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Medical treatment for 5q spinal muscular atrophy (SMA) is now standard treatment in many countries, and a growing number of studies report on improvement or stabilization in physical function as a result of medical treatment. Different countries have different practices regarding the target group for medical treatment. Age and level of function have been decisive criteria for receiving the treatment. Until July 2023, the Danish medical council had approved initiation of medical treatment for children up to 10 years of age, and during the spring of 2023 it were to be determined whether the patient target group could be expanded. Based on this potential expansion, the aim of the study was to evaluate the current physical functioning in a national cohort of patients > 10 years and – in case treatment was approved – to repeat the evaluation six month after initiation of treatment. Due to the size of the target group (n=136) and the narrow time frame it was decided to narrow the target group to non-ambulant patients and perform the evaluation online. The evaluation included two items from the revised upper limb scale (RULM) (lift hands, pick up and hold coins), the EK2-scale (17 items), Fatigue Severity Scale (7 items), a brief questionnaire on patient expectations before treatment and an online interview about experiences after initiation of treatment. 57 patients accepted the invitation, answered the questionnaire, and were examined online during the spring of 2023. In July 2023, the Danish medical council decided to expand the target group to patients up to 25 years of age. 11/57 patients met the new criteria and accepted treatment. Follow-up examinations of these patients are ongoing. Results will be reported on the poster. [ABSTRACT FROM AUTHOR]

The effects of o,p'-DDD on the DNA synthesis in the C57B1 mouse lung and liver were studied. As determined by 3H-thymidine incorporation into DNA, a selective increase in the lung DNA synthesis (+59%) was observed 2 days after a single intraperitoneal injection of 100 mg/kg o,p'-DDD. Microautoradiography showed that the incorporated 3H-thymidine was confined to a restricted number of heavily labelled cells, presumably proliferating type II cells. At the most, a 9 times higher rate of cell proliferation was observed in the lung 4 days after an intraperitoneal injection of 500 mg/kg o,p'-DDD. Using mouse lung or liver S-9 as activating system, no mutagenic activity of o,p'-DDD was detected in the Ames test. The induced cell proliferation may indicate a tissue-selective promotor activity of o,p'-DDD in the mouse lung. [ABSTRACT FROM AUTHOR]

Programs supporting the necessary combination of digital, organizational, and cultural transformational change, motivating and engaging the workforce, are scarce. This discussion paper reports on the initial experiences from a competency development program aiming at building capacity within the workforce, leaders, and organization in secondary healthcare to navigate and facilitate digitally transformative healthcare systems. The program aims to support employees and leaders who i) understand digitalization in and of practice, ii) reflect and approach digitalization in a critical and ethical way, iii) are curious and maintain a growth mind-set, iv) engage in development and implementation of digitalization, and v) can convey and communicate digitalization. The insights from the prototype can be useful in further promoting sustainable digitalization within healthcare and supporting leaders in their conduct and management of digital health initiatives.

Background/purpose: The number of dietary exposure assessment studies focussing on children is very limited. Children are however a vulnerable group due to their higher food consumption level per kg body weight. Therefore, the EXPOCHI project aims 1 to create a relational network of individual food consumption databases in children, covering different geographical areas within Europe, and 2 to use these data to assess the usual intake of lead, chromium, selenium and food colours., Methods: EXPOCHI includes 14 food consumption databases focussed on children (1-14 y old). The data are considered representative at national/regional level: 14 regions covering 13 countries. Since the aim of the study is to perform long-term exposure assessments, only data derived from 24 hr dietary recalls and dietary records recorded on at least two non-consecutive days per individual were included in the dietary exposure assessments. To link consumption data and concentration data of lead, chromium and selenium in a standardised way, categorisation of the food consumption data was based on the food categorisation system described within the SCOOP Task report 3.2.11. For food colours, the food categorisation system specified in the Council Directive 94/36/EC was used., Conclusion: The EXPOCHI project includes a pan-European long-term exposure assessment of lead, chromium, selenium and food colours among children living in 13 different EU countries. However, the different study methods and designs used to collect the data in the different countries necessitate an in-depth description of these different methods and a discussion about the resulting limitations.

