Synthesis of diacylated γ-glutamyl-cysteamine prodrugs, and in vitro evaluation of their cytotoxicity and intracellular delivery of cysteamine

To overcome the major disadvantages of cysteamine, the only registered treatment for the rare genetic disease cystinosis, nine prodrugs of γ-glutamyl-cysteamine (4) were synthesized for evaluation. Esterification of the thiol conferred oxidative stability, while sufficient lipophilicity for oral bioavailability was achieved by acylation of the α-carboxyl group of γ-glutamyl-cysteamine (4). Low cytotoxicity was observed in cultured HaCaT keratinocytes using the MTT assay, with EC50 values higher than or similar to that of cysteamine. Successful uptake of the esterified prodrugs and the subsequent release of cysteamine into cultured human proximal tubule epithelial cells were demonstrated using CMQT derivatisation and HPLC with UV detection. These prodrugs show potential as novel delivery vehicles of cysteamine to improve the treatment of the genetic disorder nephropathic cystinosis

The experiences of wives following acquired brain injury (ABI). A qualitative analysis exploring realisations of change following the ABI of a “loved one”.

The experiences of family members following Acquired Brain Injury (ABI) are well established, with spouses in particular facing multiple relational and personal changes. Qualitative studies have analysed accounts pertaining to a range of sequelae, however, “change” itself has yet to be addressed. This study explored the experiences of realisation of change for married women living with their husbands following ABI. Nine participants took part in semi-structured interviews focussing on becoming aware of changes in both their spouse and themselves post-injury. An Interpretative Phenomenological Analysis (IPA) was completed, arriving at two overarching themes; “bravery to face changes” and “lost and trapped in an unsolvable maze,” with accompanying subthemes. Participants generally experienced realisation of change gradually, in some cases finding strategies to control their exposure to distress. They often referred to “acceptance,” which held varied meanings, and metaphors appeared to aid personal meaning making. Relationship changes generated both dilemmas and the feeling of being trapped. Overall, this study contributes greater insights into the experiential mechanisms underpinning realisation of change in spouses after brain injury

Delayed chilling appears to counteract flowering advances of apricot in southern UK

Temperatures are rising across the globe, and the UK is no exception. Spring phenology of perennial fruit crops is to a large extent determined by temperature during effective chilling (endo-dormancy) and heat accumulation (eco-dormancy) periods. We used the apricot flowering records of the UK National Fruit Collections (NFC) to determine the influence of temperature trends over recent decades (1960 to 2014) on apricot (Prunus armeniaca L.) flowering time. Using Partial Least Squares (PLS) regression, we determined the respective periods for calculating chill and heat accumulation. Results suggested intervals between September 27th and February 26th and between December 31st and April 12th as the effective chilling and warming periods, respectively. Flowering time was correlated with temperature during both periods, with warming during chilling corresponding to flowering delays by 4.82 d°C-1, while warming during heat accumulation was associated with bloom advances by 9.85 d°C-1. Heat accumulation started after accumulating 62.7 ± 5.6 Chill Portions, and flowering occurred after a further 3744 ± 1538 Growing Degree Hours (above a base temperature of 4°C, with optimal growth at 26°C). When examining the time series, the increase in temperature during the chilling period did not appear to decrease overall chill accumulation during the chilling period but to delay the onset of chill accumulation and the completion of the the average chill accumulation necessary to start heat accumulation. The resulting delay in heat responsiveness appeared to weaken the phenology-advancing effect of spring warming. These processes may explain why apricot flowering time remained relatively unchanged despite significant temperature increases. A consequence of this may be a reduction of frost risk for early flowering crops such as apricot in the UK

