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

The Cys78-Asn88 loop region of the Campylobacter jejuni CstII is essential for alpha 2,3-sialyltransferase activity: analysis of the His85 mutants

CstII is a bifunctional sialyltransferase from Campylobacter jejuni that is active as a tetramer. CstIIs from different strains show substantial differences in enzyme activities (mono-versus bi-functional) and kinetic parameters. Crystal structures of CstII show that His85, conserved in CstIIs from different strains is part of an 11-residue loop that abuts the extended acceptor-binding site and is also part of the subunit interface. In this study, the role of His85 in the activity of CstII has been investigated by mutating it to Ala, Phe, Trp or Tyr. His85 is found to be essential for alpha 2,3-sialyltransferase activity but not alpha 2,8-sialyltransferase activity. Although no gross changes are observed in secondary and tertiary structures, thermal stability is affected by His85 mutation. MD simulations show changes in the flexibility of the loop regions including those in the binding site

Monomerization alters the dynamics of the lid region in Campylobacter jejuni CstII: an MD simulation study

CstII, a bifunctional (alpha 2,3/8) sialyltransferase from Campylobacter jejuni, is a homotetramer. It has been reported that mutation of the interface residues Phe121 (F121D) or Tyr125 (Y125Q) leads to monomerization and partial loss of enzyme activity, without any change in the secondary or tertiary structures. MD simulations of both tetramer and monomer, with and without bound donor substrate, were performed for the two mutants and WT to understand the reasons for partial loss of activity due to monomerization since the active site is located within each monomer. RMSF values were found to correlate with the crystallographic B-factor values indicating that the simulations are able to capture the flexibility of the molecule effectively. There were no gross changes in either the secondary or tertiary structure of the proteins during MD simulations. However, interface is destabilized by the mutations, and more importantly the flexibility of the lid region (Gly152-Lys190) is affected. The lid region accesses three major conformations named as open, intermediate, and closed conformations. In both Y121Q and F121D mutants, the closed conformation is accessed predominantly. In this conformation, the catalytic base His188 is also displaced. Normal mode analysis also revealed differences in the lid movement in tetramer and monomer. This provides a possible explanation for the partial loss of enzyme activity in both interface mutants. The lid region controls the traffic of substrates and products in and out of the active site, and the dynamics of this region is regulated by tetramerization. Thus, this study provides valuable insights into the role of loop dynamics in enzyme activity of CstII

Lessons in integration--operations research in an Indian leprosy NGO.

Since the Alma Ata Declaration in 1978, health systems supporting the treatment and control of infectious diseases like leprosy and tuberculosis have been encouraged to 'integrate' into the primary health care structure within countries. Now, more than 20 years later, countries are still grappling with the concept of integration and looking for ways to achieve it. This study reports findings from a leprosy/Tuberculosis/AIDS awareness pilot project conducted by LEPRA India, a leprosy non-governmental organization (NGO), between 1996 and 2000 in Koraput district, Orissa. The project addressed the issue of integration on two levels. On the one hand LEPRA used the context of the project to explore ways in which to integrate TB services into their existing leprosy control structure. On the other hand, lessons from the pilot study were intended to help the organization find ways of linking with the government health care structure. Following a 'qualitative approach', this operations research project assessed the perceptions of communities and providers about leprosy and tuberculosis services. Providers across the spectrum of this plural healthcare system were asked to provide comment on developing stronger networks with each other, with NGOs and with government, while patients and communities were asked to describe the resources available to them and the constraints they face in accessing health care in general, and for leprosy and TB in particular. LEPRA staff from top management to the outreach workers were also approached for their views. Patients and communities noted that physical access to treatment was a major constraint, while the existence of local providers and family support structures facilitated health and health care. Providers expressed a willingness to collaborate (with LEPRA and the government), but lacked training, adequate staff support and the appropriate equipment/technical resources. Also lacking were adequate information campaigns to inform the public about these diseases and their treatment. This information has provided LEPRA with an understanding of how they might best fill gaps in the existing system and therefore assist in the process of integrating services in their own organization and through the primary health care structure. To achieve this aim, LEPRA will increasingly become involved in developing relationships and partnerships with government in the delivery of training and services and in infrastructure development

Introducing operations research into management and policy practices of a non-governmental organization (NGO): a partnership between an Indian leprosy NGO and an international academic institution.

This paper reports on a partnership between LEPRA, a non-governmental organization (NGO), and the London School of Hygiene and Tropical Medicine (LSHTM) to explore the feasibility and appropriateness of incorporating operations research into the management and decision-making of a leprosy NGO. A pilot study in Orissa was used to determine the advantages and disadvantages of introducing operations research to assist in decision-making and programme implementation within the organization. The results highlight the difficulty and complexity of the process, but point to several important themes: partnership, changing perspectives, use of time and priority-setting, identification of gaps in systems, and building institutional and personal capabilities. The results of the study provide support to encourage NGOs to become actively involved in research. Because of their work and service to local communities, NGOs have the opportunity to collect information about the perceptions, resources and constraints of individuals, families and the communities themselves in accessing appropriate care. Their proximity to communities gives them a feeling of responsibility for ensuring that this information is translated to the district, national and ultimately international level. This will help to ensure the creation of appropriate infectious disease control policies that support the needs of patients. 'Outside' academic institutions can help NGOs to facilitate this up-stream flow of information from the local to the national and international level, to help to ensure that international disease control policies are appropriately serving local communities

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