Abstract
The term diseases of unknown aetiology (DUA) or idiopathic diseases is used to describe diseases that are of uncertain or unknown cause or origin. Among plausible geoenvironmental co-factors in causation of DUA, this article focusses on the entry of trace elements, including metals and metalloids into humans, and their involvement in humoral and cellular immune responses, representing potentially toxic agents with implications as co-factors for certain DUA. Several trace elements/metals/metalloids (micronutrients) play vital roles as co-factors for essential enzymes and antioxidant molecules, thus, conferring protection against disease. However, inborn errors of trace element/metal/metalloid metabolisms can occur to produce toxicity, such as when there are basic defects in the element transport mechanism. Ultimately, it is the amount of trace element, metal or metalloid that is taken up, its mode of accumulation in human tissues, and related geomedical attributes such as the chemical form and bioavailability that decisively determine whether the exerted effects are toxic or beneficial. Several case descriptions of DUA that are common worldwide are given to illustrate our knowledge so far of how trace element/metal/metalloid interactions in the immune system may engender its dysregulation and be implicated as causal co-factors of DUA.
Article highlights
-
The importance of a proper understanding of geochemical perturbations in human metabolisms is emphasised
-
It is proferred that such an understanding would aid greatly in the decipherment of diseases of unknown aetiology (DUA)
-
The thesis presented may pave the way towards better diagnosis and therapy of DUA
Similar content being viewed by others
1 Introduction
As far back as 1923 Marcus Haase noted the vast gap that exists in our knowledge of accurately identifying the cause of many diseases [1]. Despite the enormous advances made by modern medicine, there are several diseases today whose causes are still unknown (See examples in Table 1). These diseases are generally referred to as diseases of unknown aetiology (DUA), and as recently as 2020, an estimated seventy-six percent of unknown disease outbreaks remained undiagnosed [2]. Rappaport had earlier (2012) noted that: “Although chronic diseases are primarily environmental (i.e., not genetic) in origin, the particular environmental causes of these diseases are poorly understood.” [3].
A recent World Health Organisation (WHO) study of worldwide cancer mortality identified ten diverse environmental risk factors, including some with links to the geological environment, such as air pollution and ionising radiation exposure [4]. But on the whole, it appears that the influence of geoenvironmental factors in disease causation, in particular, the effects of involvement of trace elements/metals/metalloids in human metabolisms that produce disease, has been somewhat underestimated.
In this paper, it is argued that greater consideration should be given to the contribution of the geoenvironmental co-factor in a multi-factor explanation and diagnosis of DUA; in particular, the entry of trace elements including metals and metalloids into biological systems, and their involvement in humoral and cellular immune responses. Possible ways in which trace elements/metals/metalloids can contribute towards shaping developmental metabolic frameworks and pathways in DUA progression are described. The expectation is that a firm understanding of the role of geoenvironmental co-factors, more especially, trace element/metal/metalloid perturbations that produce errors or disturbances in metabolic processes will help greatly in unravelling the aetiology of DUA when this knowledge is applied in a circumspective way.
Rationalisation of such knowledge falls within the compass of the Medical Geologist who, according to Bundschuh et al. [5], can provide credible explanations regarding the mode of occurrence, mobility, bioavailability and bio-accessibility characteristics, as well as exposure and transfer mechanisms of geochemicals to the food-chain and humans; and the nature of related ecotoxicological and health effects that are produced.
To these parameters, can be added the chemical form of the element, a parameter that, in turn, greatly influences mobility, bioavailability and the mechanism that either transports the element to the centres (of the body) where it is needed for vital reactions, or be involved in interactions that result in disease (cf., DUA). An approach that integrates all possible or suspected co-factors is contingent upon the realisation that most DUA and other enigmatic diseases have multifactorial causes, engendering a complex networking between genetic factors (polygenic), immunological mediators (trace elements/metals/metalloids) and various other (geo)environmental factors, none of which factors would cause the disease on its own.
This approach is further buttressed by Panelli’s (2017) observation that we need to look more closely at multisystem diseases of unknown cause and seek new ways to diagnose and discriminate diseases whose aetiologies are still unclear, but are affecting large populations of patients worldwide [6].
1.1 Content
The paper is divided into eight major sections. The first of these, “Introduction”, brings to awareness the myriad of globally occurring diseases whose causes to date, are still imprecisely known. A demonstration is made of how metallome disturbances negatively affect the immune system and how a proper understanding of geochemically-related perturbations in human bodies might provide useful clues for improving diagnosis and therapy of DUA. This Section also incorporates the “Methodology”, which is based on an iterative approach in a comprehensive search and review of pertinent documents on ‘unknown aetiologies’ from a number of key databases.
In Sect. 2, brief explanations are given on how best to obviate classifying an observed association between a risk factor and disease (cf., DUA) as due to chance (random error), bias (systematic error) or confounding. The role of various geoenvironmentally-related variables as co-factors in disease causation is briefly reviewed in this Section.
In Sect. 3, brief discussions are given of how geochemical variables can have profound effects on biological systems, using the examples of ‘speciation’, ‘variations in natural isotopic ratios in tissues’, and ‘bioavailability’.
Section 4: “Geochemical variables and the immune system” presents a comprehensive review of several aspects of immune system function and autoimmune diseases (AuDs), since a number of DUAs fall under this category.
Section 5: “Criticality of the optimal range of intake and the occurrence of nutrient toxicities” emphasises the importance of optimum level of nutrient-uptake, and recommends nutritional measures that could be taken to maintain the correct level.
Section 6: “Disease risk mapping and DUA cluster detection” discusses the importance of these maps, and how they can be applied to the identification and analysis of clusters of DUA; hence providing clues on their origin.
Section 7: “Conclusions”, gives the main conclusions drawn from the study, exposes gaps in knowledge and recommends some urgent areas of research into DUA.
Section 8: “Glossary of Terms” presents definitions and explanations of technical terms, abbreviations and phrases that are unfamiliar to non-medical scientists and others from allied fields of the multidisciplinary science of ‘Medical Geology’.
1.2 Methodology
An iterative approach was adopted in a comprehensive internet search through October 10, 2021, combining the results from multiple search engines—Google scholar, PubMed, ScienceDirect and SpringerLink—to achieve an improvement in the analysis of each dataset. Initial searches used broad terms: ‘geo-environmental factors’, ‘unknown aetiology’ and ‘disease X’. Inclusion criteria were accounts of studies carried out in humans and animals and reported observational designs. The documents returned from these searches were used to identify narrower search terms, such as ‘risk factors’, ‘nutritional and toxic elements/metabolic imbalances’, ‘immune system’. Over seven hundred documents were retrieved (including some duplicates), out of which, conclusions from about four hundred and sixty were studied in detail. These included peer reviewed journal articles and conference proceedings, authentic book chapters, published and unpublished theses and reports, and selected web references.
2 Causality
In the field of medicine, cause, also sometimes referred to as aetiology is the reason or origination of a disease, or of a pathology (essential nature of disease) [7]. The word ‘aetiology’ stems from the Greek αἰτιολογία, aitiologia, “giving a reason for” (αἰτία, aitia, “cause”; and—λογία,—logia) [8].
Attempts at unravelling the aetiologies of human diseases go back as far as to antiquity. Hippocrates, a Greek physician of the fourth and fifth centuries BCE, is believed to be the first to adopt the concept that disease is not a visitation of the gods but rather, results from earthly influences [9]. Medieval European doctors were generally of the view that disease was related to the air and adopted a miasmatic approach to disease aetiology [10]. Scientists from the field of medicine and from allied sciences have since continually searched for the causes of disease and, indeed, have discovered the causes of many. Where no definite aetiological characterisation can be made, the disorder is said to be idiopathic.
Traditional accounts have linked the causes of disease to the evil eye, a phenomenon elucidated by Abu-Rabia in 2005 [11], in describing the rituals of diagnosis, treatment and prevention among the Bedouin tribes of the Negev in the Middle East.
In medicine, debates on the history of aetiological discovery always make reference to Robert Koch’s affirmation in 1882, that the tubercle bacillus (Mycobacterium tuberculosis complex) causes the disease tuberculosis, Bacillus anthracis causes anthrax, and Vibrio cholerae causes cholera [12].
This ideation and affirmation is encapsulated in Koch’s notions. In epidemiological research on infectious diseases, proof of causation is limited to individual cases where evidence of aetiology can be demonstrated experimentally. In order to infer causation, we require several lines of evidence, taken together.
2.1 Chain of causation and correlation
We need to distinguish between causation and association or statistical correlation. Events may occur simultaneously simply due to chance, bias or confounding (See: “Glossary of Terms”, this article, for definitions), instead of one event being precipitated by the other. It is also necessary to decipher which event is the cause. Confounding is said to occur when exposure to a probable disease causative agent or cofactor and an outcome have an apparent but false correlation (Fig. 1). It is important to control for the confounder, otherwise, there would seem to be a link between the exposure and the outcome, when in fact both are due to the confounding effect and bear no relationship at all (or no strong relationship). Careful sampling and analyses should be the sine qua non, rather than complex statistical analysis to establish causation. Evidence garnered from experimental studies involving interventions (providing or removing the supposed cause) provides the most convincing evidence of aetiology.
It is also necessary to state that there are times when several symptoms appear together, sometimes more than what could be expected; though it is known that one cannot cause the other. These situations are referred to as syndromes (See “Glossary of Terms”, this article). The assumption is that an underlying condition exists that explains all the symptoms. Quite often, however, a single cause for a disease cannot be found, but rather, we find a chain of causation from an initial trigger to the development of the clinical disease. An aetiological agent of disease may require an independent co-factor and be subject to a promoter (See “Glossary of Terms”, this article) to cause disease.
2.2 The geo-environment as an agent of disease
The causal co-factors of disease occurrence and progression are legion, and include genetics, microbes/fungi, environmental factors such as exposure to geogenic contaminants (geochemicals, xenobiotics), geographical patterns, seasonality, climate change, geopathic stress, heat waves and heat stress and spacio-temporal associations. In any discussion on the determinants of heath, the effect of socio-economic factors such as education, income and wealth, should never be overlooked, for they shape our health in important ways, not least, in providing clues on likely pathways and mechanisms that may explain their effects.
In 2000, Kroll-Smith et al. noted that: “Struggles over environmentally induced diseases are struggles over the very nature of what exists and how we know the nature of the phenomenon” [14]. Suggestions that the geoenvironmental milieu (geographical and climatic patterns, seasonal variations, geological and geochemical variables) can have a significant influence on the occurrence and development of disease, has for long captivated scholarly attention across a number of disciplinary and policy domains. Mehri, for instance, discusses how geoenvironmental conditions work in concert with infectious agents that activate innate and adaptive immune system (See “Glossary of Terms”, this article) and provoke DUA in genetically susceptible patients [15].
Geochemicals such as metals, metalloids, and radionuclides, as well as transuraniums, referred to as geogenic contaminants (GCs) by Bundschuh et al. [5], occur naturally in geogenic sources (e.g., minerals, rocks, ground- and surface waters and volcanic emanations). Their accelerated release globally has been attributed to rapid population rise and economic growth, and the associated increase in demand for water, energy, food, and mineral resources. The release of GCs occurring in near surface environments can be triggered into the soil, water, air and biota compartments, and subsequently enter the food chain, with often deleterious health consequences.
Writing on one of the more well-known DUAs [chronic kidney disease (CKD): Table 1), Hara et al. [16] remarked on the significance of the contribution of environmental factors compared to genetic factors in the development of CKD among individuals with the same ethnicity. In 2017, Senanayake and King, reviewing recent research done on emerging health-environment relationships, categorised the studies done into three themes, viz: complexity, uncertainty, and bodies [17]. Although there have been robust contributions to these thematic areas from geography and the social sciences, Senanayake and King [17] construe that integrating them (contributions) into an analytical framework can extend geographical perspectives on scale, knowledge production, and human–environment relations, while also incorporating valuable insights from cognate fields.
The cardinal thesis here is that proper consideration of geoenvironmental co-factors -more especially the geochemical-, can significantly contribute to resolution of causation of DUA, probably to an extent greater than what has hitherto been conceived (Table 1). Some examples of probable geoenvironmental and related co-factors to be considered are:
(i) The immune-modulatory effect of geochemical variables (e.g., chemical form, the mechanism of element transport and bioactivity) that underline nutritional and potentially toxic element (PTE) perturbations in metabolic processes (See, e.g., Lukác and Massányi [18]).
(ii) The production of reactive oxygen species (ROS) and DNA damages wrought by metabolic imbalance of trace elements/metals/metalloids (disruption of metal ion homeostasis) (See, e.g., Juan et al. [19]).
