Systematic Review of Potential Health Risks Posed by Pharmaceutical, Occupational and Consumer Exposures to Metallic and Nanoscale Aluminum, Aluminum Oxides, Aluminum Hydroxide and Its Soluble Salts

Aluminum (Al) is a ubiquitous substance encountered both naturally (as the third most abundant element) and intentionally (used in water, foods, pharmaceuticals, and vaccines); it is also present in ambient and occupational airborne particulates. Existing data underscore the importance of Al physical and chemical forms in relation to its uptake, accumulation, and systemic bioavailability. The present review represents a systematic examination of the peer-reviewed literature on the adverse health effects of Al materials published since a previous critical evaluation compiled by Krewski et al. (2007). Challenges encountered in carrying out the present review reflected the experimental use of different physical and chemical Al forms, different routes of administration, and different target organs in relation to the magnitude, frequency, and duration of exposure. Wide variations in diet can result in Al intakes that are often higher than the World Health Organization provisional tolerable weekly intake (PTWI), which is based on studies with Al citrate. Comparing daily dietary Al exposures on the basis of “total Al”assumes that gastrointestinal bioavailability for all dietary Al forms is equivalent to that for Al citrate, an approach that requires validation. Current occupational exposure limits (OELs) for identical Al substances vary as much as 15-fold. The toxicity of different Al forms depends in large measure on their physical behavior and relative solubility in water. The toxicity of soluble Al forms depends upon the delivered dose of Al+ 3 to target tissues. Trivalent Al reacts with water to produce bidentate superoxide coordination spheres [Al(O2)(H2O4)+ 2 and Al(H2O)6 + 3] that after complexation with O2•−, generate Al superoxides [Al(O2•)](H2O5)]+ 2. Semireduced AlO2• radicals deplete mitochondrial Fe and promote generation of H2O2, O2 • − and OH•. Thus, it is the Al+ 3-induced formation of oxygen radicals that accounts for the oxidative damage that leads to intrinsic apoptosis. In contrast, the toxicity of the insoluble Al oxides depends primarily on their behavior as particulates. Aluminum has been held responsible for human morbidity and mortality, but there is no consistent and convincing evidence to associate the Al found in food and drinking water at the doses and chemical forms presently consumed by people living in North America and Western Europe with increased risk for Alzheimer\u27s disease (AD). Neither is there clear evidence to show use of Al-containing underarm antiperspirants or cosmetics increases the risk of AD or breast cancer. Metallic Al, its oxides, and common Al salts have not been shown to be either genotoxic or carcinogenic. Aluminum exposures during neonatal and pediatric parenteral nutrition (PN) can impair bone mineralization and delay neurological development. Adverse effects to vaccines with Al adjuvants have occurred; however, recent controlled trials found that the immunologic response to certain vaccines with Al adjuvants was no greater, and in some cases less than, that after identical vaccination without Al adjuvants. The scientific literature on the adverse health effects of Al is extensive. Health risk assessments for Al must take into account individual co-factors (e.g., age, renal function, diet, gastric pH). Conclusions from the current review point to the need for refinement of the PTWI, reduction of Al contamination in PN solutions, justification for routine addition of Al to vaccines, and harmonization of OELs for Al substances

Evolution-informed modeling improves outcome prediction for cancers

Despite wide applications of high‐throughput biotechnologies in cancer research, many biomarkers discovered by exploring large‐scale omics data do not provide satisfactory performance when used to predict cancer treatment outcomes. This problem is partly due to the overlooking of functional implications of molecular markers. Here, we present a novel computational method that uses evolutionary conservation as prior knowledge to discover bona fide biomarkers. Evolutionary selection at the molecular level is nature’s test on functional consequences of genetic elements. By prioritizing genes that show significant statistical association and high functional impact, our new method reduces the chances of including spurious markers in the predictive model. When applied to predicting therapeutic responses for patients with acute myeloid leukemia and to predicting metastasis for patients with prostate cancers, the new method gave rise to evolution‐informed models that enjoyed low complexity and high accuracy. The identified genetic markers also have significant implications in tumor progression and embrace potential drug targets. Because evolutionary conservation can be estimated as a gene‐specific, position‐specific, or allele‐specific parameter on the nucleotide level and on the protein level, this new method can be extended to apply to miscellaneous “omics” data to accelerate biomarker discoveries.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135247/1/eva12417_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/135247/2/eva12417.pd

