A Possible Site of Calcium Regulation in Rat Exocrine Pancreas Cells: An X-Ray Microanalytical Study

We analysed four subcellular compartments in rat exocrine pancreas cells, zymogen granules, cytoplasm surrounding the zymogen granules, mitochondria and cytoplasm in the basal part of the cells for sodium, magnesium, phosphorus, sulfur, chlorine, potassium and calcium content, using ultrathin frozen-dried cryosections. The highest concentrations of calcium were measured in the zymogen granules and the surrounding apical part of the cell containing Golgi apparatus, smooth endoplasmic reticulum and condensing vacuoles. Calcium concentrations in the basal part of the cells (mostly rough endoplasmic reticulum) were 60% lower than in the apical part of the cells. The lowest calcium concentrations were measured in mitochondria. The results suggest that other subcellular compartments than the rough endoplasmic reticulum and mitochondria might be involved in the intracellular Ca2+ regulation

ABCA1, ABCG1 and SR-BI: hormonal regulation in primary rat hepatocytes and human cell lines

BACKGROUND: Scavenger receptor type B class I (SR-BI), ABC transporter A1 (ABCA1) -and G1 (ABCG1) all play important roles in the reverse cholesterol transport. Reverse cholesterol transport is a mechanism whereby the body can eliminate excess cholesterol. Here, the regulation of SR-BI, ABCA1, and ABCG1 by dexamethasone (a synthetic glucocorticoid) and insulin were studied in order to gain more insight into the role of these two hormones in the cholesterol metabolism. RESULTS: By use of real time RT-PCR and Western blotting we examined the expression of our target genes. The results show that SR-BI, ABCA1 and ABCG1 mRNA expression increased in response to dexamethasone while insulin treatment reduced the expression in primary rat hepatocytes. The stimulatory effect of dexamethasone was reduced by the addition of the anti-glucocorticoid mifepristone. In HepG2 cells and THP-1 macrophages, however, the effect of dexamethasone was absent or inhibitory with no significant change in the presence of mifepristone. The latter observation may be a result of the low protein expression of glucocorticoid receptor (GR) in these cell lines. CONCLUSION: Our results illustrates that insulin and glucocorticoids, two hormones crucial in the carbohydrate metabolism, also play an important role in the regulation of genes central in reverse cholesterol transport. We found a marked difference in mRNA expression between the primary cells and the two established cell lines when studying the effect of dexamethasone which may result from the varying expression levels of GR

Use of smartphone application versus written titration charts for basal insulin titration in adults with type 2 diabetes and suboptimal glycaemic control (My Dose Coach) : multicentre, open-label, parallel, randomised controlled trial

Background The majority of people with type 2 diabetes who require insulin therapy use only basal insulin in combination with other anti-diabetic agents. We tested whether using a smartphone application to titrate insulin could improve glycaemic control in people with type 2 diabetes who use basal insulin. Methods This was a 12-week, multicentre, open-label, parallel, randomised controlled trial conducted in 36 diabetes practices in Germany. Eligible participants had type 2 diabetes, a BMI ≥25.0 kg/m2, were on basal insulin therapy or were initiating basal insulin therapy, and had suboptimal glycaemic control (HbA1c >7.5%; 58.5 mmol/mol). Block randomisation with 1:1 allocation was performed centrally. Participants in the intervention group titrated their basal insulin dose using a smartphone application (My Dose Coach) for 12 weeks. Control group participants titrated their basal insulin dose according to a written titration chart. The primary outcome was the baseline-adjusted change in HbA1c at 12 weeks. The intention-to-treat analysis included all randomised participants. Results Between 13 July 2021 and 21 March 2022, 251 study participants were randomly assigned (control group: n = 123; intervention group: n = 128), and 236 completed the follow-up phase (control group: n = 119; intervention group: n = 117). Regarding the HbA1c a model-based adjusted between-group difference of −0.31% (95% CI: 0.01%–0.69%; p = 0.0388) in favour of the intervention group was observed. There were 30 adverse events reported: 16 in the control group, 14 in the intervention group. Of these, 15 adverse events were serious. No event was considered to be related to the investigational device. Interpretation Study results suggest that utilizing this digital health smartphone application for basal insulin titration may have resulted in a comparatively greater reduction in HbA1c levels among individuals with type 2 diabetes, as compared to basal insulin titration guided by a written titration schedule. No negative effect on safety outcomes was observed. Funding Sanofi-Aventis Deutschland GmbH

Assessing attitudes towards insulin pump therapy in adults with type 1 diabetes: Italian validation of the Insulin Pump Attitudes Questionnaire (IT-IPA questionnaire)