Probabilistic dietary acute exposure assessments of captan and tolylfluanid were performed for the populations of the Czech Republic, Denmark, Italy, the Netherlands and Sweden. The basis for these assessments was national databases for food consumption and pesticide concentration data harmonised at the level of raw agricultural commodity. Data were obtained from national food consumption surveys and national monitoring programmes and organised in an electronic platform of databases connected to probabilistic software. The exposure assessments were conducted by linking national food consumption data either (1) to national pesticide concentration data or (2) to a pooled database containing all national pesticide concentration data. We show that with this tool national exposure assessments can be performed in a harmonised way and that pesticide concentrations of other countries can be linked to national food consumption surveys. In this way it is possible to exchange or merge concentration data between countries in situations of data scarcity. This electronic platform in connection with probabilistic software can be seen as a prototype of a data warehouse, including a harmonised approach for dietary exposure modelling.

5-Hydroxymethylfurfural (HMF), a heat-induced food toxicant present in a vast number of food items, has been suggested to be genotoxic after being bioactivated by the sulfotransferase SULT1A1. The comet assay was used to evaluate the DNA damaging effect of HMF in cell lines with different activities of SULT1A1: two human cell lines (Caco-2, low activity; and HEK293, higher activity), one cell line from mouse (L5178Y, no activity) and two cell lines from Chinese hamster (V79, negligible activity; and V79-hP-PST, high activity of human SULT1A1). HMF induced significant DNA damage in all cell lines after 3 h exposure to 100 mM. Most sensitive were V79 and V79-hP-PST where HMF induced significant DNA damage at 25 mM. Consequently, in the present study we have shown that HMF is a DNA damaging agent in vitro independent of the activity of SULT1A1 in the cells. The HMF-induced DNA damage was only observed at rather high concentrations which usually was associated with a concomitant decrease in cell viability.

Treatment with 3-aminobenzamide, known as an inhibitor of poly(ADP-ribose)polymerease, decreased the toxicity and covalent binding of the herbicide dichlobenil (2,6-dichlorobenzonitrile; 12 mg/kg; i.p.) in the mouse olfactory mucosa. In vitro studies showed that 3-aminobenzamide markedly reduced the NADPH-dependent covalent binding of [14C]dichlobenil and the hydroxylation of p-nitrophenol which have previously been suggested to be mediated by a common form of cytochrome P450 (P450) in rat olfactory microsomes (Eriksson and Brittebo, Chem.-Biol. Interact. 94,183-196, 1995). Furthermore, 3-aminobenzamide markedly reduced the P450-dependent metabolic activation of [3H]NNK (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone) in rat olfactory microsomes and slightly decreased the P450 2B1-dependent pentoxyresorufindealkylase activity in liver microsomes of phenobarbital-treated rats. The present results suggest that 3-aminobenzamide is also an inhibitor of P450 and that the lack of toxicity of dichlobenil in the olfactory mucosa of 3-aminobenzamide-treated mice is related to a decreased metabolic activation of dichlobenil at this site. Further experiments showed that there was no evidence for a binding of [14C]dichlobenil metabolites to calf thymus DNA or a formation of mutagenic dichlobenil metabolites in Ames' Salmonella assay when dichlobenil was incubated in the presence of homogenates of the olfactory mucosa. Finally, analysis of proteins from olfactory microsomes incubated with [14C]dichlobenil using SDS-PAGE/fluorography revealed a binding of metabolites to all major proteins. Addition of glutathione or the P450-inhibitor metyrapone prevented the binding, suggesting the formation of relatively stable electrophilic products which can leave the activating enzyme and then unselectively bind to the major olfactory microsomal proteins.

