Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway.

Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer's disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer's Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.

Physical and material properties of an emulsion-based lipstick produced via a continuous process.

OBJECTIVES: Water-in-oil emulsions in lipsticks could have the potential to improve moisturizing properties and deliver hydrophilic molecules to the lips. The aim of this work was to investigate the effect of a continuous process (scraped surface heat exchanger (SSHE) and pin stirrer (PS)) on the physical and material properties of an emulsion-based lipstick by altering the processing conditions of both the SSHE and PS. METHODS: Emulsion formation was achieved using a SSHE and PS. Emulsions were analysed using nuclear magnetic resonance restricted diffusion (droplet size), texture analysis and rheology (mechanical properties). RESULTS: Results showed that a higher impeller rotational velocity (IRV) (1500 r.p.m.) and a lower exit temperature (52°C) produce the smallest droplets (~ 4 µm), due to greater disruptive forces and a higher viscosity of the continuous phase. The addition of a PS reduces the droplet size (14-6 µm) if the SSHE has a low IRV (500 r.p.m.), due to greater droplet disruption as the emulsion passes through the PS unit. Results also show that if the jacket temperature of a SSHE is 65°C, so that crystallization occurs in both process and post-production, droplets can be integrated into the network resulting in a stiffer wax network (G' - 0.12, in comparison to 0.02 MPa). This is due to small crystals creating a shell around water droplets which can form connections with the continuous network forming a structured network. The addition of a pin stirrer can disrupt a formed network reducing the stiffness of the emulsion (0.3-0.05 MPa). CONCLUSION: This work suggests the potential use of a continuous process in producing an emulsion-based lipstick, particularly when wax crystals are produced in the process. Future work should consider the moisturizing or lubricating properties of wax continuous emulsions and the release of hydrophilic compounds from the aqueous phase.

Effect of emulsifier type and concentration, aqueous phase volume and wax ratio on physical, material and mechanical properties of water in oil lipsticks.

OBJECTIVES: Water-in-oil emulsions in lipsticks could have the potential to improve moisturizing properties and deliver hydrophilic molecules to the lips. The aims of this work were (i) to investigate the effect of emulsifier type (polymer vs. monomer, and saturated vs. unsaturated chain) and concentration on droplet size and (ii) to investigate the effect of wax ratio (carnauba wax, microcrystalline wax, paraffin wax and performalene) and aqueous phase volume on material properties (Young's modulus, point of fracture, elastic modulus and viscous modulus). METHODS: Emulsion formation was achieved using a high shear mixer. RESULTS: Results showed that the saturated nature of the emulsifier had very little effect on droplet size, neither did the use of an emulsifier with a larger head group (droplet size ~18-25 µm). Polyglycerol polyricinoleate (PGPR) resulted in emulsions with the smallest droplets (~3-5 µm), as expected from previous studies that show that it produces a thick elastic interface. The results also showed that both Young's modulus and point of fracture increase with increasing percentage of carnauba wax (following a power law dependency of 3), but decrease with increasing percentage of microcrystalline wax, suggesting that the carnauba wax is included in the overall wax network formed by the saturated components, whereas the microcrystalline wax forms irregular crystals that disrupt the overall wax crystal network. Young's modulus, elastic modulus and viscous modulus all decrease with increasing aqueous phase volume in the emulsions, although the slope of the decrease in elastic and viscous moduli is dependent on the addition of solid wax, as a result of strengthening the network. CONCLUSIONS: This work suggests the potential use for emulsions in lipstick applications, particularly when PGPR is used as an emulsifier, and with the addition of solid wax, as it increases network strength.

Sexual function after permanent 125I-brachytherapy for prostate cancer.

We prospectively assessed patients' erectile function (EF) using the International Index of Erectile Function (IIEF) and a global assessment questionnaire (GAQ) following permanent 125I-brachytherapy for localized prostate cancer. Of 378 treated patients, 220 had a minimal 2-y follow-up and 131/220 were sexually active prior to brachytherapy, with an EF domain score of > or = 11 (study group). Patients were allowed sildenafil at any time of the study. The patients' mean EF score, without excluding patients who used sildenafil, dropped within 3 months after brachytherapy, recovered at the end of the first year and remained unchanged for at least up to 2 y after treatment regardless of the addition of neoadjuvant hormone therapy to 125I-brachytherapy. Analysis of the GAQ revealed that 80% of the patients were satisfied with their sexual function up to 3 y after treatment. Any detrimental effect of permanent brachytherapy with or without the addition of hormone therapy on EF is reversible, and recovery is expected at 1 y after treatment in most patients.