(iii) Water, soil and air pollution emanating from diverse sources that include volcanic emissions, mining, naturally contaminated groundwater, radon emanations into buildings, agriculture and industry. A substantial part of the pollution load from these sources often comprises the PTEs (e.g., arsenic, fluorine, mercury and lead) having a propensity to enter the food chain (through consumption of food crops and drinking water, as well as through other intake pathways such as inhalation and direct contact) [cf., (i) above]. Initially undetected release of a chemical from the Earth’s sub-surface into the groundwater system can occur, such as when CO2 gas was released in the Lake Nyos (Cameroon) disaster of the 1980’s (See, e.g., Rouwet et al. [20]; Boehrer et al. [21]).
(iv) Geogenic dust particles from mining, ore processing and vehicular transportation on untarred roads.
(v) Over-exposure to ionising radiation and radionuclides in the water, soil and air environments during mining, ore processing and tailings handling of uranium, gold and other radiogenic ores (See, e.g., US EPA [22]).
(vi) Geographical patterns (e.g., locality, altitude) and seasonal variations.
(vii) Climate change and geoclimatic effects.
(viii) Factors of geopathic stress and heat stress.
2.3 Role of genetics
A gene is the basic physical unit of heredity. Genes are made up of DNA (deoxytribonucleic acid) and act as instructions to synthesise molecules called proteins. Many proteins are actually enzymes, and are responsible for carrying out all cellular functions. Salzberg estimated the number of genes in the human genome (genetic complement) to be 20,000 to 25,000 [274]. Genes are passed on from parents to offspring, and contain the information needed to specify traits.
There are a number of human diseases that result from mutations in the genetic complement residing in the DNA of chromosomes. Although mutations occurring in the DNA of somatic (body) cells cannot be inherited, they can cause congenital malformations (existing at birth) and cancers. Mutations that occur in germ cells, viz., the gametes, ova and sperm, are passed on to offspring causing inherited diseases.
Studies on how environmental exposures modify the expression of genes without directly changing the genetic code stored in DNA were appraised by Rappaport in 2016 [275], and more recently by Perera et al. in 2019 [276]. Such studies belong to the field of environmental epigenetics, a field that is currently being actively researched by the United States National Institute of Environmental Health Sciences (US NIEHS) [277].
Although the principle biological function of DNA is the storage of genetic information, its unique chemical structure renders this molecule amenable to metal binding via both the phosphate backbone and nucleobases or both (Kanellis and Dos Ramedios [278]. Binding of metals to the bases usually disrupts base pair hydrogen bonding and destabilises the double helix (Anastassopoulou [279]). Research on the role of DNA-bound metal ions in the incidence of certain DUA such as the neurogenerative diseases (e.g., AD, PD and MS) has been going on with increased intensity in the last two decades (See, e.g., Anastassopoulou [279]; Dales and Desplat-Jégo [280]; Morris, Jr. [281]; Hasani Nourian et al. [282]), but exact pathways and mechanisms by which metal toxicity is induced are still not fully understood. (Ibrahim and Gabr [283]) and a number of other authors consider it likely that each metal could be toxic through specific pathways and mechanisms (See Fig. 2).
A number of studies (e.g., Balali-Mood et al. [284]; Liu et al. [285]; Singh et al. [60]) have found that excess levels of ROS produced as a result of bioaccumulation of metals during cellular events (disruption of metal ion homeostasis) lead to oxidative stress, which can overwhelm the body’s antioxidant protection, inducing DNA damage. These events can promote the development of certain metabolic diseases whose precise aetiologies are still unknown, e.g., Type 1 diabetes [122].
The state of oxidative stress is characterised by an imbalance between production and accumulation of ROS in cells and tissues and the ability of living systems to detoxify these reactive products. An excellent review written by Jomova and Valko in 2011 [286] illustrates how redox active metals such as Fe, Cu, Cr, Co and others undergo redox cycling reactions and have the potential of producing reactive radicals such as superoxide anion radical and nitric oxide in biological systems.
Other conditions associated with oxidative DNA damage (genetic) include neurodegenerative disorders of unknown aetiology such as AD and PD (Coppedè and Migliore [287]; Singh et al. [60]), autoimmune diseases such as rheumatoid arthritis, systemic Lupus erythematosus (SLE) and many others (Ramani et al. [288]).
2.4 Role of climate change
The relationship between climate change and health is becoming increasingly clear and well documented. Developments in this area of research can be followed up in a number of recent publications (e.g., Grobusch and Grobusch [289]; Romanello et al. [290]; WHO [291]; and many scientific journals are devoted exclusively to this subject or have whole sections addressing it. With DUA, specifically, however, the relationship with climate is much less clear and relatively few studies or publications exist on the subject.
Attempts in grappling with the challenges of global climate change have revealed unexpected findings on immune system mediation by toxic trace elements, infectious disease (re)emergence, and the growing field of epigenetics (See, e.g., Ackland et al. [292]). These findings have helped us recast the environment as an agent of illness. Reflecting this shift, leading international bodies assessing the science related to climate change, such as the WHO and the Intergovernmental Panel on Climate Change (IPCC) [e.g., through its Fifth Assessment Report], respectively, have begun to focus attention on contingent, non-linear, and cross-scalar cause and effect relationships between the environment and human health ([293, 294]).
3 Geochemical variables and disease
There are a number of geochemical variables that determine the behaviour of trace elements/metals/metalloids before and after entry into biological systems. Before entry, parameters such as speciation, and those of the physical environment (e.g., pH and salinity) are among the key determinative factors. Upon entry into the body, parameters such as the dose, the chemical form, bioavailability, bioaccessibility and efficacy of transport mechanisms within the body become crucial. These factors must be considered in relation to host factors, such as age, gender, size and genetic characteristics; and in the case of the built environment, socio-economic conditions (e.g., the quality of the living space), and risk perception. Some of these factors enhance uptake and absorption, whereas others moderate it. It is thus possible to postulate that detailed measurement and thorough understanding of these variables can help us better chart the aetiology of DUA.
3.1 Speciation
Changes in speciation take place as trace elements/metals/metalloids migrate within and between the environmental compartments of air, soil, water, sediments and biota. The fate of the different species of trace elements/metals/metalloids during these processes is controlled by key biogeochemical parameters including: pH (solubility), Eh, ionic strength (activity and charge-shielding), and dissolved organic carbon (complexation). A knowledge of speciation is therefore important in working out transport mechanisms, mode of accumulation, bioavailability and, in the context of the DUA, their toxicity and potential as diagnostic aid.
3.2 Use of variations in natural isotopic composition in tissues for DUA diagnosis and/or prosnostic
The importance of variations in natural isotopic compositions, which, like metal concentrations, might provide useful clues in the unravelment of DUA causality, must never be overlooked. The natural abundance of heavy stable isotopes such as 13C, 15 N and 18O varies between tissues and metabolites due to isotope fractionation effects in biological processes. Indeed, as recently pointed out by Hastuti et al. [295], variations in stable isotope ratios of essential elements can reflect alterations in their homeostasis resulting from physiological changes in malignancies with higher sensitivity than concentrations do.
Such discrimination between heavy and light isotopic forms, alongside alterations in metabolic fluxes, takes place during enzyme or transporter activities, and may reflect metabolic deregulations associated with many DUA (Tea et al. [118]). However, there is a paucity of research on causes of isotope fractionations in critical metabolic processes; and hence, we have little understanding to date of the mechanisms by which the isotopic signature of diseases are imprinted.
Moynier et al. [296] observed that the isotopic composition of copper and zinc in AD brains differs from that of controls in a way that is statistically significant. Copper, with its multiple redox states (Cu+ and Cu2+), its isotopic fractionation is enhanced by redox change, which apparently, could explain the larger and statistically more significant isotopic shift observed for copper relative to zinc. In a previous article, Moynier et al. [297] stated that the connection between zinc and brain aging makes it possible to use changes in zinc homeostasis in AD to chart the evolutionary course of the disease. Sauzéat et al. [298] also revealed that copper and zinc isotopic compositions in CSFs (cerebrospinal fluids) of patients with ALS (amyotrophic lateral sclerosis) and AD, age-matched controls show that isotopic measurements of copper in CSF may provide a more credible understanding of the ALS disease than elemental concentrations do, and holds the potential to buttress existing information regarding the mechanisms involved in the development of ALS.
Tea et al. [118] provides a synopsis on current state of knowledge on changes in natural isotope composition in various tissue samples such as hair, plasma and saliva of patients compared to controls, discuss the metabolic origin of such isotope fractionations and reviews the prospect of using natural isotopic abundances for medical diagnosis and/or prognostic.
3.3 Bioavailability
Bioavailability, from the standpoint of disease development, refers to the extent and rate at which an essential nutrient (e.g., nutritional element, vitamin, protein, water) enters systemic circulation and becomes available at the site of metabolic action. Bioavailability tends to be very variable and depends on such factors as age, sex, genetic phenotype and physical activity. Low bioavailability of the active moiety such as a metabolite means that the amount absorbed by the body is too low for maintaining vital reactions; thus, presenting clues for the unravelment of certain DUA, inter alia.
4 Geochemical variables and the immune system
Numerous geoenvironmental factors can modulate human immunity; and it is necessary to understand their interactions in development of the immune system. Such an understanding enables us to address specific aspects of diseases, such as in unravelling the aetiology of DUA; but also, to identify methodological pathways to follow in our bid to determine the necessities for attaining long-term, life-long protection from disease. Here, an attempt is made to amalgamate existing data into a cohesive vision that illustrates how exposure to geoenvironmental variables, more especially, the geochemical-, can leave a lasting impression on the human immune system, and how this impression can either have beneficial or potentially deleterious effects.
4.1 Cells of the immune system
The immune system is a complex network of cells and proteins that finds and attacks infectious agents such as bacteria, viruses and fungi (Nicholson [299]). The three broad categories of immune system cells are: lymphocytes (T-cells, B-cells and NK cells), which are a type of white blood cells; neutrophils, and monocytes/macrophages. Each cell type has specialised functions. For instance, neutrophils are important in fighting bacteria and fungi, while lymphocytes generally fight viruses. The distribution of metal- and metalloid species within a cell or tissue type, referred to as the metallome, constitutes an important study in the context of DUA.
4.2 Principles of infection and immunity
According to Galask et al. [300], virtually any organism may behave as a pathogen under the right set of conditions; and therefore, it is more instructive to place organisms along a continuum from lesser to greater virulence, rather than classifying them as either pathogens or nonpathogens. Galask et al. [300] also contend that: “… among individual human hosts, there is a continuum in the intrinsic ability of each host to resist infection.”
As long ago as 1934, Theobald Smith suggested, in what is now, perhaps the most insightful statement of the relationship between microbial virulence and host resistance to infection, that: disease was a function of the number of organisms with which a host is initially infected multiplied by the virulence of the organism [301]. This relationship is considered to accurately reflect the nature of the infectious process today, despite modern changes in the ecology of infections.
Smith’s equation states:
One can see from Eq. 1 that the result of a host’s encounter with an infectious agent, even a proven pathogen, will not necessarily be an infectious disease. However, if the host’s immunity becomes lowered for some reason, or if the host becomes overwhelmed by an increasing number of organisms, disease may appear, even with an organism of relatively low virulence. Another noteworthy point about Eq. 1, is its practical significance, which contributes to the clinician’s knowledge about the role of the individual host in infectious disease (Galask et al. [300]).
There are numerous mechanisms by which trace elements/metals/metalloids are absorbed, distributed, modified and stored in the body, and subsequently eliminated. Only a very brief look at immune system mechanisms is presented here, and only with reference to its interactions with trace elements, including metals and metalloids. Readers interested in further details should consult the many excellent publications on the topic (such as: Failla [302]; Keen et al. [303]; Plumlee and Ziegler [304]; Plumlee et al. [305]; Galask et al. [300]; Chaplin [306]; Winans et al. [307]; Nicholson [299]; Marshall et al. [308] and Paludan et al. [309].
Toll-like receptors (TLRs) which are located either on cell surfaces or within endosomes (See: “Glossary of Terms”, this article), are type I integral transmembrane receptors involved in the recognition and conveyance of pathogens (including trace elements/metals/metalloids) to the immune system (El-Zayat et al. [310]). Some micronutrients (vitamins and trace elements) may be considered as important TLR regulators, as they have immunomodulatory functions. Vitamins D, B12 and A, zinc, copper and iron, for instance, have important roles on innate immune responses (El-Zayat et al. [310]).
Thurnham’s 2004 review [311] summarises work on, inter alia, “… interactions between nutrients and genes, the influence of gene polymorphisms on micronutrients, the impact of immune responses on micronutrients and specific interactions of antioxidant micronutrients in disease processes to minimise potential pro-oxidant damage.” Mineral deficiency-induced abnormalities in the immune system are particularly profound when they occur during early development (Failla [302]).
In addition to the effect of trace elements on immune function, several studies have shown that, at certain levels, some of these elements, such as selenium can influence the genetics of a viral pathogen (Ermakov and Jovanović [312]). Thus, trace element nutrition influences not only the host response to a pathogen but also the pathogen itself (See e.g., Beck [313]).