Whole-body autoradiography of [3H]aflatoxin B1 ([3H]AFB1) in lamb showed a localization of bound labelling, in addition to the liver, in the nasal olfactory and respiratory mucosa, in the mucosa of the nasopharynx, pharynx, oesophagus, larynx, trachea, bronchi and bronchioles and in the palpebral and bulbar conjunctiva. Microautoradiography revealed that the bound material was confined to specific cell types in extrahepatic tissues. Whole-body autoradiography also showed a labelling of pigmented tissues (such as the eye melanin), which can be ascribed to a melanin affinity of AFB1. In vivo experiments, performed with microsomal preparations of tissues from ewe and lamb showed that several of the extrahepatic tissues were more efficient than the liver in forming DNA-bound AFB1 metabolites. The nasal olfactory mucosa was by far the most effective tissue in this respect. AFB1 induced a high number of gene mutations in Salmonella typhimurium TA100 when incubated with supernatant preparations (9000 g) of the nasal olfactory mucosa, whereas incubations with preparations of the liver resulted in a lower effect. It has been reported that AFB1 can induce nasal tumours in sheep. When microsomal preparations of various tissues were incubated in the presence of reduced glutathione (GSH), but without any addition of cytosolic glutathione-S-transferase (GST), a drastic decrease in the AFB1-DNA binding was seen. Analyses of the water-soluble metabolites formed in the microsomal incubations supplemented with GSH showed fluorescent and ninhydrin-positive metabolites that were not present in the absence of GSH. These results indicate that sheep tissues have intrinsic microsomal GST or cytosolic GSTs associated with the microsomal fraction with a high capacity to catalyse the conjugation of bioactivated AFB1 to GSH. The results of the present study show that several extrahepatic tissues of sheep have a potent capacity to bioactivate AFB1 and also a high capacity to GSH conjugate the bioactivated AFB1.

Nasal olfactory tumours occur in cattle in relatively high frequencies in several developing countries. Since affected animals sometimes show signs of severe aflatoxicosis, a role of aflatoxin B1 (AFB1) in tumorigenesis can be proposed. The results of the present study show that microsomal preparations of the bovine olfactory mucosa have a much higher ability than liver microsomes to induce covalent binding of AFB1 to calf thymus DNA and to microsomal proteins. The major DNA adduct formed was 8,9-dihydro-8-(N7-guanyl)-9-hydroxy-aflatoxin B1. Incubations of microsomal preparations of the bovine nasal olfactory mucosa with glutathione (GSH) and cytosolic fractions of the nasal mucosa resulted in decreased AFB1 DNA binding. A more pronounced decrease was observed when cytosolic fractions of mouse liver were added to the incubations. Mouse liver is known to contain a glutathione-S-transferase with a high ability to scavenge the reactive AFB1-epoxide via conjugation to GSH. Our results indicate that AFB1-GSH conjugation occurs less efficiently in the bovine nasal olfactory mucosa than in the mouse liver. Supernatant preparations (9000 g) of the bovine nasal olfactory mucosa incubated with AFB1 were shown to have the capacity to induce a strong genotoxic response both as regards induction of gene mutations in Salmonella typhimurium TA100 and the induction of sister chromatid exchanges in Chinese hamster ovary cells. Preparations of the bovine liver (9000 g) has a much lower ability to induce these effects. The results of the present study show that the bovine nasal olfactory mucosa has a high AFB1-bioactivating capacity, which can be related to the potent DNA damaging and mutagenic effects observed. It is considered that our results support the assumption that AFB1 plays a role in the aetiology of nasal tumours in cattle.

The polychlorinated dibenzo-p-dioxins/dibenzofurans 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,4,7,8-pentachlorodibenzofuran (PeCDF) were studied for liver tumour promoting activity in a medium-term altered foci assay in nitrosamine-initiated female Sprague-Dawley rats. The congeners under study were administered by weekly subcutaneous injections at three dose levels for 20 weeks. Evaluation of gamma-glutamyltranspeptidase (GGT+), altered hepatic foci development, showed that all congeners studied acted as potent promoters of hepatocarcinogenesis. TCDD and PeCDD were virtually equipotent as enhancers of foci development while PeCDF displayed approximately ten per cent of the activity of the dioxins. Analysis of the dioxin- and furan-congeners by gas chromatography/mass spectroscopy (GC/MS) technique showed that the retention of PeCDD and PeCDF in liver tissue was approximately 7 and 20 times, respectively, as high as the retention of TCDD. Based on the concentration of the respective congener in liver tissue, PeCDD and PeCDF were 0.14 and 0.007 times as active as TCDD as promoters of foci development. The dose related enhancement of GGT+ foci development induced by the PCDD/PCDF congeners was accompanied by an increased incidence of histological changes in the liver.