The Dynamics of Disorder-Order Transition in Hard Sphere Colloidal Dispersions

The Physics of Hard Spheres Experiment (PHaSE) seeks a complete understanding of the entropically driven disorder-order transition in hard sphere colloidal dispersions. The light scattering instrument designed for flight collects Bragg and low angle light scattering in the forward direction via a CCD camera and performs conventional static and dynamic light scattering at 10-160 deg. through fiber optic cables. Here we report on the kinetics of nucleation and growth extracted from time-resolved Bragg images and measurements of the elastic modulus of crystalline phases obtained by monitoring resonant responses to sinusoidal forcing through dynamic light scattering. Preliminary analysis of the former indicates a significant difference from measurements on the ground, while the latter confirms nicely laboratory experiments with the same instrument and predictions from computer simulations

Immunochemotherapy With Obinutuzumab or Rituximab for Previously Untreated Follicular Lymphoma in the GALLIUM Study: Influence of Chemotherapy on Efficacy and Safety

PurposeThe GALLIUM study (ClinicalTrials.gov identifier: NCT01332968) showed that obinutuzumab (GA101;G) significantly prolonged progression-free survival (PFS) in previously untreated patients with follicular lymphoma relative to rituximab (R) when combined with cyclophosphamide (C), doxorubicin, vincristine (V), and prednisone (P;CHOP);CVP;or bendamustine. This report focuses on the impact of chemotherapy backbone on efficacy and safety.Patients and Methods: A total of 1,202 patients with previously untreated follicular lymphoma (grades 1 to 3a), advanced disease (stage III or IV, or stage II with tumor diameter 7 cm), Eastern Cooperative Oncology Group performance status 0 to 2, and requiring treatment were randomly assigned 1:1 to G 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles or R 375 mg/m(2) on day 1 of each cycle, for six to eight cycles, depending on chemotherapy (allocated nonrandomly by center). Responding patients received G or R for 2 years or until disease progression.Results: Baseline Follicular Lymphoma International Prognostic Index risk, bulky disease, and comorbidities differed by chemotherapy. After 41.1 months median follow-up, PFS (primary end point) was superior for G plus chemotherapy (overall hazard ratio [HR], 0.68;95% CI, 0.54 to 0.87;P = .0016), with consistent results across chemotherapy backbones (bendamustine: HR, 0.63;95% CI, 0.46 to 0.88;CHOP: HR, 0.72;95% CI, 0.48 to 1.10;CVP: HR, 0.79;95% CI, 0.42 to 1.47). Grade 3 to 5 adverse events, notably cytopenias, were most frequent with CHOP. Grade 3 to 5 infections and second neoplasms were most frequent with bendamustine, which was associated with marked and prolonged reductions in T-cell counts. Fatal events were more frequent in patients treated with bendamustine, possibly reflecting differences in patient risk profiles.Conclusion: Improved PFS was observed for G plus chemotherapy for all three chemotherapy backbones. Safety profiles differed, although comparisons are confounded by nonrandom chemotherapy allocation

Soil carbon development in rejuvenated Indian coal mine spoil

The impact of mine spoil on the landscape is significant, as excavated rock-debris is commonly disposedin heaps that blanket the original land surface. Spoil heaps destroy the original soil habitat releasing soil-bound carbon, which is difficult to re-estate when mining operations cease and restoration begins. Thepresent work follows the development of vegetative cover on a coalmine spoil tip in India over a period of19 years following restoration. The potential of re-vegetated the mine spoil to imbibe carbon is examinedthrough the development of above- and below-ground biomass development. It was observed that the soilorganic carbon and microbial biomass carbon (MBC) significantly increased with re-vegetation age, withabove ground biomass increasing by 23 times, and belowground biomass increased by 26 times during theperiod of study. Soil organic carbon and MBC increased by 4× and 6.6× times, respectively. The averagecalculated annual carbon budget was 8.40 T/ha/year, of which 2.14 T/ha was allocated to above groundbiomass, 0.31 T/ha to belowground biomass, 2.88 T/ha to litter mass and 1.35 T/ha was sequestered intothe soil. This work has shown that the development of biomass following the restoration of mine spoilwas significant and that considerable quantities of carbon were stored in above and below ground plantmatter, and in the soil itself. It is concluded that appropriate restoration strategies can be used to rapidlyestablish a viable, healthy and sustainable ecosystem that imbibes carbon into former mine-impacted land