Factors that influence the toxicities of substances that encounter the body in bioaccessible form (those that are readily released from Earth materials into the body fluids) include: the exposure route, the dose, the chemical form of the substance at exposure, and the processes that chemically transform the substance during absorption, transport and metabolism (Plumlee et al. [305]; Finkelman et al. [314]; Hasan [315]). Sometimes, immanent errors of trace element metabolism occur to produce disease, such as when there are basic defects in the trace element transport mechanism (See e.g., Danks [316]; Ferreira and Ghal [317].
4.3 Immunotoxicity due to metals
In 2015, Nriagu and Skaar [318] noted that many countries experiencing infectious diseases endemia also have the highest prevalence of trace metal deficiencies or increased rates of trace metal pollution in the air, soil and water environments. These authors also pointed out the increased human susceptibility resulting from adverse effects of metal exposure (at suboptimal or toxic levels), and vice versa, viz., that metal excess or deficiency can increase the incidence or severity of infectious diseases.
Metals and metalloids influence the function of immunocompetent cells by a variety of mechanisms. Several of these metals and metalloids are known to be immunotoxic, including: aluminium, arsenic, beryllium, cadmium, cobalt, chromium, copper, iron, mercury, magnesium, manganese, nickel, lead, selenium, tin, vanadium and zinc. Depending on the particular metal, its speciation, concentration and bioavailability, and a number of other interdependent (geomedical) factors, a continuous metal/metalloid exposure will result in an immunosuppression or immunoenhancement effect (Kakuschke and Prange [319]).
According to Cabassi [320]), immunotoxicity occurs: “… either direct action of the free metal on the cell membrane or other organs of immunocytic components or by catalysis or inhibition of numerous enzyme reactions that are essential to cellular metabolism”. These interactions interfere with expression of the immune response. In this connection, Cabassi [320] notes that immunopotentiating effects are observed with certain metals when they occur at low concentration levels, whereas at high concentration levels, immunosuppression is the result. Theron et al. [321] affirmed this observation and went on to point out that it holds true particularly for toxic metals such as cadmium, mercury and lead, due to their cytotoxic effects which induce apoptosis and/or necrosis of immune cells leading to diminished effectiveness of the immune defences to infection.
Cabassi [320] describes some of the immunosuppression effects earlier identified by Descotes [322] that xenobiotics (including trace elements, metals and metalloids) can produce, such as “… changes in leucocyte cellularity, lymphocyte sub-population, reduced resistance of the organism to immune specific alterations, immunosuppression with increased susceptibility to infection and tumour development, immunostimulation with hypersensibility and development of autoimmune diseases.”
4.4 Autoimmune diseases
Autoimmune diseases (AuDs) are a heterogeneous group of chronic conditions that affect specific target organs or multiple organ systems. These diseases occur when the body’s immune system functions abnormally, mistakingly attacking and destroying healthy body tissues, or causing abnormal organ development, or changes in organ function. Over 80 types of autoimmune disorders are known.
Among the different environmental factors that are known to influence the development of AuDs are: infections, low vitamin D levels, UV radiation, and melatonin [323, 324], which factors are also known to exhibit seasonal variation patterns that could influence disease development, severity and progression. Autoimmune disorders may cause destruction of body tissues,
In 2004, Descotes [322] recapitulated on the importance of autoimmunity as an important area of immunotoxicology, especially because autoimmune diseases affect a significant proportion of the world population, and some GETTS (Genetic testing Evidence Tracking Tool) experimental data suggest the existence of a possible association between chemical exposures and autoimmunity. There are literally thousands of chemicals and xenobiotics that we know can modulate the immune system (See e.g., Vojdani and Vojdani, [325]), but we know very little about their specific effects on this system, and whether they may lead to autoimmunity.
For metals, in particular, we know that there are several factors that determine the ease with which they can induce autoimmune disease—these include heredity (genetic makeup) (Fig. 3), speciation, dose, route of exposure, overall health, age and gender (See, e.g., Zhang and Lawrence [326]). However, the precise mechanism by which this happens is still far from clear (Rowley and Monestia [327]; Bolon [328].
Many questions remain as to how pathogenic challenge may interfere with immune system regulation and give rise to autoimmunity; and it is likely that other apparently unexplored immune modulatory mechanisms (e.g., trace element/metal interaction) also contribute to clinical AuDs (Fig. 3. But, till quite recently, the exact etiopathogenesis of AuDs is still not well-defined (See, e.g., Getts et al. [329]).
5 Criticality of the ‘optimal range of intake’ and the occurrence of nutrient toxicities
Writing on the criticality of the optimal range for the micronutrient elements, Mao et al. [2] observed that this should correspond to an intake level of dietary requirement for an essential trace element that meets a specified criterion for adequacy, thus minimising or obviating the risk of nutrient deficiency or excess. The development of pathologic states and diseases will be the obvious result, should disruption in trace element homeostasis occur.
Many nutrients have an antagonistic relationship to one another, which can mean that when one is too high, it causes the other to become too low; and this could increase one’s susceptibility to infectious disease which may be acute or chronic. No pair of elements better exemplify this relationship than copper and zinc, which is as a result of their complex interactions in metabolic processes. In children and adults, the normal copper/zinc (Cu/Zn) ratio is about 1:1 (Faber et al. [330]; Bjørklund [82]). A similar ratio 1.0 ± 0.3 is given for body fluids (e,g., plasma) of healthy adults (Bahi et al. [331]; Kazi Tani et al. [332]).
There are many imponderables, though, that can bring about imbalances, chief of which, is the type of diet (Böckerman et al. [333]. A high intake of copper may adversely affect the absorption or utilisation of zinc, and vice versa. In other words, when your Cu/Zn ratio becomes out of balance, many health problems can occur, such as various neurodegenerative diseases (e.g., Büchl et al. [334]).
Excesses or deficiencies of trace elements/metals/metalloids and infectious diseases often co-occur and are the result of complex metabolic interactions. Most of our essential nutrient intake is from our diet, though thankfully, this portion alone is unlikely to bear excessive element intake levels. However, the consumption of fortified foods or supplements can also raise the level of trace elements/metals/metalloids and hence increase the chance of toxicity.
Environmental or occupational exposure to potentially toxic levels of elements/metals/metalloids induce concentrations that are bioavailable to immune cells, high enough to affect their function. Such an imbalance of the immune system caused by pollutants may play a significant role in the incidence of infectious diseases (See e.g., Erickson et al. [335]; Osredkar and Sustar [336]; Hara et al. [20]). In any case, our bodies have an elaborate system for managing and regulating the amount of key trace elements and limiting or eliminating the potentially toxic elements (PTEs) circulating in blood and stored in cells (Osredkar and Sustar [336]). It is when this system fails to function correctly that metabolic disturbances occur, with abnormal levels and ratios of trace elements/metals/metalloids developing and paving the way for occurrence of infectious disease (See e.g., Chandra [337]; Chaturvedi et al. [338]).
The concept of nutritional immunity in the context of host defense against pathogens (Djoko et al. [339] perceives a role for mechanisms by which a host organism sequesters trace elements/metals/metalloids to limit invading pathogens during infection. Calprotectin, for example, can restrict the acquisition of zinc or manganese (Kehl-Fie et al. [340]). The question remains however, as to whether the host is able to exploit the toxic properties of transition metal ions and use them as bactericides? (See Djoko et al. [339]).
6 Disease risk mapping and dua cluster detection
According to Lahr and Kooistra [341] the value of risk maps lies in assisting analysts and scientists characterise the spatial nature of the effects of environmental stressors such as pollutants (e.g., arsenic, mercury, lead and chromium). Environmental risk maps are used as a means for conveying the results of complex environmental risk assessments to public health authorities, policy makers, urban planners, and other stakeholders in the general public.
6.1 Cluster analysis and mapping of DUA
We know that diseases often occur in clusters (See, e.g., Whitty and Watt [342]). This is so, because of a common risk factor. Earlier, in 2016, Rodo et al. [343] reviewed the relevance of environmental factors to health outcomes of ailments whose causes are still poorly understood (cf., DUA). These authors listed several examples of emerging diseases belonging to this category, and surprisingly sharing some common epidemiological features such as their appearance in clusters (grouped geographically; and temporarily progress in nonrandom sequences that repeat year by year in a similar way). Rodo et al. [343] also noted that these diseases exhibit concurrent trend changes within regions in countries and among different world regions. Their list included: rheumatic diseases such as vasculitides, some inflammatory diseases, or even severe childhood acquired heart diseases, KD (Kawasaki disease), Henoch-Schönlein purpura, Takayasu’s aortitis, and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
It is important to map these clusters and to decipher which of them are non-random, since this can help us, inter alia, in unearthing new mechanisms for disease, which, in turn, can lead to the charting of aetiologies (cf., DUA).
6.2 Geochemical mapping
In 2014, Pinto et al. [344] described geochemical mapping as the base knowledge needed for delineating the regions of the planet with critical contents of PTEs from either natural or anthropogenic sources. These authors went on to identify sediments, soils and waters as the vehicles which link the inorganic environment to life through the provision of essential macro- and micronutrients; and that the chemical composition of surficial geological materials may bring about metabolic changes leading to the occurrence of endemic diseases in humans.
In the above context, it is possible to suggest that, for us to create a better understanding of the relationship between surficial geochemistry and public health (cf., DUA) it is necessary, first, to construct complete geochemical maps at appropriate scales across national boundaries, depicting the surficial distribution of all non-gaseous chemical elements (See: Darnley et al. [344]). The construction of such detailed maps of element distribution depicting regions of high levels of toxic compounds or those depleted in essential elements, is an urgent requirement for the proper assessment of the geochemical milieu regarding DUA causation.
Such maps have already been drawn for China [(See: Wang et al. [345]; Xie et al. [346]; Cheng et al. [347], England and Wales (See: Rawlins et al. [348], Australia (See Reimann and de Caritat [349]) the USA (See: Smith et al. [350]), and a few other countries]. An overlay of epidemiological maps (of disease distribution) on these geochemical maps would make possible the depiction of areas where disease clusters overlie anomalous element distribution (in water or soil), and so permit an evidence-based statistical assessment of the magnitude of any geochemical component in the disease causative web.
7 Conclusions
This paper has advanced reasons why greater consideration should be given to co-factors linked to the geoenvironmental milieu, especially geochemical variables, in understanding causality of DUA. The medical profession, environmental health practitioners and allied scientists, relevant government officials and other stakeholders are made aware of the huge potential contribution of medical geologists and environmental geochemists in teams investigating the causes of DUA and sudden disease outbreaks. The following additional conclusions are drawn and some directions for future research, highlighted.
-
(I)
There is currently an increasing worldwide trend in environmental geochemistry research towards determining the circulation of both nutritional elements and PTEs in the water-soil-food crop nexus, that enter the food chain. The prime motivator of this approach is considered to be the increasing concern about the significance of the entry—largely through the diet—of varying concentration levels of elements that may be bioavailable for negative interactions in metabolic processes that produce diseases, some of whose diagnoses are still ill-defined (cf., the DUA).
-
(II)
The redox activity of metal ions can generate highly reactive species that impair DNA, giving rise to different oxidation products, the types and nature of impairment depending upon a number of factors, of which, the redox potentials of the DNA bases, formation of intermediate adducts, and identity of the reactive species are, perhaps, the more important of these factors (See: Angelé-Martínez et al. [351].
-
(III)
It thus seems probable that improved knowledge on the influence of metal ion binding on the DNA structure and the differing binding behaviour of various metal ions could prove critical in elucidating the aetiology of a number of DUA in the future. As pointed out by Hegde et al. in 2011 [126] we can have a scenario in which a possible aetiological linkage exists between defects in BER/SSBR (See: “Glossary of Terms”, this article) and certain DUA, viz., the neurodegenerative diseases, as well as the restorative potential of metal chelators for DNA repair capacity.
-
(IV)
The human immune system is complex, with numerous environmental factors modulating it early in life. As such, the system is constantly in a state of flux, trying to adapt to various local constraints and conditions imposed by selective pressures of our environment. This inherent plasticity means that our exposure to different geochemicals (metals, metalloids, radionuclides and transuraniums) and pathogenic organisms can result in undesirable outcomes (cf., DUA).
-
(V)
After decades of research on the complexity and developmental trajectory of the foetal-neonatal immune system (See e.g., Amarasekera et al. [352]; Jain [353]; Scanlon [354], we are only just beginning to acquire knowledge and insights on the participation of trace elements/metals/metalloids in the selection, maturation and early activation events of the immune cells. Judicious use of modern analytical tools in cell biology- and molecular genetics research, and array technology, will no doubt hasten our understanding of outcomes in these metabolic processes. The position of the “metallome” in deciphering unknown aetiologies such as in the case of SIDS and that of many other DUA needs urgent research!
-
(VI)
A functional immune system able to prevent or limit infections of the host, is particularly important for many rural populations where exposure to novel infectious occurs frequently. From the evidence adduced in this article, it is becoming increasingly clear that the amount of trace elements/metals/metalloids taken up largely through the diet, and its outcome in metabolic processes (leading either to accumulation or to deficiency in human tissues), has a significant control on whether the exerted effects are toxic or beneficial. As we gradually begin to fully understand these processes, food safety regulators will have the important and urgent task of re-considering, harmonising and updating current legislative regimes regarding the concentrations of trace elements/metal/ metalloids in food and in drinking water.