This study was undertaken to investigate the influence of dietary vitamin A deficiency and type of diet on tetrachlorodibenzo-p-dioxin (TCDD)- and phenobarbital-induced liver tumor promotion in rats. Female Sprague-Dawley rats were partially hepatectomized and subsequently initiated with nitrosodiethylamine. One week later the rats were allocated to five different dietary regimens for the duration of the study: three purified (casein-based) diets containing 200, 1200, and 10000 IU vitamin A per kilogram, respectively, and two conventional (cereal-based) rat diets containing 2000 and 14000 IU vitamin A per kilogram, respectively. After an additional 4 weeks, groups of rats on each dietary regimen were started on one of four different promoter treatments: 0.07 micrograms TCDD/kg/week (sc); 0.7 micrograms TCDD/kg/week (sc); 500 ppm phenobarbital in the drinking water or vehicle only (arachis oil, sc). The study was terminated after 16 weeks of promoter treatment. Sections of liver were stained for gamma-glutamyltranspeptidase (GGT) activity and GGT-positive altered hepatic foci (AHF) were evaluated by stereological methods. All factors studied (TCDD, phenobarbital, dietary vitamin A content, and the type of diet) were shown to influence AHF development significantly. As expected, TCDD and phenobarbital enhanced foci development. Vitamin A deficiency enhanced foci development in its own right and increased the TCDD-induced response markedly. Dietary vitamin A content did not modulate phenobarbital promotion of AHF in the same manner. The enhancement of TCDD-induced effects on foci development by vitamin A deprivation was accompanied by an increased incidence of histological changes marking degeneration in the liver (e.g., oval cell hyperplasia) and accentuation of other TCDD-related toxic responses. In addition, the groups of rats maintained on the cereal-based diets and subjected to the various promoter/vitamin A regimens exhibited significantly higher AHF incidence as compared to correspondingly treated rats fed the purified, casein-based diets. In conclusion, vitamin A deficiency alone may promote hepatocarcinogenesis and enhance the promoting effect of TCDD treatment. However, TCDD-induced depletion of hepatic vitamin A stores was not implicated as a major cause of promotion by TCDD. Nevertheless, vitamin A deficiency brought about by TCDD alone may well act as a promotive stimulus concertedly with an as yet unidentified cellular mechanism in TCDD-induced liver tumor promotion. The differential effects of the two types of diets recorded in the study remain undocumented.

The genotoxic activity of a photochemical reaction mixture of 1,3-butadiene and nitrogen dioxide was investigated in vivo in the mouse bone marrow micronucleus assay and the somatic mutation and recombination test in Drosophila (the wing spot test). Butadiene alone was not mutagenic in Drosophila, but induced micronuclei in mice at 10 ppm after 23 h of exposure. Nitrogen dioxide was not genotoxic in either test system. The photochemical reaction products were toxic but probably not mutagenic in Drosophila and not genotoxic in mouse bone marrow. The in vivo results do not confirm earlier in vitro results that demonstrated a strong direct-acting mutagenic activity of the photochemical products in Salmonella.

Earlier, we reported that vitamin A (retinol), in vitro, exhibits a strong inhibitory effect on the mutagenicity of aflatoxin B1 in the Ames Salmonella/microsome test. This paper reports the same inhibitory effect on the mutagenicity of an aminoazo dye, ortho-aminoazotoluene. Furthermore, the inhibitory effect was exerted by retinol esters such as retinol acetate and retinol palmitate, the latter being the physiological storage form of vitamin A. The inhibition is interpreted as an effect on the mixed-function oxidases that convert ortho-aminoazotoluene to its ultimate mutagenic form.