The environmental deposition of influenza virus from patients infected with influenza A(H1N1)pdm09: implications for infection prevention and control

In a multi-center, prospective, observational study over two influenza seasons, we sought to quantify and correlate the amount of virus recovered from the nares of infected subjects with that recovered from their immediate environment in community and hospital settings. We recorded the symptoms of adults and children with A(H1N1)pdm09 infection, took nasal swabs, and sampled touched surfaces and room air. Forty-two infected subjects were followed up. The mean duration of virus shedding was 6.2 days by PCR (Polymerase Chain Reaction) and 4.2 days by culture. Surface swabs were collected from 39 settings; 16 (41%) subject locations were contaminated with virus. Overall, 33 of the 671 (4.9%) surface swabs were PCR positive for influenza, of which two (0.3%) yielded viable virus. On illness Day 3, subjects yielding positive surface samples had significantly higher nasal viral loads (geometric mean ratio 25.7; 95% CI 1.75, 376.0, p=0.021) and a positive correlation (r=0.47, p=0.006) was observed between subject nasal viral loads and viral loads recovered from the surfaces around them. Room air was sampled in the vicinity of 12 subjects, and PCR positive samples were obtained for five (42%) samples. Influenza virus shed by infected subjects did not detectably contaminate the vast majority of surfaces sampled. We question the relative importance of the indirect contact transmission of influenza via surfaces, though our data support the existence of super-spreaders via this route. The air sampling results add to the accumulating evidence that supports the potential for droplet nuclei (aerosol) transmission of influenza

Assessment of explanatory models of mental illness: effects of patient and interviewer characteristics

Background: Explanatory models (EMs) refer to patients’ causal attributions of illness and have been shown to affect treatment preference and outcome. Reliable and valid assessment of EMs may be hindered by interviewer and respondent disparities on certain demographic characteristics, such as ethnicity. The present study examined (a) whether ethnic minority patients reported different EMs to ethnically similar interviewers in comparison with those with a different ethnicity, and (b) whether this effect was related to respondents’ social desirability, the perceived rapport with the interviewer and level of uncertainty toward their EMs. Methods: A total of 55 patients of Turkish and Moroccan origins with mood and anxiety disorders were randomly assigned to ethnically similar or dissimilar interviewers. EMs were assessed, using a semi-structured interview, across 11 different categories of causes. Results: Participants who were interviewed by an ethnically similar interviewer perceived interpersonal, victimization and religious/mystical causes as more important, whereas interviews by ethnically dissimilar interviewers generated higher scores on medical causes. These effects were not mediated by the perceived rapport with the interviewer, and social desirability had a modest impact on the results. Higher uncertainty among participants toward medical and religious/mystical causes seemed to be associated with greater adjustment in the report of these EMs. Conclusion: The findings have significant implications for interviewer selection in epidemiological research and clinical practice

Epidemiology of Concomitant Infection Due to Loa loa and Mansonella perstans in Gabon

Loa loa and Mansonella perstans are blood filarial parasites, endemic in the central and western African forest block, and transmitted by chrysops and culicoides flies, respectively. Loa loa is pathogenic and represents a major obstacle to the control of co-endemic filariae. Treatment of individuals with >8000 Loa loa microfilariae/ml can result in severe adverse reactions. M. perstans is prevalent in the tropics, with undefined clinical symptoms. We screened 4392 individuals for these infections in 212 Gabonese villages. The overall prevalence rates were 22.4% for Loa loa microfilariae, 10.2% for M. perstans, and 3.2% for mixed infection. These rates varied across the different ecosystems: forest, savannah, Lakeland, river (Ogouée), and equator. A correlation was found between the prevalence and intensity of microfilariae, while a negative relationship was found between clinical symptoms (pruritis, Calabar swelling) and the prevalence of Loa loa microfilaremia. This study confirms the spatial uniformity of the relationship between parasitological indices, and provides a map and baseline data for implementation of mass chemotherapy for these infections