescription registries. Noncompliance in the use of prescribed medication may be frequent among pregnant women owing to their fear of fetotoxic side effects. To estimate compliance in the use of prescription drugs dispensed during pregnancy, we compared prescription data from the North Jutland Prescription Database with information on drug use provided by pregnant women to the Danish National Birth Cohort (DNBC), which is a health interview survey. We used the North Jutland Prescription Database to identify all prescription drugs dispensed during pregnancy for the 2,041 women who were enrolled in the DNBC in the County of North Jutland, Denmark. Compliance was defined as the probability of reporting drug use in DNBC after purchasing a dispensed prescription drug. The overall compliance to drugs purchased within 120 days before the interview was 43% (95% confidence interval = 40-46). Drugs used for treating chronic diseases, for example, beta-blockers, insulin, thyroid hormones, and diuretic and antiepileptic drugs, were always reported to be used, but compliance was low for drugs used for local or short-term treatment such as antihistamines, antibiotics, antacids, nonsteroid anti-inflammatory drugs, and gynecologic drugs. Thus, for the latter drug groups the prescription database may provide an incomplete identification of exposure. Neither data source is unbiased regarding actual drug intake. Nevertheless, our results indicate that for some drug groups risk assessment studies based on prescription data may produce false negative results as a result of noncompliance.

Smoking during pregnancy and infantile colic.

OBJECTIVE: To evaluate the association between maternal smoking during pregnancy and infantile colic (IC). METHODS: A follow-up study of singleton infants delivered by Danish mothers at the Aarhus University Hospital from May 1991 to February 1992 and still living in the municipality of Aarhus at the age of 8 months was conducted. A total of 1820 mothers and their infants were included. Self-administered questionnaires were used to collect data on smoking, other lifestyle factors, and sociodemographic variables at 16 and 30 weeks of gestation and 8 months postpartum. IC was defined in the 8-month questionnaire and based on Wessel's criteria, except that we used only the crying criterion. RESULTS: IC was seen in 10.8% of all infants. We observed a twofold increased risk of IC among infants whose mothers smoked 15 or more cigarettes per day during their pregnancy(relative risk: 2.1; 95% confidence interval: 1.4-3.2) or in the postpartum period (relative risk: 2.0; 95% confidence interval: 1.3-3.1). Women who smoked continuously during pregnancy and the postpartum period had a relative risk of 1.5 (95% confidence interval: 1.1-2.0) of having a infant with IC compared with women who did not smoke during this period. Adjustment for maternal age, parity, marital status, alcohol intake, birth weight, gestational age, breastfeeding, caffeine intake postpartum, and paternal smoking did not change the effect measures. CONCLUSION: The results indicate that maternal smoking during pregnancy may increase the risk of IC.

Influence of day care attendance on the use of systemic antibiotics in 0- to 2-year-old children.

OBJECTIVE: To examine the association between time spent in different public day care settings and prescription of systemic antibiotics. Design. Population-based cohort study of 5035 Danish children born in 1997 followed from birth to June 30, 1999. METHODS: The study was performed by the linkage of records drawn from administrative registries. Exposure was the total time spent in a day care home or day care center. Outcome was the first prescription of a systemic antibiotic. Possible perinatal and sociodemographic confounding factors were considered by statistical analysis. RESULTS: During the first year of life, 39.8% of the girls and 51.1% of the boys received at least 1 antibiotic prescription drug. Enrollment in a day care setting doubled a child's risk of receiving a prescription drug (adjusted relative risk in day care home 1.9, 95% confidence interval: 1.7-2.0; adjusted relative risk in day care center 2.0, 95% confidence interval: 1.7-2.3). Only age confounded the analyses. Age >1 year at the starting time in day care reduced the risk of receiving antibiotic prescriptions during the first 3 months after enrollment. CONCLUSIONS: Enrollment in public day care facilities raised the risk of receiving an antibiotic prescription drug to the same extent in day care homes as well as in day care centers, so we cannot recommend one facility over the other based on the present study. Children <1 year old at enrollment were most at risk, suggesting that extension of parental leave may reduce the use of antibiotics.

The Danish National Birth Cohort--its background, structure and aim.

BACKGROUND: It is well known that the time from conception to early childhood has importance for health conditions that reach into later stages of life. Recent research supports this view, and diseases such as cardiovascular morbidity, cancer, mental illnesses, asthma, and allergy may all have component causes that act early in life. Exposures in this period, which influence fetal growth, cell divisions, and organ functioning, may have long-lasting impact on health and disease susceptibility. METHODS: To investigate these issues the Danish National Birth Cohort (Better health for mother and child) was established. A large cohort of pregnant women with long-term follow-up of the offspring was the obvious choice because many of the exposures of interest cannot be reconstructed with sufficient validity back in time. The study needs to be large, and it is aimed to recruit 100,000 women early in pregnancy, and to continue follow-up for decades. The Nordic countries are better suited for this kind of research than most other countries because of their population-based registers on diseases, demography and social conditions, linkable at the individual level by means of the unique ID-number given to all citizens. Exposure information is mainly collected by computer-assisted telephone interviews with the women twice during pregnancy and when their children are six and 18 months old. Participants are also asked to fill in a self-administered food frequency questionnaire in mid-pregnancy. Furthermore, a biological bank has been set up with blood taken from the mother twice during pregnancy and blood from the umbilical cord taken shortly after birth. Data collection started in 1996 and the project covered all regions in Denmark in 1999. By August 2000. a total of 60,000 pregnant women had been recruited to the study. It is expected that a large number of gene-environmental hypotheses need to be based on case-control analyses within a cohort like this.

Fetal growth and infantile colic.

AIM: To describe how fetal growth and gestational age affect infantile colic, while considering other potential risk factors. STUDY DESIGN: A population based follow up study of 2035 healthy singleton infants without any disability born to Danish mothers. Information was collected by self administered questionnaires at 16 and 30 weeks of gestation, at delivery, and 8 months post partum. Infantile colic is defined according to Wessel's criteria, but symptoms are restricted to crying for more than three hours a day, for more than three days a week, and for more than three weeks. RESULTS: The cumulated incidence of infantile colic was 10.9%. Low birth weight babies (< 2500 g) had more than twice the risk (odds ratio = 2.7, 95% confidence interval 1.2 to 6.1) of infantile colic when controlled for gestational age, maternal height, and smoking. CONCLUSION: Low birth weight may be associated with infantile colic, and further research will be aimed to focus on fetal growth and infantile colic.