Visual Search in Progressive Supranuclear Palsy

Progressive supranuclear palsy is often considered a disease of the motor system and is characterised by a profound oculomotor impairment. The oculomotor system is also known to be fundamentally important in cognitive processes such as attention and working memory, but the way in which these functions are affected by PSP is not well understood. In this chapter we outline the pathology and typical presentation of PSP, with a focus on the oculomotor impairment, briefly outline the role of the oculomotor system in spatial cognition and discuss some key studies examining spatial attention and memory in PSP. We then present new data from a study that specifically examined the effect of PSP on visual search. Our results demonstrated a profound impairment of visual search which is most severe for feature search along the vertical axis. These findings are interpreted with respect to the biased-competition theory of attention, and we discuss possible clinical applications of our results

Sulfadiazine-based drug delivery systems prepared by an effective sol-gel process

In the present contribution a versatile and sustainable strategy for the formulation of a Drug Delivery System (DDS) for the controlled release of antibiotics for topical administration was developed. Silver sulfadiazine (AgSD), an antimicrobial agent for preventing infections on burn wounds, was selected as model drug. The DDS was formulated by an effective one-pot sol-gel approach by using chitosan and silica alkoxides as organic and inorganic precursor, respectively, in order to obtain a hybrid material. Different silica alkoxides, characterized by different functionalities of the organic chain, and a series of synthetic parameters (water/precursor ratio, excipients, drug amount) were evaluated. The composition of the hybrid gel was selected to achieve the optimal synergy between the physico-chemical features and the gel texture taking into great account the final application, i.e., a topical administration. Drug delivery tests were performed in vitro with a Franz vertical diffusion cell. The new DDS reaches the therapeutic concentration in the same time of a commercial sample and allows the complete release of even 2.5wt% AgSD. The drug delivery is totally controlled and gradual over 48 hours and the formulated is stable in time. Such innovative organic-inorganic hybrid material is therefore an efficient DDS for acute skin infections treatment by controlled delivery.In the present contribution a versatile and sustainable strategy for the formulation of a drug delivery system for the controlled release of antibiotics for topical administration was developed. Silver sulfadiazine (AgSD), an antimicrobial agent for preventing infections on burn wounds, was selected as model drug. The drug delivery system was formulated by an effective one-pot sol-gel approach by using chitosan and silica alkoxides as organic and inorganic precursor, respectively, in order to obtain a hybrid material. Different silica alkoxides, characterized by different functionalities of the organic chain, and a series of synthetic parameters (water/precursor ratio, excipients, and drug amount) were evaluated. The composition of the hybrid gel was selected to achieve the optimal synergy between the physico-chemical features and the gel texture taking into great account the final application, i.e., a topical administration. Drug delivery tests were performed in vitro with a Franz vertical diffusion cell. The new drug delivery system reaches the therapeutic concentration in the same time of a commercial sample and allows the complete release of even 2.5 wt% AgSD. The drug delivery is totally controlled and gradual over 48 h and the formulated is stable in time. Such innovative organic-inorganic hybrid material is therefore an efficient drug delivery system for acute skin infections treatment by controlled delivery.[GRAPHICS

Upper and lower respiratory tract microbiota in horses: bacterial communities associated with health and mild asthma (inflammatory airway disease) and effects of dexamethasone

Abstract Background The microbial composition of the equine respiratory tract, and differences due to mild equine asthma (also called Inflammatory Airway Disease (IAD)) have not been reported. The primary treatment for control of IAD in horses are corticosteroids. The objectives were to characterize the upper and lower respiratory tract microbiota associated with respiratory health and IAD, and to investigate the effects of dexamethasone on these bacterial communities using high throughput sequencing. Results The respiratory microbiota of horses was dominated by four major phyla, Proteobacteria (43.85%), Actinobacteria (21.63%), Firmicutes (16.82%), and Bacteroidetes (13.24%). Fifty genera had a relative abundance > 0.1%, with Sphingomonas and Pantoea being the most abundant. The upper and lower respiratory tract microbiota differed in healthy horses, with a decrease in richness in the lower airways, and 2 OTUs that differed in abundance. There was a separation between bacterial communities in the lower respiratory tract of healthy and IAD horses; 6 OTUs in the tracheal community had different abundance with disease status, with Streptococcus being increased in IAD horses. Treatment with dexamethasone had an effect on the lower respiratory tract microbiota of both heathy and IAD horses, with 8 OTUs increasing in abundance (including Streptococcus) and 1 OTU decreasing. Conclusions The lower respiratory tract microbiota differed between healthy and IAD horses. Further research on the role of Streptococcus in IAD is warranted. Dexamethasone treatment affected the lower respiratory tract microbiota, which suggests that control of bacterial overgrowth in IAD horses treated with dexamethasone could be part of the treatment strategy