Astrocyte Unfolded Protein Response Induces a Specific Reactivity State that Causes Non-Cell-Autonomous Neuronal Degeneration.

Recent interest in astrocyte activation states has raised the fundamental question of how these cells, normally essential for synapse and neuronal maintenance, become pathogenic. Here, we show that activation of the unfolded protein response (UPR), specifically phosphorylated protein kinase R-like endoplasmic reticulum (ER) kinase (PERK-P) signaling-a pathway that is widely dysregulated in neurodegenerative diseases-generates a distinct reactivity state in astrocytes that alters the astrocytic secretome, leading to loss of synaptogenic function in vitro. Further, we establish that the same PERK-P-dependent astrocyte reactivity state is harmful to neurons in vivo in mice with prion neurodegeneration. Critically, targeting this signaling exclusively in astrocytes during prion disease is alone sufficient to prevent neuronal loss and significantly prolongs survival. Thus, the astrocyte reactivity state resulting from UPR over-activation is a distinct pathogenic mechanism that can by itself be effectively targeted for neuroprotection

Emollients for preventing atopic eczema: Cost‐effectiveness analysis of the BEEP trial

BackgroundRecent discoveries have led to the suggestion that enhancing skin barrier from birth might prevent eczema and food allergy. ObjectiveTo determine the cost‐effectiveness of daily all‐over‐body application of emollient during the first year of life for preventing atopic eczema in high‐risk children at 2 years from a health service perspective. We also considered a 5‐year time horizon as a sensitivity analysis. MethodsA within‐trial economic evaluation using data on health resource use and quality of life captured as part of the BEEP trial alongside the trial data. Parents/carers of 1394 infants born to families at high risk of atopic disease were randomised 1:1 to the emollient group, which were advised to apply emollient (Doublebase Gel or Diprobase Cream) to their child at least once daily to the whole body during the first year of life or usual care. Both groups received advice on general skin care. The main economic outcomes were incremental cost‐effectiveness ratio (ICER), defined as incremental cost per percentage decrease in risk of eczema in the primary cost‐effectiveness analysis. Secondary analysis, undertaken as a cost‐utility analysis, reports incremental cost per Quality‐Adjusted Life Year (QALY) where child utility was elicited using the proxy CHU‐9D at 2 years. ResultsAt 2 years, the adjusted incremental cost was £87.45 (95% CI −54.31, 229.27) per participant, whilst the adjusted proportion without eczema was 0.0164 (95% CI −0.0329, 0.0656). The ICER was £5337 per percentage decrease in risk of eczema. Adjusted incremental QALYs were very slightly improved in the emollient group, 0.0010 (95% CI −0.0069, 0.0089). At 5 years, adjusted incremental costs were lower for the emollient group, −£106.89 (95% CI −354.66, 140.88) and the proportion without eczema was −0.0329 (95% CI −0.0659, 0.0002). The 5‐year ICER was £3201 per percentage decrease in risk of eczema. However, when inpatient costs due to wheezing were excluded, incremental costs were lower and incremental effects greater in the usual care group. ConclusionsIn line with effectiveness endpoints, advice given in the BEEP trial to apply daily emollient during infancy for eczema prevention in high‐risk children does not appear cost‐effective

HPLC & NMR-based forced degradation studies of ifosfamide: The potential of NMR in stability studies.

PURPOSE: The aim of this study is to conduct a forced degradation study on ifosfamide under several stress conditions to investigate the robustness of the developed HPLC method. It also aims to provide further insight into the stability of ifosfamide and its degradation profile using both HPLC and NMR. METHODS: Ifosfamide solutions (20mg/mL; n=15, 20mL) were stressed in triplicate by heating (70°C), under acidic (pH 1 & 4) and alkaline (pH 10 & 12) conditions. Samples were analysed periodically using HPLC and FT-NMR. RESULTS AND DISCUSSION: Ifosfamide was most stable under weakly acidic conditions (pH 4). NMR results suggested that the mechanism of ifosfamide degradation involves the cleavage of the PN bond. For all stress conditions, HPLC was not able to detect ifosfamide degradation products that were detected by NMR. CONCLUSION: These results suggest that the developed HPLC method for ifosfamide did not detect the degradation products shown by NMR. It is possible that degradation products co-elute with ifosfamide, do not elute altogether or are not amenable to the detection method employed. Therefore, investigation of ifosfamide stability requires additional techniques that do not suffer from the aforementioned shortcomings

Can a self-management plan, which includes a four-fold increase in inhaled corticosteroid dose, reduce severe asthma exacerbations: a randomised, pragmatic trial

Asthma exacerbations are frightening for patients and are occasionally fatal. We tested the concept that a self-management plan, which included a temporary quadrupling of the dose of inhaled corticosteroid when asthma control starts to deteriorate, would reduce severe asthma exacerbations

Predicting the onset of transformation under noncontinuous cooling conditions: Part II. Application to the austenite pearlite transformation

A detailed review of the additivity principle with respect to the incubation of the austenite decomposition was summarized in Part 1 of this two-part series and led to the concept of an ideal time-temperature-transformation (TTT) diagram. This curve is characteristic of the chemistry and austenite grain size in the steel and allows nonisothermal behavior to be described assuming additivity holds. The derivation of mathematical relationships between the ideal and experimental cooling data was presented in the first article. In this second article, an ideal curve for the austenite-to-pearlite transformation was derived from cooling data. The applicability of the ideal TTT curve for predicting the start of transformation under continuous cooling conditions was assessed for a range of cooling rates. Experiments were conducted under both isothermal and varying temperature conditions, including an industrial cooling schedule, using a Gleeble Thermal Simulator. Reasonable agreement was found between the predictions and the observed transformation start temperatures; predictions were consistent and compared favorably against other methods which have been frequently used to estimate the transformation start temperature for nonisothermal conditions

Assessment and management of bipolar disorder: Summary of updated NICE guidance

Bipolar disorder is a complex, recurrent, and severe mental illness that has an onset typically between 13 and 30 years of age and a lifetime prevalence of 1.4%. It is characterised by episodes of mania or hypomania with elation, overactivity, and disinhibited behaviour, as well as episodes of depression with profound loss of interest and motivation, often with milder depressed mood in between episodes. Bipolar disorder is associated with an increased risk of suicide and physical illness, such as ischaemic heart disease, diabetes, chronic obstructive airways disease, pneumonia, and unintentional injury. Around two thirds of people with bipolar disorder also experience another mental disorder, usually anxiety disorders, substance misuse disorders, or impulse control disorders. The risk of recurrence in the year after a mood episode is especially high (50% in one year and >70% at four years) compared with other psychiatric disorders, and this has important implications for the long term management of the disorder