Induction of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin-O-deethylase (7-EOD) activities as well as of benzo[a]pyrene (BP) metabolite formation in rat prostatic microsomes has been demonstrated after treatment with beta-naphthoflavone (BNF). The capacity to convert promutagenic compounds to ultimate mutagenic metabolites in the Ames' Salmonella assay by 5000 X g supernatant of rat ventral prostate was investigated. Male rats were treated with BNF, polychlorinated biphenyls (PCB; Arochlor 1254), phenobarbital (PB) and the vehicle, corn oil. PCB or BNF pretreatment increased the AHH- and 7-EOD activities 100-200-fold in the rat prostate 5000 X g supernatant (S-5 fraction). Epoxide hydrolase (EH) and glutathione-S-transferase (GST) activities were not affected while UDP-glucuronosyltransferase (UDP-GT) was increased 2.2- and 2.5-fold by PCB and BNF, respectively. PB did not significantly affect any of the enzyme activities measured. A dose-dependent increase in mutagenic response versus amount of 5000 X g supernatant and promutagen (aflatoxin B1 (AFB), 2-aminofluorene (2-AF), BP) was observed. The most pronounced activation was obtained with S-5 fraction from BNF- or PCB-treated rats. The great sensitivity of prostatic AHH to certain inducers and the capacity of the prostate to produce mutagenic metabolites might be of importance for initiation of prostatic cancer by environmental factors.

Vitamin A (retinol) was shown to inhibit the mutagenic activity of aflatoxin B1 (AFB1), when added to the Ames Salmonella/mammalian microsome assay. The inhibition was dose-dependent and not caused by a direct toxic effect on the test bacteria. On the other hand the mutagenicity of diepoxybutane, a mutagen not requiring metabolic activation, was not affected by retinol, indicating that the vitamin does not act as a general scavenger of reactive compounds. The mutagenicity of AFB1 depends on the balance between formation and breakdown of aflatoxin 2,3-epoxide, the presumed ultimate mutagenic/carcinogenic metabolite. Inhibition of AFB1 mutagenicity could thus result from decreased formation or increased breakdown of the 2,3-epoxide.

Vitamin A (retinol)has been demonstrated to modify the mutagenic activity of the aromatic amines, 2-aminofluorene (2AF) and 2-acetylaminofluorene (2AAF) when added to the Ames Salmonella/mammalian microsome assay. Low amounts of retinol(2-20 micrograms/plate) increased the mutagenicity of both 2AF and 2AAF. At higher doses (50-150 micrograms/plates) the mutagenicity of 2AAF remained unchanged while the mutagenicity of 2AF gradually decreased. The present data do not support the hypothesis that retinol generally acts as an inhibitor of in vitro metabolic activation of procarcinogens.

Retinol (vitamin A) has earlier been shown to inhibit the mutagenicity of o-aminoazotoluene (OAAT) in the Salmonella/microsome assay when OAAT is activated with S9 from Sprague-Dawley rats. The results presented in this paper confirm this and also show that S9 from mice, hamsters and gerbils activates OAAT to mutagenic metabolites detected by Salmonella typhimurium TA100. However, S9 from rabbits is inactive. The S9 fraction from rabbits also shows a low aryl hydrocarbon hydroxylase (AHH) activity. The AHH activity or protein content of the microsomal fraction cannot be used to predict the activating capacity of S9 from the other species. Retinol, added in vitro, inhibits the mutagenic effect of OAAT activated by mouse, gerbil or hamster S9. The strongest inhibition is observed with hamster S9 while the inhibition of mouse and gerbil S9 is lower but still higher than in the rat.

Vitamin A has been shown to affect the in vitro metabolism of 2AAF. At low concentrations of retinol or retinyl palmitate, a decreased production of ring-hydroxylated as well as deacetylated and N-hydroxylated metabolites was observed, measured by high performance liquid chromatography. The increased mutagenicity of 2AAF observed after addition of vitamin A in the Ames test cannot therefore be explained as a result of stimulated N-hydroxylation. However, the addition of retinol was found to enhance the mutagenicity of the metabolite N-OH-2AAF in the presence of an S-9 fraction of rat liver homogenate. No differences with regard to the covalent binding of 2AAF or its metabolites to rat liver DNA/RNA in vivo could be demonstrated in animals fed diets with normal or high vitamin A content.