Docking of LDCVs Is Modulated by Lower Intracellular [Ca2+] than Priming

Many regulatory steps precede final membrane fusion in neuroendocrine cells. Some parts of this preparatory cascade, including fusion and priming, are dependent on the intracellular Ca2+ concentration ([Ca2+]i). However, the functional implications of [Ca2+]i in the regulation of docking remain elusive and controversial due to an inability to determine the modulatory effect of [Ca2+]i. Using a combination of TIRF-microscopy and electrophysiology we followed the movement of large dense core vesicles (LDCVs) close to the plasma membrane, simultaneously measuring membrane capacitance and [Ca2+]i. We found that a free [Ca2+]i of 700 nM maximized the immediately releasable pool and minimized the lateral mobility of vesicles, which is consistent with a maximal increase of the pool size of primed LDCVs. The parameters that reflect docking, i.e. axial mobility and the fraction of LDCVs residing at the plasma membrane for less than 5 seconds, were strongly decreased at a free [Ca2+]i of 500 nM. These results provide the first evidence that docking and priming occur at different free intracellular Ca2+ concentrations, with docking efficiency being the most robust at 500 nM

Effective combination chemotherapy with paclitaxel and cisplatin with or without human granulocyte colony-stimulating factor and/or erythropoietin in patients with advanced gastric cancer

A phase II trial was performed to determine the antitumour efficacy and tolerance of combined paclitaxel and cisplatin with or without hematopoetic growth factor support in patients with advanced gastric cancer. Forty-five patients with histologically confirmed metastatic gastric cancer were entered in this trial. Treatment consisted of 2-weekly courses of paclitaxel 160 mg per m2 and cisplatin 60 mg per m2 both given on day 1. Depending on absolute neutrophil counts on the days of scheduled chemotherapeutic drug administration (1000–2000 per μl), a 5-day course of human granulocyte colony-stimulating factor 5 μg kg−1 per day was given subcutaneously; in addition, if haemoglobin was <12.0 mg dl−1, erythropoietin 10 000 IU was administered subcutaneously three times per week. The confirmed overall response rate (intent-to-treat) was 44%, including five complete (11%) and 15 partial remissions (33%). Twelve patients had stable disease (27%), 11 (24%) progressed while on chemotherapy, and two patients were not evaluable. The median time to response was 3 months, the median time to progression 7.0 months, and the median survival time was 11.2 months with 12 patients currently alive. Haematologic toxicity was common, though WHO grade 4 neutropenia occurred in only five patients (11%). Apart from total alopecia in 16 patients (36%), severe non-haematologic adverse reactions included grade 3 peripheral neuropathy in six (13%) and anaphylaxis in two patients. In addition, there was one patient each who experienced grade 3 emesis, diarrhea, and infection, respectively. Our data suggest that the combination of paclitaxel and cisplatin with or without G-CSF and/or erythropoietin has promising therapeutic activity in patients with advanced gastric cancer

Serum levels of selenium and smoking habits at age 50 influence long term prostate cancer risk; a 34 year ULSAM follow-up

Background: Serum selenium level (s-Se) has been associated with prostate cancer (PrCa) risk. We investigated the relation between s-Se, smoking and non-screening detected PrCa and explored if polymorphisms in two DNA repair genes: OGG1 and MnSOD, influenced any effect of s-Se. Methods: ULSAM, a population based Swedish male cohort (n = 2322) investigated at age 50 for s-Se and s-Se influencing factors: serum cholesterol, erythrocyte sedimentation rate and smoking habits. At age 71 a subcohort, (n = 1005) was genotyped for OGG1 and MnSOD polymorphisms. Results: In a 34-year-follow-up, national registries identified 208 PrCa cases further confirmed in medical records. Participants with s-Se in the upper tertile had a non-significantly lower risk of PrCa. Smokers with s-Se in the two lower tertiles (&lt;= 80 mu g/L) experienced a higher cumulative incidence of PrCa than smokers in the high selenium tertile (Hazard Ratio 2.39; 95% CI: 1.09-5.25). A high tertile selenium level in combination with non-wt rs125701 of the OGG1 gene in combination with smoking status or rs4880 related variation of MnSOD gene appeared to protect from PrCa. Conclusions: S-Se levels and smoking habits influence long-term risk of PrCa. Smoking as a risk factor for PrCa in men with low s-Se is relevant to explore further. Exploratory analyses of variations in OGG1 and MnSOD genes indicate that hypotheses about patterns of exposure to selenium and smoking combined with data on genetic variation in genes involved in DNA repair can be valuable to pursue

Mass media representation of suicide in a high suicide state in India: an epidemiological comparison with suicide deaths in the population.

Objectives Suicide rates in India are among the highest in the world, equating to over 200 000 suicides annually. Reports of suicides are a routine feature in major newspapers in India, and reporters may selectively present ‘newsworthy’ suicide stories. The aim of this paper was to systematically investigate whether mass media reports of suicides reflect the epidemiological data on suicide in a high suicide state in India. Design We undertook a content analysis study to extract sociodemographic data on suicides reported among nine of the most highly read daily newspapers in the high suicide southern state of Tamil Nadu between June and December 2016. A total of 1258 newspaper articles were retrieved containing reports on 1631 suicides. Two-tailed binomial tests on aggregate frequencies assessed whether the sociodemographic characteristics of suicides in the newspaper articles were different to the population suicide statistics for Tamil Nadu. Results We identified some statistically significant discrepancies between suicide characteristics in the population and the media. Suicides involving females (p<0.001), those aged under 30 years (p<0.001), separated or widowed males (p<0.001), unmarried females (p<0.001), those using methods with a higher case fatality rate (ie, hanging (p<0.001), jumping off high structures (p<0.001) and coming under vehicles (p<0.001) and those who were students (p<0.001) or working in the agricultural sector (p<0.001) were significantly over-reported relative to their occurrence in the broader population. Suicides involving men (p<0.001), those aged over 30 years and above (p<0.001), those who were married and suicides by poisoning (p<0.001) were significantly under-reported relative to their occurrence in the broader population. Conclusions The suicide characteristics in the print media were not entirely representative of suicides in the broader Tamil Nadu population, which may lead the general public to develop misunderstandings about suicide in their state. The discrepancies we identified will inform tailored suicide prevention education for media professionals

Status for 2019, CERN NA63

In the NA63 experiment of April 2018 data was taken for 20, 40 and 80 GeV electrons and positrons aligned to the h100i axis of a diamond crystal of thickness 1.5 mm, as well as for 40 and 80 GeV electrons on a 1.0 mm thick diamond aligned to the h100i axis. Off-line analysis has shown that the direction of the crystallographic axis cannot be found with certainty for the 2018 data for 20 GeV, and thus this data set has been discarded. However, the comparison between data and theoretical simulations performed for several angular settings for the 40 and 80 GeV data show remarkable agreement with calculations including the Landau Lifshitz force with a few quantum corrections. A draft of a paper for submission will be finished within the coming month. For the 2017 data, the analysis is finished, shows good results, and a draft of a paper for submission will be finished within the coming month