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To elucidate the potential influence of stimulating bone marrow before cell-cycle-dependent irradiation, we sought to determine overall survival in mice receiving total-body irradiation (TBI) when administered granulocyte stimulating factor (G-CSF) at different time points. Gender differences were also studied. C57/BL/6J mice, aged 9–14 weeks, received 8 Gy TBI in a perspex cage using a linear accelerator. In each of five different experiments, three groups were studied: 1. one control group receiving TBI only; 2. one group treated with filgrastim [500 lg/kg subcutaneously/intraperitoneally (s.c./i.p.)] the day before TBI, followed by daily filgrastim injections postirradiation (1–5 days); and 3. one group treated with daily filgrastim injections only post-TBI (1–5 days). Each experimental group included male and female mice. Survival of the mice was monitored daily, and mice were euthanized when their condition deteriorated. A total of 293 mice were monitored for at least 37 days post-TBI. Control mice that received 8 Gy TBI showed a significant gender difference, with a median survival of 22 days in females and 17 days in males. Addition of G-CSF, irrespective of pre- or postirradiation, significantly improved survival, but in males the improvement was significantly better when G-CSF was not given before TBI. Improved survival in females was independent of the order of administration of GCSF. Multiple filgrastim injections were more effective than a single injection, and s.c. administration was not better than i.p. In conclusion, these findings indicate that male mice are more sensitive to TBI than females. Filgrastim improved survival in both genders irrespective of whether given pre- or postirradiation, but in males the improvement was significantly less if an injection was given before irradiation. These results suggest that, to prevent toxicity most effectively, GCSF should not be given before cytotoxic therapy. While a completely different experimental model was used here, these results may also be extrapolated to indicate that endocrine cell-cycle suppression therapy should not be given before or during cytotoxic therapy of hormone-dependent tumors (e.g., breast and prostate cancer), thus a reduction in the efficacy of cell-cycle-dependent therapy can be prevented. [ABSTRACT FROM AUTHOR]

In the Go¨teborg Ozone-Spruce Project (GOSP), two independent open-top chamber experiments were conducted during four growing seasons, using one clone of Norway spruce (Picea abies). The experiments tested the impact of ozone, alone and in combination with low phosphorus supply and in combination with drought stress, respectively, on biomass accumulation. In this paper, the results from both experiments were combined for the first time in order to analyse the relationship between relative biomass accumulation and different exposure indices (accumulated exposure over a threshold (AOT) with different cut-off concentrations, and the sum of ozone concentrations above 60 nl l−1, referred to as SUM06). In addition, a pooled analysis was made on several European studies of Norway spruce as a first effort to synthesize independent data and test the relative growth in relation to the AOT40 index. Significant negative relationships between the relative biomass of the GOSP-clone and the different indices were obtained. AOT20 and AOT30 resulted in the highest correlations. Based on the regression model, ozone is predicted to reduce the biomass of the GOSP-clone by 1% at the critical level for forest trees in Europe, a seasonal AOT40 of 10 μl l−1 h. A significant negative relationship between relative growth and AOT40 was obtained also with the European data set. At the present ozone critical level, the model predicted a 6% reduction in growth for the most sensitive Norway spruce trees in this data set. [Copyright &y& Elsevier]

Norway spruce saplings [Picea abies (L.) Karst.] were exposed during four growing seasons to different ozone treatments in open-top chambers: charcoal filtered air (CF), non-filtered air (NF) and non-filtered air with extra ozone (NF+, 1.4×ambient concentrations). The CF and NF+ ozone treatments were combined with phosphorous deficiency and drought stress treatments. The total biomass of the trees was harvested at different intervals during the experimental period. The ozone uptake to current-year needles of the Norway spruce saplings was estimated using a multiplicative stomatal conductance simulation model. There was a highly significant correlation between the reduction of total biomass and the estimated cumulative ozone uptake, which did not vary when different thresholds were applied for the rate of ozone uptake. The reduction of the total biomass was estimated to 1% per 10 mmol m−2 cumulated ozone uptake, on a projected needle area basis. [Copyright &y& Elsevier]