-
(VII)
In order to promote immune-mediated health for life, we must consider the importance of our exposure to geoenvironmental variables and the dynamics of pathogen invasion in immune programming. To do this, however, we still need to seek knowledge on several aspects of immune system programming that starts in early life, and its influence on the risk of developing various DUA. Such research would generate information needed for articulation of future public health initiatives and for drawing renewed attention to the vulnerability of children in early life.
-
(VIII)
Only recently (2021), Tea et al. [118] brought our awareness to the realisation that in many human diseases, including DUA, the natural abundance of stable isotopes in affected tissues might provide additional information helpful to better constrain and diagnose them. We still do not know enough about what causes isotope fractionations in specific metabolic reactions; and hence, do not fully understand the precise mechanisms at the origin of the isotopic signature of diseases. More basic research on both metabolic fluxes and enzymatic isotope effects is therefore necessary to increase the possibility of discovering new diagnostic biomarkers based on stable isotopes.
-
(IX)
It is submitted that the efficiency of cluster investigation teams would be greatly enhanced by inclusion of medical geologists and environmental geochemists, from whom information on significant geoenvironmental exposure/exposure to geochemicals can be obtained, as well as for an increased potential for unravelment of environment and disease relationships. Whenever sudden disease outbreaks appear in clusters, it is always desirable to examine changes in the ambient soil, water and air trace element/metal/metalloid composition for any association with the disease. The overarching need for development of techniques for recognising the grouping of cases of a particular disorder in space and time (disease clusters), is that this may provide useful clues about the underlying aetiology (of DUA).
-
(X)
It is submitted that the construction of correlation maps featuring complete geochemical databases, would, among other applications, enable the depiction of areas where disease clusters overlie anomalous element distribution (in water, soil or air), and so permit an evidence-based statistical assessment of the magnitude of any geochemical component in the disease causative web.
8 Glossary of terms
-
Acute disease/illness is any disease or illness that develops quickly, is intense or severe and lasts a relatively short period of time, or, any condition, e.g., infection, trauma, fracture—with a short (often less than 1 month) clinical course.
-
Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7—13 nm in diameter, a beta sheet secondary structure and ability to be stained by particular dyes. Amyloidosis is a rare disease that occurs when an abnormal protein, called amyloid, builds up in your organs and interferes with their normal function.
-
Apoptosis refers to an orderly process of cell breakdown that occurs in multicellular organisms.
-
BER refers to ‘base excision repair’ which is the main pathway for repair of base lesions, which is known to be associated with DNA replication.
-
Bias: In the field of statistics, bias refers to the tendency of a statistic to overestimate or underestimate a parameter.
-
Calprotectin is a protein biomarker released by a neutrophil when there is inflammation in the gastrointestinal (GI) tract, resulting in an increased level in the stool.
-
Chakra (pl. chakras), a concept is found in the early traditions of Hinduism, refers to various focal points used in a variety of ancient meditation practices, collectively denominated as Tantra, or the esoteric or inner traditions of Hinduism. [Wikipedia, 2021. https://en.wikipedia.org/wiki/Chakra (accessed 20.01.2021)].
-
A chronic condition is a human health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term chronic is often applied when the course of the disease lasts for more than three months.
-
Communicable diseases are those that can be spread from person to person via an infectious agent, such as bacteria, viruses, fungi or parasites. Non-communicable diseases (NCDs) are the conditions or diseases which are not caused by transmission of infections like that in communicable diseases.
-
A confounding factor also called a confounding variable, or confounder is a third variable in a study examining a potential cause-and-effect relationship. A confounding variable is related to both the supposed cause and the supposed effect of the study.
-
Correlational research is a type of non-experimental research method in which a researcher measures two variables, understands and assesses the statistical relationship between them with no influence from any extraneous variable. “Correlation is not causation” means that just because two things correlate does not necessarily mean that one causes the other.
-
Endosomes are membrane-bound vesicles, formed via a complex family of processes collectively known as endocytosis, and found in the cytoplasm of virtually every animal cell.
-
The etheric body, ether-body or æther body, is a name given by neo-Theosophy to a vital body or subtle body coined by esoteric philosophers to describe the first or lowest layer in the “human energy field” or aura. It is thought to be in immediate contact with the physical body, to sustain it and connect it with “higher” bodies.
-
Gametes, also referred to as sex cells, are an organism’s reproductive cells.
-
Homeostasis. In biology, the tendency towards a relatively stable state (equilibrium)—internal, physical, and chemical conditions—maintained in physiological processes while adjusting to changing external conditions. Dyshomeostasis, on the other hand, refers to an imbalance or other breakdown of a homeostasis system.
-
Infectious diseases are disorders caused by organisms such as bacteria, viruses, fungi or parasites. Many organisms live in and on our bodies. They are normally harmless or even helpful. But under certain conditions, some organisms may cause disease.
-
The immune system is a series of complex defence mechanisms found in humans and other vertebrates, that helps to combat and destroy pathogenic organisms such as bacteria, fungi, viruses, and parasites. The immune system consists of two types of response mechanisms: (i) An antigen-specific adaptive immune response mechanism, also referred as the acquired immune system, which is composed of specialised, systemic cells and processes that eliminate pathogens by preventing their growth; and (ii) The innate immune system is a collection of cells and proteins that are functionally diverse and that defend against invasion by foreign organisms. An innate immune response mechanism, also called natural, is the set of processes that operate to protect the host from the surrounding environment in.
-
Immunosuppression refers a state of decreased immunity.
-
Lymphocytes are white blood cells that are also one of the body’s main types of immune cells.
-
Macrophages are large, specialised cells that detect, engulf and destroy bacteria and other harmful organisms.
-
Melatonin (sometimes referred to as the sleep hormone) is a natural hormone made by the pineal gland (a pea-sized gland situated just above the middle of the brain). It plays a central role in the body’s sleep–wake cycle. With its production rising with evening darkness, it promotes healthy sleep and helps orient our circadian rhythm (natural internal processes that follow a 24-h cycle).
-
Meridian (as used in acupuncture and Chinese medicine) refers to each of a set of pathways in the body along which vital energy is said to flow.
-
Metallome: In biochemistry, the metallome is the distribution of metal ions in a cellular compartment.
-
The miasma theory (also called the miasmatic theory) is one in the field of medicine proffering that that certain diseases were caused by a miasma (μίασμα, Ancient Greek for “pollution”), form of bad air, quite noxious, and also known as night air.
-
Mitochondrial dysfunction occurs when the mitochondria (tiny compartments that are present in almost every cell of the body) fail to work correctly, due to another disease or condition.
-
Monocytes are the largest type of leukocyte (white blood cells). As a part of the vertebrate innate immune system monocytes also influence the process of adaptive immunity.
-
Mutations are permanent changes in the DNA sequence, and they are a main cause of diversity among organisms.
-
Myalgia: Pain in a muscle or group of muscles.
-
Necrosis refers to the premature death of cells in living tissue when too little blood flows to them as a result of disease or injury.
-
Neutrophils are a type of white blood cell. Most of the white blood cells that lead the immune system’s response are neutrophils.
-
Neurodegenerative disorders are illnesses that involve the death of certain parts of the brain.
-
An oligomer is a molecule consisting of a few similar or identical repeating units which could be derived, actually or conceptually, from copies of a smaller molecule, its monomer.
-
Pathogenesis refers to the way (biological mechanism) in which a disease develops. Pathogenicity is the ability of an agent to cause disease (i.e., to harm the host).
-
In genetics, a promoter is a sequence of DNA (deoxyribonucleic acid) to which proteins bind that initiate transcription of a single RNA (ribonucleic acid) from the DNA downstream of it. [Wikipedia, 2021. Promoter (genetics). https://en.wikipedia.org/wiki/Promoter_(genetics) (accessed 26.01.2021].
-
Reactive oxygen species (ROS): An unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. ROS are the contributors of oxidative stress which leads to various diseases and disorders.
-
Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect neurotransmitter receptors, ion channels, and other membrane proteins to various metabolic pathways.
-
SSBR refers to single-strand breaks in DNA, which are discontinuities in one strand of the DNA double helix.
-
SIDS is the abbreviation for ‘sudden infant death syndrome’, also known as ‘cot death’ or ‘crib death’, which is the sudden, unexpected and unexplained death, usually during sleep, of a seemingly healthy child of less than one year of age.
-
A syndrome is a set of medical signs and symptoms which are correlated with each other and often associated with a particular disease or disorder. [Wikipedia, 2020. Syndrome. https://en.wikipedia.org/wiki/Syndrome (accessed 10.01.2021)].
-
Toll-like receptors (TLRs) are a class of proteins (receptors) that constitute the first line of defence system against microbes.
-
“A xenobiotic is a chemical substance found within an organism that is not naturally produced or expected to be present within the organism. It can also cover substances that are present in much higher concentrations than are usual.” [Wikipedia, 2020. https://en.wikipedia.org/wiki/Xenobiotic (accessed 26.01. 2021)].
Data availability
No data pertaining to human tissues were reproduced from articles reviewed in this study, obviating the need for ethical approval.
References
Haase M (1923) Etiology unknown. J Am Med Assoc 81(9):703–704. https://doi.org/10.1001/jama.1923.02650090001001
Mao RJ, Moa A, Chughtai A (2020) The epidemiology of unknown disease outbreak reports globally. Glob Biosecurity 1:4
Rappaport SM (2012) Discovering environmental causes of disease. J Epidemiol Commun Health 66(2):99–102. https://doi.org/10.1136/jech-2011-200726
World Health Organisation (WHO) (2018) Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. Accessed 11 Dec 2020
Bundschuh J, Maity JP, Mushtaq S, Vithanage M, Seneweera S et al (2017) Medical geology in the framework of the sustainable development goals. Sci Total Environ. https://doi.org/10.1016/Calderoj.scitotenv.2016.11.208
Panelli MC (2017) JTM advances in uncharted territories: Diseases and disorders of unknown etiology. J Transl Med 15(1):192. https://doi.org/10.1186/s12967-017-1293-6
Ross LN (2018) The doctrine of specific etiology. PhilSci Archive 15079. http://philsci-archive.pitt.edu/15079/1/DSE.pdf. Accessed 03 Dec 2020
Simpson J, Weiner E (eds) (2002) Aetiology. The Oxford English Dictionary, 2nd edn. Oxford University Press, Oxford
Britannica (2020) The causes of disease. https://www.britannica.com/science/human-disease/The-causes-of-disease. Accessed 03 Dec 2020
Kannadan A (2018) History of the Miasma theory of disease. ESSAI 16, Article 18. https://dc.cod.edu/essai/vol16/iss1/18 . Accessed 11 Apr 2022
Abu-Rabia A (2005) The evil eye and cultural beliefs among the Bedouin Tribes of the Negev. Middle East Folklore 116(3):241–254. https://doi.org/10.1080/00155870500282677
Cambau E, Drancourt M (2014) Steps towards the discovery of Mycobacterium tuberculosis by Robert Koch, 1882. Clin Microbiol Infect 20(3):196–201. https://doi.org/10.1111/1469-0691.12555
Jager KJ, Zoccali C, Macleod A, Dekker FW (2008) Confounding: What it is and how to deal with it. Kidney Int 73(3):256–260. https://doi.org/10.1038/sj.ki.5002650
Kroll-Smith S, Brown PM, Gunter V (2000) Illness and the environment: a reader in contested medicine. https://www.thebookstall.com/book/9780814747292. Accessed 30 Jan 2021
Mehri A (2020) Trace elements in human nutrition (II)-an update. Int J Prev Med 11:2. https://doi.org/10.4103/ijpvm.IJPVM_48_19
Hara T, Nakashima Y, Sakai Y, Nishio H, Motomura Y, Yamasaki S (2016) Kawasaki disease: a matter of innate immunity. Clin Exp Immunol 186(2):134–143. https://doi.org/10.1111/cei.12832
Senanayake N, King B (2017) Health-environment futures: complexity, uncertainty, and bodies. Prog Hum Geogr 43(4):711–728. https://doi.org/10.1177/0309132517743322
Lukác N, Massányi P (2007) Effects of trace elements on the immune system. Epidemiol Mikrobiol Imunol 56(1):3–9
Juan CA, Pérez de la Lastra JM, Plou FJ, Pérez-Lebeña E (2021) The chemistry of reactive oxygen species (ROS) revisited: outlining their role in biological macromolecules (DNA, lipids and proteins) and induced pathologies. Int J Mol Sci 22(9):4642. https://doi.org/10.3390/ijms22094642
Rouwet D, Tanyileke G, Costa A (2016) Cameroon’s Lake Nyos gas burst: 30 Years later. Eos. https://doi.org/10.1029/2016eo055627
Boehrer B, Saiki K, Ohba T, Tanyileke G, Rouwet D, Kusakabe M (2021) Carbon dioxide in Lake Nyos, Cameroon, estimated quantitatively from sound speed measurements. Front Earth Sci 9:645011. https://doi.org/10.3389/feart.2021.645011
US EPA (The U.S. Environmental Protection Agency) (2021) Radioactive Waste From Uranium Mining and Milling. https://www.epa.gov/radtown/radioactive-waste-uranium-mining-and-milling . Accessed 12 Apr 2022.