Aims: The aim of the study was to adapt the German version of the insulin pump therapy (IPA) questionnaire to Italian (IT-IPA) and to evaluate its psychometric properties in adults with type 1 diabetes. Methods: We conducted a cross-sectional study, data were collected through an online survey. In addition to IT-IPA, questionnaires evaluating depression, anxiety, diabetes distress, self-efficacy, and treatment satisfaction were administered. The six factors identified in the IPA German version were assessed using confirmatory factor analysis; psychometric testing included construct validity and internal consistency. Results: The online survey was compiled by 182 individuals with type 1 diabetes: 45.6% continuous subcutaneous insulin infusion (CSII) users and 54.4% multiple daily insulin injection users. The six-factor model had a very good fit in our sample. The internal consistency was acceptable (Cronbach's α = 0.75; 95% IC [0.65-0.81]). Diabetes treatment satisfaction was positively correlated with a positive attitude towards CSII therapy (Spearman's rho = 0.31; p < 0.01), less Technology Dependency, higher Ease of Use, and less Impaired Body Image. Furthermore, less Technology Dependency was associated with lower diabetes distress and depressive symptoms. Conclusions: The IT-IPA is a valid and reliable questionnaire evaluating attitudes towards insulin pump therapy. The questionnaire can be used for clinical practice during consultations for shared decision-making to CSII therapy

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Intralobular Distribution of Vitamin A-Storing Lipid Droplets in Hepatic Stellate Cells with Special Reference to Polar Bear and Arctic Fox

We examined the liver of adult polar bears, arctic foxes, and rats by gold chloride staining, fluorescence microscopy for the detection of autofluorescence of vitamin A, hematoxylin-eosin staining, staining with Masson's trichrome, Ishii and Ishii's silver impregnation, and transmission electron microscopical morphometry. The liver lobules of the arctic animals showed a zonal gradient in the storage of vitamin A. The density (i.e., cell number per area) of hepatic stellate cells was essentially the same among the zones. These results indicate that the hepatic stellate cells of the polar bears and arctic foxes possess heterogeneity of vitamin A-storing capacity in their liver lobules

Everolimus after failure of one prior VEGF-targeted therapy in metastatic renal cell carcinoma : Final results of the MARC-2 trial

MARC-2, a prospective, multicenter phase IV trial, aimed to investigate clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus after failure of one initial vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy and to identify subgroups benefiting most, based on clinical characteristics and biomarkers. Patients with clear cell mRCC failing one initial VEGFR-TKI received everolimus until progression or unacceptable toxicity. Primary endpoint was 6-month progression-free survival rate (6moPFS). Secondary endpoints were overall response rate (ORR), PFS, overall survival (OS), and safety. Between 2011 and 2015, 63 patients were enrolled. Median age was 65.4 years (range 43.3-81.1). 6moPFS was 39.3% (95% confidence interval [CI], 27.0-51.3) overall, 54.4% (95% CI, 35.2-70.1) vs 23.7% (95% CI, 10.5-39.9) for patients aged ≥65 vs 25 vs ≤25 kg/m2. A Cox proportional hazards model confirmed a longer PFS for patients aged ≥65 years (hazard ratio [HR] 0.46; 95% CI, 0.26-0.80) and a longer OS for patients with BMI >25 kg/m2 (HR 0.36; 95% CI, 0.18-0.71). Median PFS and median OS were 3.8 months (95% CI, 3.2-6.2) and 16.8 months (95% CI, 14.3-24.3). ORR was 7.9% and disease control rate was 60.3%. No new safety signals emerged. Most common adverse events were stomatitis (31.7%), fatigue (31.7%), and anemia (30.2%). One patient died from treatment-related upper gastrointestinal hemorrhage. Everolimus remains a safe and effective treatment option for mRCC patients after one prior VEGFR-TKI therapy. Patients aged ≥65 years and patients with BMI >25 kg/m2 benefited most

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Effects of hatching system on chick quality, welfare and health of young breeder flock offspring

Alternative hatching systems have been developed for broiler chickens to provide immediately feed and water after hatch and reduce the number or severity of early life stressors. Besides beneficial effects of these alternative hatching systems on chick quality and performance, broiler health and welfare may be positively affected as well. Especially offspring from young broiler breeder flocks may benefit, as they have been shown to be more sensitive to preturbations than offspring from older breeder flocks. This study evaluated effects of hatching systems on chick quality, health and welfare of young breeder flock offspring, using 3 different hatching systems: conventional hatchery-hatched (HH), hatchery-fed (HF), and on-farm hatching (OH). A total of 24 pens were used in a completely randomized block design, with 8 pens per hatching system and 30 chickens per pen. Chick quality at hatch and performance until 35 d of age was improved in the HF and OH compared to HH treatment, but only minor effects were found on the welfare indicators: footpad dermatitis, hock burn, cleanliness, skin lesion and gait score. No effect was observed on the dynamics of a humoral immune response after NCD vaccination, given at d 0 and 14 of age, as no differences between NCD titers were found at d 18. Animals were vaccinated with a live attenuated infectious bronchitis vaccine virus (IBV) at d 28 to address treatment related differences to disease resilience. The expressions of inflammation and epithelial integrity related genes in the trachea and histo-pathological changes in the trachea were examined at 3 d after vaccine administration. No differences between treatment groups were observed. Although beneficial effects of HF and OH systems were found for young breeder flock offspring on chick quality at hatch and body weight posthatch, only one effect of alternative hatching systems on welfare and health indicators were found. No effect of hatching system on humoral immune response or disease resilience was found