Background: Chemotherapy drug distribution varies greatly among individual patients. Therefore, we developed an individualised fluorouracil, epirubicin, cyclophosphamide (FEC) regimen to improve outcomes in patients with high-risk early breast cancer. We then did a randomised trial to compare this individually tailored FEC regimen with conventional adjuvant chemotherapy followed by consolidation with high-dose chemotherapy with stem-cell support.Methods: 525 women younger than 60 years of age with high-risk primary breast cancer were randomised after surgery to receive nine cycles of tailored FEC to haematological equitoxicity with granulocyte colony-stimulating factor (G-CSF) support (n=251), or three cycles of FEC at standard doses followed by high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTCb), and peripheral-blood stem-cell or bone-marrow support (n=274). Both groups received locoregional radiation therapy and tamoxifen for 5 years. The primary outcome measure was relapse-free survival, and analysis was by intention to treat.Findings: At a median follow-up of 34.3 months, there were 81 breast-cancer relapses in the tailored FEC group versus 113 in the CTCb group (double triangular method p=0.04). 60 deaths occurred in the tailored FEC group and 82 in the CTCb group (log-rank p=0.12). Patients in the CTCb group experienced more grade 3 or 4 acute toxicity compared with the tailored FEC group (p<0.0001). Two treatment-related deaths (0.7%) occurred in the CTCb group. Six patients in the tailored FEC group developed acute myeloid leukaemia and three developed myelodysplastic syndrome.Interpretation: Tailored FEC with G-CSF support resulted in a significantly improved relapse-free survival and fewer grade 3 and 4 toxicities compared with marrow-supported high-dose chemotherapy with CTCb as adjuvant therapy of women with high-risk primary breast cancer. [ABSTRACT FROM AUTHOR]

Aim: To explore family-reported neurodevelopmental functioning and quality of life in 6-year-olds who had screened positive for developmental language disorder at age 2.5 years., Methods: Parents of 85 6-year-old children completed questionnaires about child neurodevelopmental difficulties and quality of life. The children were interviewed regarding quality of life, and their language was assessed by speech and language pathologists. Test results at 6 years identified three subgroups: children with developmental language disorder (n = 68) or speech sound disorder (n = 6) and children with no current language disorder (n = 11)., Results: Out of the 68 children with developmental language disorder, 33 (48%) had significant parent-rated problems with language, executive functions 17 (25%), perception 15 (22%) and/or motor skills 15 (22%). Four (67%) of the children with speech sound disorder had significant problems with language. Significant problems were reported with language in five (45%) and with perception in four (36%) children with no current language disorder. The parents reported no impaired quality of life, whereas the children themselves reported impairment mainly with school functioning., Conclusions: Overlap between language difficulties and other neurodevelopmental problems was higher in 6-year-olds who had screened positive for developmental language disorder about 3 years earlier, than in the general population. The parent and child reports of quality of life were not consistent., (© 2021 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Background Medication-related hospital admissions (MRAs) are frequently used to measure outcomes in studies involving medication reviews. The process of identifying MRAs is subjective and time-consuming, and practical, validated alternatives are required. Objective The aim of this study was to develop and validate a practical tool to identify MRAs. Setting Uppsala University Hospital, Sweden. Method We reviewed existing literature on methods to identify MRAs. The tool AT-HARM10 was developed using an iterative process including content validity and feasibility testing. The tool's inter-rater reliability (IRR) and criterion-related validity (CRV) were assessed: four pairs of either final-year undergraduate or postgraduate pharmacy students applied the tool to one of two batches of 50 older patients' hospital admissions. Assessment of the same 100 admissions by two experienced clinicians acted as gold standard. Main outcome measure Cohen's and Fleiss' kappa for IRR, and sensitivity, specificity, and positive and negative predictive value for CRV. Results AT-HARM10 consists of ten closed questions to distinguish between admissions that are unlikely to be and those that are possibly medication-related. The IRR was moderate to substantial (Cohen's kappa values were 0.45-0.75 and Fleiss' kappa values were 0.46 and 0.58). The sensitivity and specificity values were 70/86% and 74/70%, positive and negative predictive values were 73/74% and 71/83% respectively. Both AT-HARM10 and the gold standard identified approximately 50% of the admissions as MRAs. Conclusion AT-HARM10 has been developed as a practical tool to identify MRAs and the tool is valid for use in older patients by final-year undergraduate and postgraduate pharmacy students.

In 2015, a research study on student product development projects was conducted at the Norwegian University of Science (NTNU) in Gjøvik. The student projects lasted eight weeks and were done by twenty-four third year occupational therapy students and twenty-four third year industrial design students forming eight cross-professional project groups. The theme was welfare technology from a Universal Design perspective. Problems to work on for each group were given by the occupational therapy students, based on problems they had experienced or identified while doing their practice training periods in municipal healthcare facilities and in the homes of patients. A general objective of this study was to build a knowledge base for increased cross-professional cooperation among students in higher education. One aim was to better prepare the students for their future professional roles. Another aim was for the students to acquire knowledge, understanding, and experience on how to work in a project with issues related to the knowledge and skills they had previously acquired in their education. Another aim was to reinforce their capabilities and competences regarding use of Universal Design in the area of welfare technology. The main result of the study is extended knowledge on how to form and carry out cross-functional project work in a university environment.

Background: Wilms' tumor gene 1 (WT1) can act as a suppressor or activator of tumourigenesis in different types of human malignancies. The role of WT1 in squamous cell carcinoma of the head and neck (SCCHN) is not clear. Overexpression of WT1 has been reported in SCCHN, suggesting a possible oncogenic role for WT1. In the present study we aimed at investigating the function of WT1 and its previously identified protein partners p63 and p53 in the SCCHN cell line FaDu., Methods: Silencing RNA (siRNA) technology was applied to knockdown of WT1, p63 and p53 in FaDu cells. Cell proliferation was detected using MTT assay. Chromatin immunoprecipitation (ChIP)/PCR analysis was performed to confirm the effect of WT1 on the p63 promoter. Protein co-immunoprecipitation (co-IP) was used to find protein interaction between WT1 and p53/p63. Microarray analysis was used to identify changes of gene expression in response to knockdown of either WT1 or p63. WT1 RNA level was detected using real-time quantitative PCR (RT-qPCR) in patients with SCCHN., Results: We found that WT1 and p63 promoted cell proliferation, while mutant p53 (R248L) possessed the ability to suppress cell proliferation. We reported a novel positive correlation between WT1 and p63 expression. Subsequently, p63 was identified as a WT1 target gene. Furthermore, expression of 18 genes involved in cell proliferation, cell cycle regulation and DNA replication was significantly altered by downregulation of WT1 and p63 expression. Several known WT1 and p63 target genes were affected by WT1 knockdown. Protein interaction was demonstrated between WT1 and p53 but not between WT1 and p63. Additionally, high WT1 mRNA levels were detected in SCCHN patient samples., Conclusions: Our findings suggest that WT1 and p63 act as oncogenes in SCCHN, affecting multiple genes involved in cancer cell growth.

Purpose: Persistent severe swallowing dysfunction with aspiration is a common and sometimes overlooked sequelae after treatment for squamous cell carcinoma of the head and neck (SCCHN) and may impact food intake and nutritional status. More knowledge is needed to increase the understanding of severe swallowing dysfunction as a risk factor for persistent nutritional deteriorations in SCCHN survivors. The purpose of the study was to investigate weight loss and body mass index (BMI) in relation to pharyngeal swallowing function in a long-term perspective in patients after SCCHN treatment., Methods: Data from 101 patients were available for the analyses. Swallowing function was assessed by videofluoroscopy at a mean of 71.6 months after the start of radiotherapy (RT). Percent weight change (calculated with weight at the start of RT as the reference) and BMI at follow-up were the primary nutritional measures., Results: Aspiration was present in 48 of 101 patients (48 %). Patients with aspiration had a significantly higher mean weight loss and a lower BMI (-10.9 % and 23.1, respectively) at follow-up compared with patients without aspiration (-2.8 % and 26.0, respectively). Patients with aspiration were unable to gain weight after 23 months. Only ten of 101 patients (10 %) were underweight at follow-up., Conclusions: Swallowing dysfunction with aspiration was related to long-term weight loss and reduced BMI. Few patients were underweight despite the high prevalence of swallowing dysfunction.