Kurklinsky AK, Miller VM, Rooke TW (2011) Acrocyanosis: the flying Dutchman. Vasc Med 16(4):288–301. https://doi.org/10.1177/1358863X11398519
Grobe VJ (1976) Peripheral circulatory disorders and acrocyanosis in arsenic exposed Moselle wine-growers. Berufsdermatosen 24(3):78–84
Tseng WP (1977) Effects and dose-response relationships of skin cancer and Blackfoot disease with arsenic. Environ Health Perspect 19:109–119
Mak OT (1988) Prostacyclin production in vascular endothelium of patients with Blackfoot disease. Adv Exp Med Biol 242:119–125. https://doi.org/10.1007/978-1-4684-8935-4_14
Gordon ME (2000) Arsenic and old places. Lancet 356(9224):170
Crocq M (1896) De l’ “acrocyanose.” Semaine Med 16:298
Carpentier PH (1998) Definition and epidemiology of vascular acrosyndromes. Rev Prat 48(15):1641–1646
Das S, Maiti A (2013) Acrocyanosis: an overview. Indian J Dermatol 58(6):417–420. https://doi.org/10.4103/0019-5154.119946
Kent JT, Carr D (2020) A visually striking case of primary acrocyanosis: a rare cause of the blue digit. Am J Emerg Med 40:227.e3-227.e4. https://doi.org/10.1016/j.ajem.2020.07.064
Bhaskaran D, Chadha SS, Sarin S, Sen R, Arafah S, Dittrich S (2019) Diagnostic tools used in the evaluation of acute febrile illness in South India: a scoping review. BMC Infect Dis 19:970. https://doi.org/10.1186/s12879-019-4589-8
Crump J, Morrissey AB, Nicholson WL, Massung RF, Stoddard RA, Galloway RL et al (2013) Etiology of severe non-malaria febrile illness in northern Tanzania: a prospective cohort study. PLoS Neglect Trop Dis 7. https://doi.org/10.1371/journal.pntd.0002324
D’Acremont V, Kilowoko M, Kyungu E, Philipina S, Sangu W, Kahama-Maro J et al (2014) Beyond malaria-causes of fever in outpatient Tanzanian children. N Engl J Med 370:809–817
Lee J-H, Kim JH (2012) Comparison of serum zinc levels measured by inductively coupled plasma mass spectrometry in preschool children with febrile and afebrile seizures. Ann Lab Med 32(3):190–193. https://doi.org/10.3343/alm.2012.32.3.190
Amouian S, Mohammadian S, Behnampour N, Tizrou M (2013) Trace elements in febrile seizure compared to febrile children admitted to an Academic Hospital in Iran, 2011. J Clin Diagn Res 7(10):2231–2233. https://doi.org/10.7860/JCDR/2013/5548.3478
Kaboré B, Post A, Lompo P, Bognini JD, Diallo S, Kam BTD et al (2020) Aetiology of acute febrile illness in children in a high malaria transmission area in West Africa. Clin Microbiol Infect 57(4):590–596. https://doi.org/10.1016/j.cmi.2020.05.029
Carlsson JA, Bayes HK (2020) Acute severe asthma in adults. Medicine 48(5):297–302. https://doi.org/10.1016/j.mpmed.2020.02.008
Soriano JB, Abajobir AA, Abate KH, Abera SF, Agrawal A, Ahmed MB (2017) Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Resp Med 5:691–706. https://doi.org/10.1016/S2213-2600(17)30293-X
Johnston SL, Pattemore PK, Sanderson G, Smith S, Lampe F, Josephs L, Symington P, O’Toole S, Myint SH, Tyrrell DAJ et al (1995) Community study of role of viral infections in exacerbations of asthma in 9–11-year-old children. BMJ 310(6989):1225–1229. https://doi.org/10.1136/bmj.310.6989.1225
Jackson DJ, Johnston SL (2010) The role of viruses in acute exacerbations of asthma. J Allergy Clin Immunol 125:1178–1187. https://doi.org/10.1016/j.jaci.2010.04.021
Guarnieri M, Balmes JR (2014) Outdoor air pollution and asthma. Lancet 383(9928):1581. https://doi.org/10.1016/S0140-6736(14)60617-6
Shmool JL, Kubzansky LD, Newman OD, Spengler J, Shepard P, Clougherty JE (2014) Social stressors and air pollution across New York City communities: a spatial approach for assessing correlations among multiple exposures. Environ Health 13:91. https://doi.org/10.1186/1476-069X-13-91
Uzuner N, Karaman Ö, Coker C, Turgut F, Uzuner H, Önvural B (2001) Serum trace element levels in bronchial asthma. Turk Resp J 2(3):10–15
Hussein MM, Yousif AA, Saeed AM (2008) Serum levels of selenium, zinc, copper and magnesium in asthmatic patients: a case control study. Sudan J Med Sci 3(1):45–48
Beggs PJ, Bambrick HJ (2005) Is the global rise of asthma an early impact of anthropogenic climate change? Environ Health Perspect 113(8):915–919. https://doi.org/10.1289/ehp.7724
Cecchi L, D’Amato G, Ayres JG, Galan C, Forastiere F, Forsberg B, Gerritsen J, Nunes C, Behrendt H, Akdis C, Dahl R, Annesi-Maesano I (2010) Projections of the effects of climate change on allergic asthma: the contribution of aerobiology. Allergy 65:1073–1081
Hyrkäs H, Ikäheimo TM, Jaakkola JJ, Jaakkola MS (2016) Asthma control and cold weather-related respiratory symptoms. Respir Med 2016(113):1–7. https://doi.org/10.1016/j.rmed.2016.02.005
D’Amato M, Molino A, Calabrese G, Cecchi L, Annesi-Maesano I, D’Amato G (2018) The impact of cold on the respiratory tract and its consequences to respiratory health. Clin Transl Allergy 8:20. https://doi.org/10.1186/s13601-018-0208-9
Kostakou E, Kaniaris E, Filiou E, Vasileiadis I, Katsaounou P, Tzortzaki E, Koulouris N, Koutsoukou A, Rovina N (2019) Acute severe asthma in adolescent and adult patients: current perspectives on assessment and management. J Clin Med 8(9):1283. https://doi.org/10.3390/JCM8091283
Qiu C, Kivipelto M, von Strauss E (2009) Epidemiology of Alzheimer’s disease: occurrence, determinants, and strategies toward intervention. Dialog Clin Neurosci 11(2):111–128. https://doi.org/10.31887/DCNS.2009.11.2/cqiu
Russ TC, Murianni L, Icaza G, Slachevsky A, Starr JM (2016) Geographical variation in dementia mortality in Italy, New Zealand, and Chile: the impact of latitude, Vitamin D, and air pollution. Dementia Geriatric Cogn Disord 42(1–2):31–41. https://doi.org/10.1159/000447449
Ehmann WD, Markesbery WR, Alauddin M, Hossain TI, Brubaker EH (1986) Brain trace elements in Alzheimer’s disease. Neurotoxicology 7(1):195–206
Jagannatha Rao KS, Ranganath Rao V, Shanmugavelu P, Menon RB (1999 (Last modified 2018)) Trace elements in Alzheimer’s Disease brain: a new hypothesis. In Alzheimer’s disease brain: a new hypothesis. Alzheimer’s Rep 2(4):211–216
Loef M, Walach H (2012) Copper and iron in Alzheimer’s disease: a systematic review and its dietary implications. Br J Nutr 107(1):7–19. https://doi.org/10.1017/S000711451100376X
Chapman TL (2008) Genetic heavy metal toxicity: explaining SIDS, Autism, Tourette’s, Alzheimer’s and other epidemics. Universe Publisher, California City
Greenough MA, Camakaris J, Bush AI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer’s disease. Neurochem Int 62(5):540–555. https://doi.org/10.1016/j.neuint.2012.08.014
Li Y, Jiao Q, Xu H, Du X, Shi L, Jia F, Jiang H (2017) Biometal dyshomeostasis and toxic metal accumulations in the development of Alzheimer’s Disease. Front Mol Neurosci 10:339. https://doi.org/10.3389/fnmol.2017.00339
Bagheri S, Squitti R, Haertlé T, Siotto M, Saboury AA (2018) Role of copper in the onset of Alzheimer’s Disease compared to other metals. Front Aging Neurosci 9:446. https://doi.org/10.3389/fnagi.2017.00446
Liu Y, Nguyen M, Robert A, Meunier B (2019) Metal ions in Alzheimer’s Disease: a key role or not? Acc Chem Res 52(7):2026–2035. https://doi.org/10.1021/acs.accounts.9b00248
Mocanu CS, Jureschi M, Drochioiu G (2020) Aluminium binding to modified amyloid-β peptides: implications for Alzheimer’s Disease. Molecules (Basel, Switzerland) 25(19):4536. https://doi.org/10.3390/molecules25194536
Cilliers K (2021) Trace element alterations in Alzheimer’s disease: a review. Clin Anat 34:766–773. https://doi.org/10.1002/ca.23727
Constantinidis J (1991) The hypothesis of zinc deficiency in the pathogenesis of neurofibrillary tangles. Med Hypotheses 35(4):319–323. https://doi.org/10.1016/0306-9877(91)90277-6
Richarz A, Brätter P (2002) Speciation analysis of trace elements in the brains of individuals with Alzheimer’s disease with special emphasis on metallothioneins. Anal Bioanal Chem 372:412–417. https://doi.org/10.1007/s00216-001-1187-5
De Benedictis CA, Vilella A, Grabrucker AM (2019) The role of trace metals in Alzheimer’s Disease. In: Wisniewski T (ed) Alzheimer’s Disease (Chap. 6). Codon, Brisbane
Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X (2014) Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Biochem Biophys Acta 1842(8):1240–1247. https://doi.org/10.1016/j.bbadis.2013.10.015
Thielke S, Slatore CG, Banks WA (2015) Association between Alzheimer Dementia mortality rate and altitude in California Counties. JAMA Psychiat 72(12):1253–1254. https://doi.org/10.1001/jamapsychiatry.2015.1852
Hu SL, Xiong W, Dai ZQ, Zhao HL, Feng H (2016) Cognitive changes during prolonged stay at high altitude and its correlation with C-reactive protein. PLoS ONE 11(1):e0146290. https://doi.org/10.1371/journal.pone.0146290
Lall R, Mohammed R, Ojha U (2019) What are the links between hypoxia and Alzheimer’s Disease? Neuropsychiatr Dis Treat 15:1343–1354
Koester-Hegmann C, Bengoetxea H, Kosenkov D, Thiersch M, Haider T, Gassmann M, Schneider GEM (2019) High-altitude cognitive impairment is prevented by enriched environment including exercise via VEGF signalling. Front Cell Neurosci 12:532. https://doi.org/10.3389/fncel.2018.00532
Calderón-Garcidueñas L (2021) Alzheimer’s Disease and air pollution: the ignored side of Alzheimer’s research. In: Calderón-Garcidueñas L (ed) Alzheimer’s Disease and air pollution, section 1, Series: Advances in Alzheimer’s disease, vol 8. IOS Press, Amsterdam, pp 1–1
Wei Y, Wang Y, Lin C-K, Yin K, Yang J, Shi L, Li L, Zanobetti A, Schwartz JD (2019) Associations between seasonal temperature and dementia-associated hospitalizations in New England. Environ Int 126:228–233. https://doi.org/10.1016/j.envint.2018.12.054
Habibi L, Perry G, Mahmoudi M (2014) Global warming and neurodegenerative disorders: speculations on their linkage. Bioimpacts 4(4):167–170. https://doi.org/10.15171/bi.2014.013
ADI (Alzheimer’s Disease International) (2019) World Alzheimer Report 2019: Attitudes to dementia. London: Alzheimer’s Disease International, London. https://www.alzint.org/u/WorldAlzheimerReport2019-Summary.pdf . Accessed 29 Jan 2021.
