Goserelin, as an ovarian protector during (neo)adjuvant breast cancer chemotherapy, prevents long term altered bone turnover

Background: The Ovarian Protection Trial In Premenopausal Breast Cancer Patients “OPTION” trial (NCT00427245) was a prospective, multicenter, randomised, open label study evaluating the frequency of primary ovarian insufficiency (POI) at 12 months in women randomised to 6–8 cycles of (neo)adjuvant chemotherapy (CT) þ/ goserelin (G). Here we report the results of a secondary endpoint analysis of the effects of CTþ/-G on markers of bone turnover. Methods: Serum for bone alkaline phosphatase (BALP) and urine for N-terminal telopeptide (NTX) were collected at baseline, 6, 12, 18, 24 and 36 months. Changes in median levels of bone turnover markers were evaluated for the overall population, according to age stratification at randomisation (r40 vs 440 years) and with exploratory analysis according to POI rates at 12 months. Results: In the overall population, there was a significant increase in NTX at 6 months compared to baseline in patients treated with CTþG (40.81 vs 57.82 p¼0.0074) with normalisation of levels thereafter. BALP was significantly increased compared to baseline at 6 months and 12 months in those receiving CTþG, but normalised thereafter. BALP remained significantly higher compared to baseline at 12, 24 and 36 months in patients receiving CT, resulting in a significant difference between treatment groups at 36 months (CTþG 5.845 vs CT 8.5 p¼0.0006). These changes were predominantly seen in women 440 years. Women with POI at 12 months showed altered bone formation compared to baseline levels for a longer duration than women who maintained menses. Conclusion: Addition of G to CT increases bone turnover during treatment with normalisation after cessation of treatment suggesting G may offer sufficient ovarian protection against CT induced POI to negate longstanding altered bone turnover associated with POI

Epidemiology of gastrostomy insertion for children and adolescents with intellectual disability

The largest group of recipients of pediatric gastrostomy have neurological impairment with intellectual disability (ID). This study investigated trends in first gastrostomy insertion according to markers of disadvantage and ID etiology. Linked administrative and health data collected over a 32-year study period (1983–2014) for children with ID born between 1983 and 2009 in Western Australia were examined. The annual incidence rate change over calendar year was calculated for all children and according to socioeconomic status, geographical remoteness, and Aboriginality. The most likely causes of ID were identified using available diagnosis codes in the linked data set. Of 11,729 children with ID, 325 (2.8%) received a first gastrostomy within the study period. The incidence rate was highest in the 0–2 age group and there was an increasing incidence trend with calendar time for each age group under 6 years of age. This rate change was greatest in children from the lowest socioeconomic status quintile, who lived in regional/remote areas or who were Aboriginal. The two largest identified groups of ID were genetically caused syndromes (15.1%) and neonatal encephalopathy (14.8%). Conclusion: Gastrostomy is increasingly used in multiple neurological conditions associated with ID, with no apparent accessibility barriers in terms of socioeconomic status, remoteness, or Aboriginality.What is Known:• The use of gastrostomy insertion in pediatrics is increasing and the most common recipients during childhood have neurological impairment, most of whom also have intellectual disability (ID).What is New:• Nearly 3% of children with ID had gastrostomy insertion performed, with the highest incidence in children under 3 years of age.• Gastrostomy use across different social groups was equitable in the Australian setting

Two-week isocaloric time-restricted feeding decreases liver inflammation without significant weight loss in obese mice with non-alcoholic fatty liver disease

Prolonged, isocaloric, time-restricted feeding (TRF) protocols can promote weight loss, improve metabolic dysregulation, and mitigate non-alcoholic fatty liver disease (NAFLD). In addition, 3-day, severe caloric restriction can improve liver metabolism and glucose homeostasis prior to significant weight loss. Thus, we hypothesized that short-term, isocaloric TRF would improve NAFLD and characteristics of metabolic syndrome in diet-induced obese male mice. After 26 weeks of ad libitum access to western diet, mice either continued feeding ad libitum or were provided with access to the same quantity of western diet for 8 h daily, over the course of two weeks. Remarkably, this short-term TRF protocol modestly decreased liver tissue inflammation in the absence of changes in body weight or epidydimal fat mass. There were no changes in hepatic lipid accumulation or other characteristics of NAFLD. We observed no changes in liver lipid metabolism-related gene expression, despite increased plasma free fatty acids and decreased plasma triglycerides in the TRF group. However, liver Grp78 and Txnip expression were decreased with TRF suggesting hepatic endoplasmic reticulum (ER) stress and activation of inflammatory pathways may have been diminished. We conclude that two-week, isocaloric TRF can potentially decrease liver inflammation, without significant weight loss or reductions in hepatic steatosis, in obese mice with NAFLD

Sensory percepts elicited by chronic macro-sieve electrode stimulation of the rat sciatic nerve

Objective: Intuitive control of conventional prostheses is hampered by their inability to provide the real-time tactile and proprioceptive feedback of natural sensory pathways. The macro-sieve electrode (MSE) is a candidate interface to amputees’ truncated peripheral nerves for introducing sensory feedback from external sensors to facilitate prosthetic control. Its unique geometry enables selective control of the complete nerve cross-section by current steering. Unlike previously studied interfaces that target intact nerve, the MSE’s implantation requires transection and subsequent regeneration of the target nerve. Therefore, a key determinant of the MSE’s suitability for this task is whether it can elicit sensory percepts at low current levels in the face of altered morphology and caliber distribution inherent to axon regeneration. The present in vivo study describes a combined rat sciatic nerve and behavioral model developed to answer this question.Approach: Rats learned a go/no-go detection task using auditory stimuli and then underwent surgery to implant the MSE in the sciatic nerve. After healing, they were trained with monopolar electrical stimuli with one multi-channel and eight single-channel stimulus configurations. Psychometric curves derived by the method of constant stimuli (MCS) were used to calculate 50% detection thresholds and associated psychometric slopes. Thresholds and slopes were calculated at two time points 3 weeks apart.Main Results: For the multi-channel stimulus configuration, the average current required for stimulus detection was 19.37 μA (3.87 nC) per channel. Single-channel thresholds for leads located near the nerve’s center were, on average, half those of leads located near the periphery (54.92 μA vs. 110.71 μA, or 10.98 nC vs. 22.14 nC). Longitudinally, 3 of 5 leads’ thresholds decreased or remained stable over the 3-week span. The remaining two leads’ thresholds increased by 70–74%, possibly due to scarring or device failure.Significance: This work represents an important first step in establishing the MSE’s viability as a sensory feedback interface. It further lays the groundwork for future experiments that will extend this model to the study of other devices, stimulus parameters, and task paradigms

Airway microbiota-host interactions regulate secretory leukocyte protease inhibitor levels and influence allergic airway inflammation

Homeostatic mucosal immune responses are fine-tuned by naturally evolved interactions with native microbes, and integrating these relationships into experimental models can provide new insights into human diseases. Here, we leverage a murine-adapted airway microbe, Bordetella pseudohinzii (Bph), to investigate how chronic colonization impacts mucosal immunity and the development of allergic airway inflammation (AAI). Colonization with Bph induces the differentiation of interleukin-17A (IL-17A)-secreting T-helper cells that aid in controlling bacterial abundance. Bph colonization protects from AAI and is associated with increased production of secretory leukocyte protease inhibitor (SLPI), an antimicrobial peptide with anti-inflammatory properties. These findings are additionally supported by clinical data showing that higher levels of upper respiratory SLPI correlate both with greater asthma control and the presence of Haemophilus, a bacterial genus associated with AAI. We propose that SLPI could be used as a biomarker of beneficial host-commensal relationships in the airway

The Burst and Transient Source Experiment Earth Occultation Technique

An Earth orbiting detector sensitive to gamma ray photons will see step-like occultation features in its counting rate when a gamma ray point source crosses the Earth's limb. This is due to the change in atmospheric attenuation of the gamma rays along the line of sight. In an uncollimated detector, these occultation features can be used to locate and monitor astrophysical sources provided their signals can be individually separated from the detector background. We show that the Earth occultation technique applied to the Burst and Transient Source Experiment (BATSE) on the Compton Gamma Ray Observatory (CGRO) is a viable and flexible all-sky monitor in the low energy gamma ray and hard X-ray energy range (20 keV - 1 MeV). The method is an alternative to more sophisticated photon imaging devices for astronomy, and can serve well as a cost-effective science capability for monitoring the high energy sky. Here we describe the Earth occultation technique for locating new sources and for measuring source intensity and spectra without the use of complex background models. Examples of transform imaging, step searches, spectra, and light curves are presented. Systematic uncertainties due to source confusion, detector response, and contamination from rapid background fluctuations are discussed and analyzed for their effect on intensity measurements. A sky location-dependent average systematic error is derived as a function of galactic coordinates. The sensitivity of the technique is derived as a function of incident photon energy and also as a function of angle between the source and the normal to the detector entrance window. Occultations of the Crab Nebula by the Moon are used to calibrate Earth occultation flux measurements independent of possible atmospheric scattering effects.Comment: 39 pages, 24 figures. Accepted for publication in the Astrophysical Journal Supplement

The Burst and Transient Source Experiment (BATSE) Earth Occultation Catalog of Low-Energy Gamma-Ray Sources

The Burst and Transient Source Experiment (BATSE), aboard the Compton Gamma Ray Observatory (CGRO), provided a record of the low-energy gamma-ray sky (20-1000 keV) between 1991 April and 2000 May (9.1y). Using the Earth Occultation Technique to extract flux information, a catalog of sources using data from the BATSE large area detectors has been prepared. The first part of the catalog consists of results from the monitoring of 58 sources, mostly Galactic. For these sources, we have included tables of flux and spectral data, and outburst times for transients. Light curves (or flux histories) have been placed on the world wide web. We then performed a deep-sampling of 179 objects (including the aforementioned 58 objects) combining data from the entire 9.1y BATSE dataset. Source types considered were primarily accreting binaries, but a small number of representative active galaxies, X-ray-emitting stars, and supernova remnants were also included. The deep sample results include definite detections of 83 objects and possible detections of 36 additional objects. The definite detections spanned three classes of sources: accreting black hole and neutron star binaries, active galaxies and supernova remnants. Flux data for the deep sample are presented in four energy bands: 20-40, 40-70, 70-160, and 160-430 keV. The limiting average flux level (9.1 y) for the sample varies from 3.5 to 20 mCrab (5 sigma) between 20 and 430 keV, depending on systematic error, which in turn is primarily dependent on the sky location. To strengthen the credibility of detection of weaker sources (5-25 mCrab), we generated Earth occultation images, searched for periodic behavior using FFT and epoch folding methods, and critically evaluated the energy-dependent emission in the four flux bands.Comment: 64 pages, 17 figures, abstract abridged, Accepted by ApJ