Background: Weight loss is a common problem in patients with Squamous Cell Carcinoma of the Head and Neck (SCCHN) treated with radiotherapy (RT). The aims of the present study were to determine if treated volume (TV), as a measure of the radiation dose burden, can predict weight loss in patients with oropharyngeal cancer and to analyze weight loss and body mass index (BMI) in the same patient group in relation to 5-year overall survival., Methods: The ARTSCAN trial is a prospective, randomized, multicenter trial in patients with SCCHN. Nutritional data from the ARTSCAN trial were analyzed retrospectively using univariate and multivariate statistical methods based on information on percentage weight loss from the start of RT up to five months after the termination of RT (study cohort 1, n = 232) and information on patients' BMI at the start of RT (study cohort 2, n = 203). TV was defined as the volume of the patient receiving at least 95% of the prescribed dose. TV64.6 Gy encompasses macroscopic tumor and TV43.7 Gy elective lymph nodes of the neck., Results: TV64.6 Gy and TV43.7 Gy were both significantly correlated with higher weight loss up to five months after the termination of RT in study cohort 1 (p < 0.001 for both). BMI at the start of RT was shown to be a prognostic factor for 5-year overall survival in study cohort 2 but weight loss was not. The hazard ratios and 95% confidence intervals were 3.78 (1.46-9.75) and 2.57 (1.43-4.62) in patients with underweight and normal weight, respectively., Conclusions: TV can predict weight loss during RT in patients with oropharyngeal cancer regardless of clinical stage. A high BMI (>25 kg/m2) at the start of RT is positively associated with survival in patients with oropharyngeal cancer.

Background: Weight loss is common among patients with squamous cell carcinoma of the head and neck (SCCHN) and is mainly due to tumor and treatment related factors. The aim of the present study was to evaluate weight loss in patients with SCCHN undergoing two different radiotherapy (RT) schedules., Material and Methods: Nutritional data were analyzed from the ARTSCAN study, a controlled randomized prospective Swedish multicenter study conducted with the aim of comparing conventional fractionation (2.0 Gy per day, total 68 Gy during 7 weeks) and accelerated fractionation (1.1 + 2.0 Gy per day, total 68 Gy during 4.5 weeks). Seven hundred and fifty patients were randomized and 712 patients were followed from the start of RT in the present nutritional study., Results: The patients had a weight loss of 11.3% (± 8.6%) during the acute phase (start of RT up to five months after the termination of RT). No difference in weight loss was seen between the two RT fractionation schedules (p = 0.839). Three factors were significantly predictive for weight loss during the acute phase, i.e. tumor site, overweight/obesity or lack of tube feeding at the start of RT. Moreover, the nadir point of weight loss occurred at five months after the termination of RT., Conclusion: The results of the present study showed no difference in weight loss between the two RT fractionation schedules and also highlight that weight loss in SCCHN is a multifactorial problem. Moreover, the nadir of weight loss occurred at five months after the termination of treatment which calls for more intense nutritional interventions during the period after treatment.

Aims and Objectives: To describe the experience of food, eating and meals following radiotherapy in patients with head and neck cancer., Background: Eating problems are common in patients with head and neck cancer and may remain for a long period of time after treatment., Design: A qualitative study design using in-depth semi-structured interviews., Methods: Interviews were conducted nine months after the termination of radiotherapy. A purposive sample of thirteen patients with head and neck cancer participated in the study. The interviews were tape-recorded, transcribed verbatim and analysed using content analysis., Results: The experience of food, eating and meals up to nine months after radiotherapy was captured in six categories: 'A long journey - taking small steps to an uncertain future', 'A new way of eating', 'Eating without satisfaction', 'Challenging meals outside the family', 'Support and information - the key to a successful journey' and 'The creation and acceptance of a new normal'., Conclusion: This study provides new information on the long-term aspects of food, eating and meals in patients with head and neck cancer. Head and neck cancer signifies a long journey with problems affecting physical, psychological and social aspects of food. Information and support and the use of strategies are important for patients with head and neck cancer to adapt to new possibilities for living after cancer treatment., Relevance to Clinical Practice: All members of the multiprofessional team need to be aware of the struggles with food and eating experienced by patients with head and neck cancer during the convalescent period. It is therefore important that the follow-up focuses on all aspects of food, eating and meals as a part of a holistic approach., (© 2013 Blackwell Publishing Ltd.)

Saplings of one clone of Norway spruce, Picea abies (L.) Karst, were planted in 120 l pots in 1991 and exposed to three levels of ozone, two levels of phosphorus and two levels of water supply in 42 open-top chambers (OTCs), during 1992-1996. The effects of pots and OTCs were also tested. Nutrient concentrations of the needles were not affected by ozone, while the low phosphorus supply (LP) and drought stress (D) treatments had significant effects on several mineral nutrients, e.g. phosphorus, calcium, magnesium, manganese, sulphur and boron. Ozone reduced the chlorophyll concentration in the 2- and 3-year-old needles in 1994 and 1995. The highest ozone concentration reduced the stem volumes (- 8%), as well as the stem lengths (- 5%), of the saplings in 1993 and 1994, after two and three years of exposure. After the fourth growing season this ozone-induced reduction in stem volume disappeared which might be caused by pot limitation. LP supply and D both caused large decreases in the stem volume and length. The needles from LP treatment had as high P concentration as 1.2-1.5 mg g-1, implying a need for increasing the critical value for phosphorus. The OTC enclosure stimulated the stem volume growth significantly compared to saplings growing in ambient plots. This was suggested to be attributed to the slightly higher temperature in the OTCs. The overall result is that ozone in southern Sweden is likely to have negative effects on Norway spruce trees, although much less than other environmental factors, e.g. water and phosphorus.

A study of the feasibility of gradually increased epirubicin and cyclophosphamide dosage in an FEC regimen with G-CSF (granulocyte colony stimulating factor) support in 18 high-risk breast cancer patients as adjuvant treatment was carried out. The FEC regimen was initiated with 5-fluorouracil 600 mg/m2, epirubicin 75 mg/m2 and cyclophosphamide 900 mg/m2 together with G-CSF 5 micrograms/kg subcutaneously on days 2-15 q 3 weeks for nine cycles, increasing individually through four dose levels to a maximum of 5-FU 600 mg/m2 (not escalated), epirubicin 120 mg/m2 and cyclophosphamide 1800 mg/m2. Transient cytopenias were regularly observed without major clinical complications. Rapid recovery and a biphasic overshoot of granulocytes required individualization of G-CSF support. During the 6-month treatment period, a general decline in granulocytes, platelets and haemoglobin was observed, resulting in maximal dose intensity in the middle of the treatment period. Compared to a conventional FEC regimen (5-Fluorouracil 600 mg/m2, Epirubicin 60 mg/m2, Cyclophosphamide 600 mg/m2 q 3 w) without dose reductions, it was feasible to increase the dose of epirubicin by more than 50 per cent with an increased dose intensity between 25 and 70 per cent. The dose of cyclophosphamide was increased by more than 100 per cent. All patients suffered from complete alopecia and moderate nausea, but there was no acute cardiac or severe mucosal toxicity. It was concluded that intensified, G-CSF supported FEC therapy can be safely administered in an outpatient setting, provided the patients are thoroughly informed and adequately monitored. High-risk patients are enrolled in a study comparing the described regimen and a myeloablative regimen including peripheral stem-cell support. Breast cancer seems to respond to chemotherapy in a dose dependent manner, suggesting the use of dose intensified regimens (1,8,9,11). This approach is currently under investigation in studies comparing standard regimens with myelo-ablative regimens in high-risk primary breast cancer (3,10). In a Scandinavian multicenter study (2), two high dose regimens, G-CSF supported dose-escalated FEC and myeloablative cyclophosphamide-thiotepacarboplatin with peripheral stem cell support, are compared as adjuvant therapy in operable high-risk breast cancer. This phase I study was performed to assess the feasibility and achievable dose intensity of an individually dose-escalated FEC regimen not in previous use.

Helicobacter pylori infection in humans has been shown to be associated with changes in gastric physiology, including exaggerated basal and meal-stimulated gastrin levels. This has been suggested to be due to the direct effects of the bacterium through inflammation and its urease enzyme. The gastric bacteria Helicobacter felis and Helicobacter heilmannii colonize the antrum of rats in large numbers and induce no significant inflammatory response. Thus, the direct effect of Helicobacter infection on gastric physiology, independent of gastritis, could be studied. Basal, freely fed and stimulated acid and gastrin levels were recorded from animals infected with H. felis, H. heilmannii or uninfected controls over a 30 week period. No significant difference was found between freely fed gastrin over 7 weeks or fasting gastrin over 24 weeks or basal and stimulated acid over 30 weeks between all three groups. Triple therapy did not alter gastrin or acid output. The antrum of all Helicobacter-infected rats was well colonized; triple therapy cleared H. felis but not H. heilmannii. Very little inflammation was seen in control or Helicobacter-infected animals. In conclusion, Helicobacter-induced effects on gastric physiology are unlikely to be due to direct bacterial effects, but are best explained by other factors (i.e. inflammatory damage).