Taylor CA, Greenlund SF, McGuire LC, Lu H, Croft JB (2017) Deaths from Alzheimer’s Disease-United States, 1999–2014. MMWR Morb Mortal Wkly Rep. https://doi.org/10.15585/mmwr.mm6620a1
Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcín C, Montiel-Nava C, Patel V, Paula CS, Wang C, Yasamy MT, Fombonne E (2012) Global prevalence of autism and other pervasive developmental disorders. Autism Res 5(3):160–179. https://doi.org/10.1002/aur.239
Hoffman K, Weisskopf MG, Roberts AL, Raz R, Hart JE, Lyall K, Hoffman EM, Laden F, Vieira VM (2017) Geographic patterns of autism spectrum disorder among children of participants in nurses’ health study II. Am J Epidemiol 186(7):834–842. https://doi.org/10.1093/aje/kwx158
Pillay S, Duncan M, de Vries PJ (2021) Autism in the Western Cape province of South Africa: rates, socio-demographics, disability and educational characteristics in one million school children. Autism 25(4):1076–1089. https://doi.org/10.1177/1362361320978042
Sealey LA, Hughes BW, Sriskanda AN, Guest JR, Gibson AD, Johnson-Williams L, Pace DG, Bagasra O (2016) Environmental factors in the development of autism spectrum disorders. Environ Int 88:288–298. https://doi.org/10.1016/j.envint.2015.12.021
Ha HTT, Leal-Ortiz S, Lalwani K, Kiyonaka S, Hamachi I, Mysore SP, Montgomery JM, Garner CC, Huguenard JR, Kim SA (2018) Shank and zinc mediate an AMPA receptor subunit switch in developing neurons. Front Mol Neurosci 11:405. https://doi.org/10.3389/fnmol.2018.00405
Al-Ayadhi LY (2005) Heavy metals and trace elements in hair samples of autistic children in central Saudi Arabia. Neurosciences (Riyadh) 10(3):213–218
Bjørklund G (2013) The role of zinc and copper in autism spectrum disorders. Acta Neurobiol Exp 73(2):225–236
Saghazadeh A, Ahangari N, Hendi K, Saleh F, Rezaei N (2017) Status of essential elements in autism spectrum disorder: systematic review and meta-analysis. Rev Neurosci 28(7):783–809. https://doi.org/10.1515/revneuro-2017-0015
Fiłon J, Ustymowicz-Farbiszewska J, Krajewska-Kułak E (2020) Analysis of lead, arsenic and calcium content in the hair of children with autism spectrum disorder. BMC Public Health 20:383. https://doi.org/10.1186/s12889-020-08496-w
Baj J, Flieger W, Flieger M, Forma A, Sitarz E, Skórzyńska-Dziduszko K, Grochowski C, Maciejewski R, Karakuła-Juchnowicz H (2021) Autism spectrum disorder: trace elements imbalances and the pathogenesis and severity of autistic symptoms. Neurosci Biobehav Rev 129:117–132. https://doi.org/10.1016/j.neubiorev.2021.07.029
Zhang J, Li X, Shen L, Khan NU, Zhang X, Chen L, Zhao H, Luo P (2021) Trace elements in children with autism spectrum disorder: a meta-analysis based on case-control studies. J Trace Elem Med Biol 67:126782. https://doi.org/10.1016/j.jtemb.20
Jung CR, Lin YT, Hwang BF (2013) Air pollution and newly diagnostic Autism Spectrum Disorders: a population-based cohort study in Taiwan. PLoS ONE 8(9):e75510. https://doi.org/10.1371/journal.pone.0075510
Lee BK, Gross R, Francis RW, Karlsson H, Schendel DE, Sourander A, Reichenberg A, Parner ET, Hornig M, Yaniv A, Leonard H, Sandin S (2019) Birth seasonality and risk of autism spectrum disorder. Eur J Epidemiol 34(8):785–792. https://doi.org/10.1007/s10654-019-00506-5
Lim E, Ahn Y-C, Jang E-S, Lee SW, Lee S-H, Son C-G (2020) Systematic review and meta-analysis of the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). J Transl Med 18:100
EME CFS (Encyclopaedia of Myalgic Encephalomyelitis) (2020) Epidemiology of Myalgic Encephalomyelitis and Chronic Fatigue Syndrome. https://mepedia.org/wiki/Epidemiology_of_myalgic_encephalomyelitis_and_chronic_fatigue_syndrome#:~:text=Statistics%20on%20the%20prevalence%20of,that%20estimate%20at%2030%20million . Accessed 29 Oct 2020
Manousek J, Privarova L, Pavkova GM (2014) Metal hypersensitivity as the cause of chronic fatigue syndrome: case report. In: Hudson C (ed) Chronic Fatigue Syndrome-Risk Factors, managements and impacts on daily life. Neuroscience Research Progress. Nova Science, New York, p 154
Bjørklund G, Dadar M, Pen JJ, Chirumbolo S, Aaseth J (2019) Chronic fatigue syndrome (CFS): suggestions for a nutritional treatment in the therapeutic approach. Biomed Pharmacother 109:1000–1007. https://doi.org/10.1016/j.biopha.2018.10.076
Pacini S, Fiore MG, Magherini S, Morucci G, Branca JJ, Gulisano M, Ruggiero M (2012) Could cadmium be responsible for some of the neurological signs and symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Med Hypotheses 79(3):403–407. https://doi.org/10.1016/j.mehy.2012.06.007
Nguyen T, Johnston S, Clarke L, Smith P, Staines D, Marshall-Gradisnik S (2017) Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. Clin Exp Immunol 187(2):284–293. https://doi.org/10.1111/cei.12882
US CDC (United States Centres for Disease Control and Prevention) (2018) Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Diagnosis of ME/CFS. https://www.cdc.gov/me-cfs/symptoms-diagnosis/diagnosis.html . Accessed 29 Oct 2020
Njoku MGC, Jason LA, Torres-Harding SR (2007) The prevalence of chronic fatigue syndrome in Nigeria. J Health Psychol 12(3):461–474
Sierpina VS, Carter R (2002) Alternative and integrative treatment of fibromyalgia and chronic fatigue syndrome. Clin Fam Pract 4(4):853–872
Mills K, Xu Y, Zhang W, Bundy JD, Chen C, Kelly T, Chen J, He J (2015) A systematic analysis of world-wide population-based data on the global burden of chronic kidney disease in 2010. Kidney Int 88:950–957
Bikbov B, Purcell CA, Levey AS, Smith M (2020) Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 395(10225):709–733
Cockwell P, Fisher L-N (2020) The global burden of chronic kidney disease. Lancet 395(10225):662–664
Edwards JR, Prozialeck WC (2009) Cadmium, diabetes and chronic kidney disease. Toxicol Appl Pharmacol 238:289–293. https://doi.org/10.1016/j.taap.2009.03.007
Wanigasuriya KP, Peiris-John RJ, Wickremasinghe R (2011) Chronic kidney disease of unknown aetiology in Sri Lanka: is cadmium a likely cause? BMC Nephrol 12:32. https://doi.org/10.1186/1471-2369-12-32
Schiffrin EL, Lipman ML, Mann JFE (2007) Chronic kidney disease: effects on the cardiovascular system. Circulation 116:85–97. https://doi.org/10.1161/CIRCULATIONAHA.106.678342
Jayasekara JM, Dissanayake DM, Adhikari SB, Bandara P (2013) Geographical distribution of chronic kidney disease of unknown origin in North Central Region of Sri Lanka. Ceylon Med J 58:6–10. https://doi.org/10.4038/cmj.v58i1.5356
Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R et al (2013) Chronic kidney disease: global dimension and perspectives. Lancet 382:260–272. https://doi.org/10.1016/S0140-6736(13)60687-X
Wijetunge S, Ratnatunga NV, Abeysekera TD, Wazil AW, Selvarajah M (2015) Endemic chronic kidney disease of unknown etiology in Sri Lanka: correlation of pathology with clinical stages. Indian J Nephrol 25(5):274–280. https://doi.org/10.4103/0971-4065.145095
Redmon JH, Elledge MF, Womack DS, Wickremashinghe R, Wanigasuriya KP, Peiris-John RJ, Lunyera J, Smith K, Raymer JH, Levine KE (2014) Additional perspectives on chronic kidney disease of unknown aetiology (CKDu) in Sri Lanka-lessons learned from the WHO CKDu population prevalence study. BMC Nephrol 15:125. https://doi.org/10.1186/1471-2369-15-125
Dharma-Wardana MW, Amarasiri SL, Dharmawardene N, Panabokke CR (2015) Chronic kidney disease of unknown aetiology and groundwater ionicity: study based on Sri Lanka. Environ Geochem Health 37(2):221–231. https://doi.org/10.1007/s10653-014-9641-4
Rajapakse S, Shivanthan MC, Selvarajah M (2016) Chronic kidney disease of unknown etiology in Sri Lanka. Int J Occup Environ Health 22(3):259–264. https://doi.org/10.1080/10773525.2016.1203097
Lunyera J, Mohottige D, Von Isenburg M, Jeuland M, Patel UD, Stanifer JW (2016) CKD of uncertain etiology: a systematic review. Clin J Am Soc Nephrol 11(3):379–385. https://doi.org/10.2215/cjn.07500715
Sengupta P (2013) Potential health impacts of hard water. Int J Prev Med 4(8):866–875
Wickramarathna S, Balasooriya S, Diyabalanage S, Chandrajith R (2017) Tracing environmental aetiological factors of chronic kidney diseases in the dry zone of Sri Lanka-a hydrogeochemical and isotope approach. J Trace Elem Med Biol 44:298–306. https://doi.org/10.1016/j.jtemb.2017.08.013
Balasooriya S, Munasinghe H, Herath AT, Diyabalanage S, Ileperuma OA et al (2020) Possible links between groundwater geochemistry and chronic kidney disease of unknown etiology (CKDu): an investigation from the Ginnoruwa region in Sri Lanka. Expos Health 12:823–834. https://doi.org/10.1007/s12403-019-00340-w
Wimalawansa SJ, Dissanayake CB (2020) Factors affecting the environmentally induced, chronic kidney disease of unknown aetiology in dry zonal regions in tropical countries-novel findings. Environments 7(1):2. https://doi.org/10.3390/environments7010002
Gobalarajah K, Prabagar S, Jayawardena U, Rasiah G, Rajendra S, Prabagar J (2020) Impact of water quality on chronic kidney disease of unknown etiology (CKDu) in Thunukkai Division in Mullaitivu District. Res Sq, Sri Lanka. https://doi.org/10.21203/rs.3.rs-19873/v2
Almaguer M, Herrera R, Orantes CM (2014) Chronic kidney disease of unknown etiology in agricultural communities. MEDICC Rev 16(2):9–15. https://doi.org/10.37757/MR2014.V16.N2.3
Glaser J, Lemery J, Rajagopalan B, Diaz HF, García-Trabanino R, Taduri G, Madero M, Amarasinghe M, Abraham G, Anutrakulchai S, Jha V, Stenvinkel P, Roncal-Jimenez C, Lanaspa MA, Correa-Rotter R, Sheikh-Hamad D, Burdmann EA, Andres-Hernando A, Milagres T, Weiss I, Johnson RJ (2016) Climate change and the emergent epidemic of CKD from heat stress in rural communities: the case for heat stress nephropathy. Clin J Am Soc Nephrol 11(8):1472–1483. https://doi.org/10.2215/CJN.13841215
Sorensen C, Garcia-Trabanino R (2019) A new era of climate medicine-addressing heat-triggered renal disease. N Engl J Med 381:693–696. https://doi.org/10.1056/NEJMp1907859
Floris M, Lepori N, Angioi A, Cabiddu G, Piras D, Loi V, Swaminathan S, Rosner MH, Pani A (2021) Chronic kidney disease of undetermined etiology around the world. Kidney Blood Press Res 46:142–151. https://doi.org/10.1159/000513014
Salas RN, Malina D, Solomon CG (2019) Prioritizing health in a changing climate. N Engl J Med 381:773–774. https://doi.org/10.1056/NEJMe1909957
Gifford FJ, Gifford RM, Eddleston M, Dhaun N (2017) Endemic nephropathy around the World. Kidney Int Rep 2(2):282–292. https://doi.org/10.1016/j.ekir.2016.11.003
Caplin B, Yang C-W, Anand S, Levin A, Madero M, Saran R et al (2019) The International Society of Nephrology’s International Consortium of Collaborators on chronic kidney disease of unknown etiology: report of the working group on approaches to population-level detection strategies and recommendations for a minimum dataset. Kidney Int 95(1):4–10. https://doi.org/10.1016/j.kint.2018.08.019
Khalil SI (2020) Endomyocardial fibrosis: diagnosis and management. J Vasc Diagn Interven 8:1–9. https://doi.org/10.2147/JVD.S196348
Eapen JT, Kartha CC, Valiathan MS (1997) Cerium levels are elevated in the serum of patients with endomyocardial fibrosis (EMF). Biol Trace Elem Res 59:41–44. https://doi.org/10.1007/BF02783228
Bhatti K, Bandlamudi M, Lopez-Mattei J (2021) Endomyocardial fibrosis. StatPearls, Treasure Island
Smith B, Chenery SRN, Cook JM, Styles MT, Tiberindwa JV, Hampton C, Freers J, Rutakinggirwa M, Sserunjogi L, Tomkins A, Brown CJ (1998) Geochemical and environmental factors controlling exposure to cerium and magnesium in Uganda. J Geochem Explor 65(1):1–15. https://doi.org/10.1016/S0375-6742(98)00066-1
Tharakan J, Bohora S (2009) Current perspective on endomyocardial fibrosis. Curr Sci 97(3):405–410
Mocumbi AO, Stothard JR, Correia-de-Sá P, Yacoub M (2019) Endomyocardial fibrosis: an update after 70 years. Curr Cardiol Rep 21(11):148. https://doi.org/10.1007/s11886-019-1244-3
Mocumbi AOH (2014) Endomyocardial fibrosis. In: Da Cruz E, Ivy D, Jaggers J (eds) Pediatric and congenital cardiology, cardiac surgery and intensive care. Springer, London
Marques AP, Santo A, Berssaneti AA, Matsutani LA, Yuan S (2017) Prevalence of fibromyalgia: literature review update. Rev Bras Reumatol 57(4):356–363. https://doi.org/10.1016/j.rbre.2017.01.005
Rosborg I, Hyllén E, Lidbeck J, Nihlgård B, Gerhardsson L (2007) Trace element pattern in patients with fibromyalgia. Sci Total Environ 385(1–3):20–27. https://doi.org/10.1016/j.scitotenv.2007.05.014
Sendur OF, Tastaban E, Turan Y, Ulman C (2008) The relationship between serum trace element levels and clinical parameters in patients with fibromyalgia. Rheumatol Int 28(11):1117–1121. https://doi.org/10.1007/s00296-008-0593-9
Stejskal V, Ockert K, Bjørklund G (2013) Metal-induced inflammation triggers fibromyalgia in metal-allergic patients. Neuro Endocrinol Lett 34(6):559–565
Shukla V, Das SK, Mahdi AA, Agarwal S, Alok R, Ansari JA, Khandpur S (2021) Metal-induced oxidative stress level in patients with fibromyalgia syndrome and its contribution to the severity of the disease: a correlational study. J Back Musculoskelet Rehabil 34(2):319–326. https://doi.org/10.3233/BMR-200102
Al-Khalifa II, Hassan MF, , AL-Deri SM, Gorial FI (2016) Determination of some essential and non-essential metals in patients with Fibromyalgia Syndrome (FMS). Int J Pharm Sci Res 8(5):306–311
Kim YS, Kim KM, Lee DJ, Kim BT, Park SB, Cho DY et al (2011) Women with fibromyalgia have lower levels of calcium, magnesium, iron and manganese in hair mineral analysis. J Korean Med Sci 26(10):1253–1257. https://doi.org/10.3346/jkms.2011.26.10.1253
Andretta A, Dias Batista E, Madalozzo Schieferdecker ME, Petterly RR, Boguszewski CL, dos Santos Paiva E (2019) Relation between magnesium and calcium and parameters of pain, quality of life and depression in women with fibromyalgia. Adv Rheumatol 59:55. https://doi.org/10.1186/s42358-019-0095-3
Fors EA, Sexton H (2002) Weather and the pain in fibromyalgia: are they related? Ann Rheum Dis 61:247–250
Siracusa R, Paola RD, Cuzzocrea S, Impellizzeri D (2021) Fibromyalgia: pathogenesis, mechanisms, diagnosis and treatment options update. Int J Mol Sci 22(8):3891. https://doi.org/10.3390/ijms22083891
Ship JA, Phelan J, Kerr AR (2003) Biology and Pathology of the Oral Mucosa. In: Freedberg IM, Eisen AZ, Wolff K et al (eds) Fitzpatrick’s dermatology in general medicine, 6th Edn (Chap 112). McGraw-Hill, New York
Picciani BLS, Santos LR, Teixeira-Souza T, Dick TNA, Carneiro S, Pinto JMN et al (2020) Geographic tongue severity index: a new and clinical scoring system. Oral Surg Oral Med Oral Pathol Oral Radiol 129(4):330–338. https://doi.org/10.1016/j.oooo.2019.12.007
Ogueta CI, Ramírez PM, Jiménez OC, Cifuentes MM (2019) Geographic tongue: what a dermatologist should know. Actas Dermosifiliogr 110(5):341–346. https://doi.org/10.1016/j.ad.2018.10.022
Nandini DB, Bhavana SB, Deepak BS, Ashwini R (2016) Paediatric geographic tongue: a case report, review and recent updates. J Clin Diagn Res 10(2):5–9
Picciani BL, Domingos TA, Teixeira-Souza T, Santos Vde C, Gonzaga HF, Cardoso-Oliveira J, Gripp AC, Dias EP, Carneiro S (2016) Geographic tongue and psoriasis: clinical, histopathological, immunohistochemical and genetic correlation-A literature review. Braz Ann Dermatol 91(4):410–421. https://doi.org/10.1590/abd1806-4841.20164288
Picciani B, Santos VC, Teixeira-Souza T, Izahias LM, Curty Á, Avelleira JC, Azulay D, Pinto J, Carneiro S, Dias E (2017) Investigation of the clinical features of geographic tongue: unveiling its relationship with oral psoriasis. Int J Dermatol 56(4):421–427. https://doi.org/10.1111/ijd.13460
Khayamzadeh M, Najafi S, Sadrolodabaei P, Vakili F, Kharrazi Fard MJ (2019) Determining salivary and serum levels of iron, zinc and vitamin B12 in patients with geographic tongue. J Dent Res Dent Clin Dent Prospect 13(3):221–226. https://doi.org/10.15171/joddd.2019.034
Stewart CG, Burroughs GW (2020) Infectious diseases of livestock, Part 3: Disease complexes-unknown aetology: Ill-thrift. Anipedia. https://www.anipedia.org/resources/disease-complexes-/-unknown-aetiology-ill-thrift/982 . Accessed 31 Oct 2020
Crawshaw M, Caldow G (2005) Trace elements in beef cattle. Technical Note, No.: TN 572. file:///D:/SAC-TN572-Trace-element-disorders-in-beef-cattle.pdf . Accessed 30 Oct 2020
Ali MA, El-Khodery SA, El-Said WE (2015) Potential risk factors associated with ill-thrift in buffalo calves (Bubalus bubalis) raised at smallholder farms in Egypt. J Adv Res 6(4):601–607. https://doi.org/10.1016/j.jare.2014.02.005
Ismael M, El-Sayed MS, Metwally AM, Abdullaziz IA (2015) Trace elements status and antioxidants profile in ill-thrift buffalo calves. Alexander J Veterinary Sci 44(1):130–135. https://doi.org/10.5455/ajvs.170301
MLA (Meat and Livestock Australia) (2020) Mineral deficiencies. https://www.mla.com.au/research-and-development/animal-health-welfare-and-biosecurity/diseases/nutritional/mineral-deficiencies . Accessed 31 Oct 2020
Rowley AH, Shulman ST (2018) The epidemiology and pathogenesis of Kawasaki Disease. Front Pediatr 6:374. https://doi.org/10.3389/fped.2018.00374
Badoe EV, Neequaye J, Oliver-Commey JO, Amoah J, Osafo A, Aryee I, Nyarko MY (2011) Kawasaki disease in Ghana: case reports from Korle Bu Teaching Hospital. Ghana Med J 45(1):38–42. https://doi.org/10.4314/gmj.v45i1.68922
Animasahun AB, Adekunle MO, Yejide K, Fadipe C (2017) The diagnosis of Kawasaki disease among Nigerian children: a nightmare for the caregivers and the doctors. J Public Health Emergency 1:7
Noorani M, Lakhani N (2018) Kawasaki disease: two case reports from the Aga Khan Hospital, Dar es Salaam-Tanzania. BMC Pediatr 18:334. https://doi.org/10.1186/s12887-018-1306-5
Davaalkham D, Nakamura Y, Baigalmaa D, Chimedsuren O, Sumberzul N et al (2011) Kawasaki disease in Mongolia: results from 2 nationwide retrospective surveys, 1996–2008. J Epidemiol 21(4):293–298
Orlowski JP, Mercer RD (1980) Urine mercury levels in Kawasaki disease. Pediatrics 66(4):633–636
Mutter J, Yeter D (2008) Kawasaki’s disease, acrodynia, and mercury. Curr Med Chem 15(28):3000–3010. https://doi.org/10.2174/092986708786848712
Yeter D, Portman MA, Aschner M, Farina M, Chan WC, Hsieh KS, Kuo HC (2016) Ethnic Kawasaki disease risk associated with blood mercury and cadmium in U.S. children. Int J Environ Res Public Health 13(1):101
Portman MA, Yeter D, Kuo H-C (2018) Ethnic variations in mercury exposure from seafood consumption and the risk of Kawasaki disease in young children. FASEB J 31(1):982–985
Rodo X, Curcoll R, Robinson M, Ballester J, Burns JC, Cayan DR, Lipkin WI et al (2014) Tropospheric winds from northeastern China carry the etiologic agent of Kawasaki disease from its source to Japan. Proc Natl Acad Sci USA 111(22):7952–7957. https://doi.org/10.1073/pnas.1400380111
Rodo X, Ballester J, Curcoll R, Morguí J (2016) Revisiting the role of environmental and climate factors on the epidemiology of Kawasaki disease. Ann N Y Acad Sci 1382(1):84–98. https://doi.org/10.1111/nyas.13201
UCSDH (UC San Diego Health) (2013) Data from Across Globe Defines Distinct Kawasaki Disease Season. https://health.ucsd.edu/news/releases/Pages/2013-09-23-data-defines-kawasaki-disease-seasonal.aspx . Accessed 28 Aug 2020
Lin MT, Wu MH (2017) The global epidemiology of Kawasaki disease: review and future perspectives. Glob Cardiol Sci Pract 2017(3). https://doi.org/10.21542/gcsp.2017.20
Rypdal M, Rypdal V, Burney JA, Cayan D, Bainto E, Skochko S et al (2018) Clustering and climate associations of Kawasaki Disease in San Diego County suggest environmental triggers. Sci Rep 8:16140. https://doi.org/10.1038/s41598-018-33124-4
Kim GB (2019) Reality of Kawasaki disease epidemiology. Korean J Pediatrics 62(8):292–296. https://doi.org/10.3345/kjp.2019.00157
Elakabawi K, Lin J, Jiao F, Guo N, Yuan Z (2020) Kawasaki disease: global burden and genetic background. Cardiol Res 11(1):9–14
Toubiana J, Poirault C, Corsia A, Bajolle F, Fourgeaud J, Angoulvant F, Debray A et al (2020) Kawasaki-like multisystem inflammatory syndrome in children during the covid-19 pandemic in Paris, France: prospective observational study. BMJ 369:2094
Pedro EM, , da Rosa Franchi Santos LF, Scavuzzi BM, Iriyoda TMV, Peixe TS, Lozovoy MAB (2019) Trace elements associated with systemic Lupus erythematosus and insulin resistance. Biol Trace Element Res 191(1):34–44. https://doi.org/10.1007/s12011-018-1592-7
Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W (2017) The worldwide incidence and prevalence of systemic Lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford) 56(11):1945–1961. https://doi.org/10.1093/rheumatology/kex260
Essouma M, Nkeck JR, Endomba FT, Bigna JJ, Singwe-Ngandeu M, Hachulla E (2020) Systemic Lupus erythematosus in Native sub-Saharan Africans: a systematic review and meta-analysis. J Autoimmun 106:102348. https://doi.org/10.1016/j.jaut.2019.102348
Sahebari M, Abrishami-Moghaddam M, Moezzi A, Ghayour-Mobarhan M, Mirfeizi Z, Esmaily H, Ferns G (2014) Association between serum trace element concentrations and the disease activity of systemic Lupus erythematosus. Lupus 23(8):793–801. https://doi.org/10.1177/0961203314530792
Hua-Li Z, Shi-Chao X, De-Shen T, Dong L, Hua-Feng L (2011) Seasonal distribution of active systemic Lupus erythematosus and its correlation with meteorological factors. Clinics 66(6):1009–1013. https://doi.org/10.1590/s1807-59322011000600015
Justiz Vaillant AA, Goyal A, Bansal P (2020) Systemic Lupus erythematosus. StatPearls, Treasure Island
Compston A, Coles A (2002) Multiple sclerosis. Lancet 359(9313):1221–1231. https://doi.org/10.1016/S0140-6736(02)08220-X
Compston A, Coles A (2008) Multiple sclerosis. Lancet 372(9648):1502–1517. https://doi.org/10.1016/S0140-6736(08)61620-7
Murray ED, Buttner EA, Price BH (2012) Depression and psychosis in neurological practice. In: Daroff R, Fenichel G, Jankovic J, Mazziotta J (eds) Bradley’s neurology in clinical practice, 6th edn. Elsevier, Philadelphia, pp 92–116
Kister I, Bacon TE, Chamot E, Salter AR, Cutter GR, Kalina JT, Herbert J (2013) Natural history of multiple sclerosis symptoms. Int J MS Care 15(3):146–158. https://doi.org/10.7224/1537-2073.2012-053
Wade BJ (2014) Spatial analysis of global prevalence of multiple sclerosis suggests need for an updated prevalence scale. Mult Scler Int 2014:124578. https://doi.org/10.1155/2014/124578
World Global Burden of Disease (WGBD, 2016) Multiple Sclerosis Collaborators et al (2019) Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 18 (3):269–285. https://doi.org/10.1016/S1474-4422(18)30443-5
Bhigjee A, Moodley K, Ramkissoon K (2007) Multiple sclerosis in KwaZulu Natal, South Africa: an epidemiological and clinical study. Mult Scler 13(9):1095–1099. https://doi.org/10.1177/1352458507079274
Rieder HP, Schoettli G, Seiler H (1983) Trace elements in whole blood of multiple sclerosis. Eur Neurol 22(2):85–92. https://doi.org/10.1159/000115542
Smith DK, Feldman EB, Feldman DS (1989) Trace element status in multiple sclerosis. Am J Clin Nutr 50(1):136–140. https://doi.org/10.1093/ajcn/50.1.136
Melø TM, Larsen C, White LR, Aasly J, Sjøbakk TE, Flaten TP et al (2003) Manganese, copper, and zinc in cerebrospinal fluid from patients with multiple sclerosis. Biol Trace Elem Res 93:1–8. https://doi.org/10.1385/BTER:93:1-3:1
Tamburo E, Varrica D, Dongarrà G, Grimaldi LME (2015) Trace elements in scalp hair samples from patients with relapsing-remitting Multiple Sclerosis. PLoS ONE 10(4):e0122142. https://doi.org/10.1371/journal.pone.0122142
Bredholt M, Frederiksen JL (2016) Zinc in multiple sclerosis: a systematic review and meta-analysis. ASN Neuro 8(3):1759091416651511. https://doi.org/10.1177/1759091416651511
Janghorbani M, Shaygannejad V, Hakimdavood M, Salari M (2017) Trace elements in serum samples of patients with multiple sclerosis. Athens J Health 4(2):145–154
Sarmadi M, Bidel Z, Najafi F, Ramakrishnan R, Teymoori F, AzhdariZarmehri H, Nazarzadeh M (2020) Copper concentration in multiple sclerosis: a systematic review and meta-analysis. Multiple Sclerosis Relat Disord 45:102426. https://doi.org/10.1016/j.msard.2020.102426
van Horssen J, Witte ME, Schreibelt G, de Vries HE (2011) Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta 1812(2):141–150. https://doi.org/10.1016/j.bbadis.2010.06.011
Tavassolifar MJ, Vodjgani M, Salehi Z, Izad M (2020) The Influence of reactive oxygen species in the immune system and pathogenesis of multiple sclerosis. Autoimmune Dis 2020:5793817. https://doi.org/10.1155/2020/5793817
Hesamian MS, Eskandari N (2020) Potential role of trace elements (Al, Cu, Zn, and Se) in multiple sclerosis physiopathology. NeuroImmunoModulation 27:163–177. https://doi.org/10.1159/000511308
MS International Federation (2016) Geographical latitude and the onset of MS. https://www.msif.org/news/2016/12/05/geographical-latitude-and-the-onset-of-ms/ . Accessed 31 Jul 2020
Simpson SJ, Blizzard L, Otahal P, Van der Mei I, Taylor B (2011) Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 82(10):1132–1141. https://doi.org/10.1136/jnnp.2011.240432
Simpson SJ, Wang W, Otahal P, Blizzard L, van der Mei IAF, Taylor BV (2019) Latitude continues to be significantly associated with the prevalence of multiple sclerosis: an updated meta-analysis. J Neurol Neurosurg Psychiatry 90(11):1193–1200. https://doi.org/10.1136/jnnp-2018-320189
Warren S, Warren KG (2001) Multiple sclerosis. World Health Organisation, Geneva
Staples JA, Ponsonby AL, Lim LL, McMichael AJ (2003) Ecologic analysis of some immune-related disorders, including type 1 diabetes, in Australia: latitude, regional ultraviolet radiation, and disease prevalence. Environ Health Perspect 111(4):518–523. https://doi.org/10.1289/ehp.5941
Sabel CE, Pearson JF, Mason DF, Willoughby E, Abernethy DA, Taylor BV (2021) The latitude gradient for multiple sclerosis prevalence is established in the early lifecourse. Brain. https://doi.org/10.1093/brain/awab104
Korevaar DA, Visser BJ (2013) Reviewing the evidence on nodding syndrome, a mysterious tropical disorder. Int J Infect Dis 17(3):e149–e152. https://doi.org/10.1016/j.ijid.2012.09.015
GU/WHO [The Government of Uganda (GU)/World Health Organization (WHO)] (2012) Uganda adopts a multi-sectoral response to nodding syndrome. Press Release Kampala, March 2, 2012. http://reliefweb.int/sites/reliefweb.int/files/resources/kampala-nodding-press-release-02032012.pdf. Accessed 25 Aug 2020
Foltz JL, Makumbi I, Sejvar JJ, Malimbo M, Ndyomugyenyi R, Atai-Omoruto AD, Alexander LN, Abang B, Melstrom P, Kakooza AM, Olara D, Downing RG, Nutman TB, Dowell SF, Lwamafa DK (2013) An Epidemiologic investigation of potential risk factors for Nodding Syndrome in Kitgum District, Uaganda. PLoS ONE 8(6):e66419. https://doi.org/10.1371/journal.pone.0066419
Donnelly J (2012) CDC planning trial for mysterious nodding syndrome. Lancet 379(9813):287–384. https://doi.org/10.1016/S0140-6736(12)60126-3
Kaiser C, Benninger C, Asaba G, Mugisa C, Kabagambe G, Kipp W, Rating D (2000) Clinical and electro-clinical classification of epileptic seizure in west Uganda. Bull Soc Pathol Exotique 93:255–259
Nyungura JL, Akim T, Lako A, Gordon A, Lejeng L, William G (2011) Investigation into the nodding syndrome in Witto Payam, Western Equatoria State, 2010. Southern Sudan Med J 4:3–6
Dowell SF, Sejvar JJ, Riek L, Vandemaele KA, Lamunu M, Kuesel AC, Schmutzhard E, Matuja W, Bunga S, Foltz J, Nutman TB, Winkler AS, Mbonye AK (2013) Nodding syndrome. Emerg Infect Dis 19(9):1374–1384. https://doi.org/10.3201/eid1909.130401
Olum S, Scolding P, Hardy C, Obol J, Scolding NJ (2020) Nodding syndrome: a concise review. Brain Commun 2(1):37. https://doi.org/10.1093/braincomms/fcaa037
Srour ML, Marck K, Baratti-Mayer D (2017) Noma: overview of a neglected disease and human rights violation. Am J Trop Med Hyg 96(2):268–274. https://doi.org/10.4269/ajtmh.16-0718
Baratti-Mayer D, Pittet B, Montandon D, Bolivar IB et al (2003) Noma: an “infectious” disease of unknown aetiology. Lancet Infect Dis 3(7):419–431
Enwonwu CO, Falkler WA Jr, Idigbe EO, Afolabi BM, Ibrahim M, Onwujekwe D, Savage O, Meeks VI (1999) Pathogenesis of cancrum oris (noma): confounding interactions of malnutrition with infection. Am J Trop Med Hyg 60(2):223–232. https://doi.org/10.4269/ajtmh.1999.60.223
Srour ML, Baratti-Mayer D (2020) Why is noma a neglected-neglected tropical disease? PLoS Negl Trop Dis 14(8):e0008435. https://doi.org/10.1371/journal.pntd.0008435
Farley E, Ariti C, Amirtharajah M, Kamu C, Oluyide B, Shoaib M, Isah S, Adetunji AS, Saleh F, Ihekweazu C, Pereboom M, Sherlock M (2021) Noma, a neglected disease: a viewpoint article. PLoS Negl Trop Dis 15(6):e0009437. https://doi.org/10.1371/journal.pntd.0009437
Sian J, Youdim MBH, Riederer P, Gerlach M (1999) Parkinson’s Disease. In: Siegel GJ, Agranoff BW, Albers RW et al (eds) Basic neurochemistry: molecular, cellular and medical aspects, 6th edition (Chap. 45). Lippincott-Raven, Philadelphia
Dorsey ER, the 2016 Global Burden of Disease Collaborators (2018) Global, Regional and National Burden of Parkinson’s Disease, 1990–2016. Lancet Neurol 17(11):939–953
Yasui M, Kihira T, Ota K (1992) Calcium, magnesium and aluminum concentrations in Parkinson’s disease. Neurotoxicology 13(3):593–600
Bocca B, Alimonti A, Petrucci F, Violante N, Sancesario G, Forte G, Senofonte O (2004) Quantification of trace elements by sector field inductively coupled plasma mass spectrometry in urine, serum, blood and cerebrospinal fluid of patients with Parkinson’s disease. Spectrochim Acta Part B 59(4):559–566. https://doi.org/10.1016/j.sab.2004.02.007
Forte G, Bocca B, Senofonte O, Petrucci F, Brusa L, Stanzione P et al (2004) Trace and major elements in whole blood, serum, cerebrospinal fluid and urine of patients with Parkinson’s disease. J Neural Transm (Vienna) 111(8):1031–1040. https://doi.org/10.1007/s00702-004-0124-0
Gellein K, Syversen T, Steinnes E, Nilsen TIL, Dahl OP, Mitrovic S, Duraj D, Flatten TP (2008) Trace elements in serum from patients with Parkinson’s disease-a prospective case-control study: the Nord-Trøndelag Health Study (aUNT). Brain Res 1219:111–115. https://doi.org/10.1016/j.brainres.2008.05.002
Zhao HW, Lin J, Wang XB, Cheng X, Wang JY, Hu BL, Zhang Y, Zhang X, Zhu JH (2013) Assessing plasma levels of selenium, copper, iron and zinc in patients of Parkinson’s disease. PLoS ONE 8(12):e83060. https://doi.org/10.1371/journal.pone.0083060
Raj K, Kaur P, Gupta GD, Singh S (2021) Metals associated neurodegeneration in Parkinson’s disease: insight to physiological, pathological mechanisms and management. Neurosci Lett 753:135873. https://doi.org/10.1016/j.neulet.2021.135873
Ellwanger JH, Franke SI, Bordin DL, Prá D, Henriques JA (2016) Biological functions of selenium and its potential influence on Parkinson’s disease. Ann Braz Acad Sci 88(3 Suppl.):1655–1674. https://doi.org/10.1590/0001-3765201620150595
Bourke CA (2018) Astrocyte dysfunction following molybdenum-associated purine loading could initiate Parkinson’s disease with dementia. NPJ Parkinson’s Dis 4:7. https://doi.org/10.1038/s41531-018-0045-5
Sun H (2018) Association of soil selenium, strontium, and magnesium concentrations with Parkinson’s disease mortality rates in the USA. Environ Geochem Health 40:349–357. https://doi.org/10.1007/s10653-017-9915-8
Adani G, Filippini T, Michalke B, Vinceti M (2020) Selenium and other trace elements in the etiology of Parkinson’s Disease: a systematic review and meta-analysis of case-control studies. Neuroepidemiology 54:1–23. https://doi.org/10.1159/000502357
Lemelle L, Simionovici A, Colin P, Knott G, Bohic S, Cloetens P, Schneider BL (2020) Nano-imaging trace elements at organelle levels in substantia nigra overexpressing α-synuclein to model Parkinson’s disease. Commun Biol 3:364. https://doi.org/10.1038/s42003-020-1084-0
Ogunrin O, Sanya E, Komolafe M, Osubor CC (2013) Trace metals in patients with Parkinson’s Disease: a multi-center case-control study in Nigerian patients. J Neurol Epidemiol 1:31–38. https://doi.org/10.12974/2309-6179.2013.01.01.4
Rowell D, Nghiem S, Ramagopalan S, Meier UC (2017) Seasonal temperature is associated with Parkinson’s disease prescriptions: an ecological study. Int J Biometeorol 61(12):2205–2211. https://doi.org/10.1007/s00484-017-1427-9
Capcha KM, Pezo AP, Cosentino C, Ramirez LET (2018) Presentation of Parkinson’s disease in patients originating of different geographical altitudes. Neurology 90(15):2080
Thomas J (2019) Increasing the altitude to decrease the symptoms of Parkinson’s Disease. High Altitude Health. https://highaltitudehealth.com/2019/04/15/increasing-the-altitude-to-decrease-the-symptoms-of-parkinsons-disease/. Accessed 13 Sept 2020
Cao Y, Li G, Xue J, Zhang G, Gao S, Huang Y, Zhu A (2021) Depression and related factors in patients with Parkinson’s Disease at high altitude. Neuropsychiatr Dis Treat 17:1353–1362. https://doi.org/10.2147/NDT.S300596
Ullah I, Zhao L, Hai Y, Fahim M, Alwayli D, Wang X, Li H (2021) Metal elements and pesticides as risk factors for Parkinson’s disease-a review. Toxicol Rep 8:607–616. https://doi.org/10.1016/j.toxrep.2021.03.009
Patil P, Jain H, