Evaluation of a Mobile Health Intervention to Improve Wellness Outcomes for Breast Cancer Survivors.

PURPOSE: Breast cancer survivors are at increased risk of cancer recurrence, second malignancies, and other comorbid conditions. This study examined if use of a convenient, commercially available, $65 per month app that gives breast cancer survivors access to a health and wellness coach is more effective than a self-guided toolkit and one-time health education session at achieving the following goals: 1) improving adherence to a plant-based diet, 2) increasing physical activity, 3) assisting with weight loss and reduction in body mass index, 4) reducing elevated depression and fatigue scores, and 5) leading to sustained adherence to lifestyle and wellness plan at and beyond 6 months. METHODS: A nonrandomized 2-group control study design with pre-post repeated measures (N=127 subjects) was utilized. Women 18 years of age or older, with curative-intent breast cancer, were included in the study. App users received a survivorship care plan and enrolled in a 6-month subscription to the health app. A control group received the same information but, instead of access to the app, were given a self-guided toolkit. RESULTS: At 6 months, more patients in the app group experienced weight loss and had a significantly greater reduction in overall body mass index (P<0.01). The app group also demonstrated statistically significant improvements in "strenuous" physical activity (P=0.04) and had significant improvement in their dietary patterns (P<0.001), as compared to the self-guided group. The app group had greater reduction in fatigue and improvement in depression, but these changes were not statistically significant. At 12 months, none of the app users were still using the app, but many were still following their wellness plan and had maintained their weight loss. Outliers in both groups and low rate of response made evaluation of results difficult. CONCLUSIONS: The results of this advanced practice provider-led study demonstrated that a live health coaching app that provides wellness coaching can offer motivated breast cancer survivors and cancer programs a modality that offers convenient, effective support at a reasonable cost.

Characterising the spatial and temporal brain metal profile in a mouse model of tauopathy.

A dysregulation in the homeostasis of metals such as copper, iron and zinc is speculated to be involved in the pathogenesis of tauopathies, which includes Alzheimer's disease (AD). In particular, there is a growing body of evidence to support a role for iron in facilitating the hyperphosphorylation and aggregation of the tau protein into neurofibrillary tangles (NFTs) - a primary neuropathological hallmark of tauopathies. Therefore, the aim of this study was to characterize the spatial and temporal brain metallomic profile in a mouse model of tauopathy (rTg(tauP301L)4510), so as to provide some insight into the potential interaction between tau pathology and iron. Using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS), our results revealed an age-dependent increase in brain iron levels in both WT and rTg(tauP301L)4510 mice. In addition, size exclusion chromatography-ICP-MS (SEC-ICP-MS) revealed significant age-related changes in iron bound to metalloproteins such as ferritin. The outcomes from this study may provide valuable insight into the inter-relationship between iron and tau in ageing and neurodegeneration.

Zn-DTSM, A Zinc Ionophore with Therapeutic Potential for Acrodermatitis Enteropathica?

Acrodermatitis enteropathica (AE) is a rare disease characterised by a failure in intestinal zinc absorption, which results in a host of symptoms that can ultimately lead to death if left untreated. Current clinical treatment involves life-long high-dose zinc supplements, which can introduce complications for overall nutrient balance in the body. Previous studies have therefore explored the pharmacological treatment of AE utilising metal ionophore/transport compounds in an animal model of the disease (conditional knockout (KO) of the zinc transporter, Zip4), with the perspective of finding an alternative to zinc supplementation. In this study we have assessed the utility of a different class of zinc ionophore compound (zinc diethyl bis(N4-methylthiosemicarbazone), Zn-DTSM; Collaborative Medicinal Development, Sausalito, CA, USA) to the one we have previously described (clioquinol), to determine whether it is effective at preventing the stereotypical weight loss present in the animal model of disease. We first utilised an in vitro assay to assess the ionophore capacity of the compound, and then assessed the effect of the compound in three in vivo animal studies (in 1.5-month-old mice at 30 mg/kg/day, and in 5-month old mice at 3 mg/kg/day and 30 mg/kg/day). Our data demonstrate that Zn-DTSM has a pronounced effect on preventing weight loss when administered daily at 30 mg/kg/day; this was apparent in the absence of any added exogenous zinc. This compound had little overall effect on zinc content in various tissues that were assessed, although further characterisation is required to more fully explore the cellular changes underlying the physiological benefit of this compound. These data suggest that Zn-DTSM, or similar compounds, should be further explored as potential therapeutic options for the long-term treatment of AE.

Targeting metals rescues the phenotype in an animal model of tauopathy.

Tauopathies are characterized by the pathological accumulation of the microtubule associated protein tau within the brain. We demonstrate here that a copper/zinc chaperone (PBT2, Prana Biotechnology) has rapid and profound effects in the rTg(tauP301L)4510 mouse model of tauopathy. This was evidenced by significantly improved cognition, a preservation of neurons, a decrease in tau aggregates and a decrease in other forms of "pathological" tau (including phosphorylated tau and sarkosyl-insoluble tau). Our data demonstrate that one of the primary mechanisms of action of PBT2 in this model may be driven by an interaction on the pathways responsible for the dephosphorylation of tau. Specifically, PBT2 increased protein levels of both the structural and catalytic subunits of protein phosphatase 2A (PP2A), decreased levels of the methyl esterase (PME1) that dampens PP2A activity, and increased levels of the prolyl isomerase (Pin1) that stimulates the dephosphorylation activity of PP2A. None of these effects were observed when the metal binding site of PBT2 was blocked. This highlights the potential utility of targeting metal ions as a novel therapeutic strategy for diseases in which tau pathology is a feature, which includes conditions such as frontotemporal dementia and Alzheimer's disease.

Improving cranial ultrasound scanning strategy in neonates.

Cranial ultrasound scans are undertaken in this tertiary neonatal intensive care unit by the doctors within the department. A quality improvement project was undertaken by means of two PDSA cycles to determine adherence to neonatal cranial ultrasound scanning schedule, assess the quality of scan reporting, and formulate a comprehensive guideline outlining best practice. The baseline measurements assessed 93 scans of preterm infants and 9 of term infants. The results of this prompted intradepartmental education (PDSA cycle 1) then creation and implementation of a documentation template, a local guideline, and education via presentations, posters, and email (PDSA cycle 2). These encompassed 77 preterm and 5 term scans. In our baseline measurements, 52% of preterm infant scans and 44% of term infant scans were performed to schedule. Of premature baby scan reports, 75% had the time documented and 92% the name of the scanning doctor. After implementing changes PDSA cycle 2 data showed that 74% of preterm infant scans and all term infant scans were performed according to schedule, with 100% having the doctor's name and time of scan documented. We successfully introduced a guideline and documentation template, improving performance to schedule and documentation in most areas. It remains an ongoing challenge to adhere to basic standards of documentation; a template can assist in achieving this. Rotating trainees may offer insight into areas that could benefit from quality improvement. This enthusiasm can be successfully harnessed to implement changes to improve quality of patient care.

Neurological Dysfunction in Early Maturity of a Model for Niemann-Pick C1 Carrier Status.

Autosomal recessive inheritance of NPC1 with loss-of-function mutations underlies Niemann-Pick disease, type C1 (NP-C1), a lysosomal storage disorder with progressive neurodegeneration. It is uncertain from limited biochemical studies and patient case reports whether NPC1 haploinsufficiency can cause a partial NP-C1 phenotype in carriers. In the present study, we examined this possibility in heterozygotes of a natural loss-of-function mutant Npc1 mouse model. We found partial motor dysfunction and increased anxiety-like behavior in Npc1 (+/-) mice by 9 weeks of age. Relative to Npc1 (+/+) mice, Npc1 (+/-) mice failed to show neurodevelopmental improvements in motor coordination and balance on an accelerating Rotarod. In the open-field test, Npc1 (+/-) mice showed an intermediate phenotype in spontaneous locomotor activity compared with Npc1 (+/+) and Npc1 (-/-) mice, as well as decreased center tendency. Together with increased stride length under anxiogenic conditions on the DigiGait treadmill, these findings are consistent with heightened anxiety. Our findings indicate that pathogenic NPC1 allele carriers, who represent about 0.66 % of humans, could be vulnerable to motor and anxiety disorders.

Correction: Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging.

[This corrects the article DOI: 10.1039/C5SC02231B.].

Correction: Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging.

[This corrects the article DOI: 10.1039/C5SC02231B.].

Visualising mouse neuroanatomy and function by metal distribution using laser ablation-inductively coupled plasma-mass spectrometry imaging.

Metals have a number of important roles within the brain. We used laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to map the three-dimensional concentrations and distributions of transition metals, in particular iron (Fe), copper (Cu) and zinc (Zn) within the murine brain. LA-ICP-MS is one of the leading analytical tools for measuring metals in tissue samples. Here, we present a complete data reduction protocol for measuring metals in biological samples, including the application of a pyramidal voxel registration technique to reproducibly align tissue sections. We used gold (Au) nanoparticle and ytterbium (Yb)-tagged tyrosine hydroxylase antibodies to assess the co-localisation of Fe and dopamine throughout the entire mouse brain. We also examined the natural clustering of metal concentrations within the murine brain to elucidate areas of similar composition. This clustering technique uses a mathematical approach to identify multiple 'elemental clusters', avoiding user bias and showing that metal composition follows a hierarchical organisation of neuroanatomical structures. This work provides new insight into the distinct compartmentalisation of metals in the brain, and presents new avenues of exploration with regard to region-specific, metal-associated neurodegeneration observed in several chronic neurodegenerative diseases.

A novel approach to rapidly prevent age-related cognitive decline.

The loss of cognitive function is a pervasive and often debilitating feature of the aging process for which there are no effective therapeutics. We hypothesized that a novel metal chaperone (PBT2; Prana Biotechnology, Parkville, Victoria, Australia) would enhance cognition in aged rodents. We show here that PBT2 rapidly improves the performance of aged C57Bl/6 mice in the Morris water maze, concomitant with increases in dendritic spine density, hippocampal neuron number and markers of neurogenesis. There were also increased levels of specific glutamate receptors (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate), the glutamate transporter (VGLUT1) and glutamate itself. Markers of synaptic plasticity [calmodulin-dependent protein kinase II (CaMKII) and phosphorylated CaMKII, CREB, synaptophysin] were also increased following PBT2 treatment. We also demonstrate that PBT2 treatment results in a subregion-specific increase in hippocampal zinc, which is increasingly recognized as a potent neuromodulator. These data demonstrate that metal chaperones are a novel approach to the treatment of age-related cognitive decline.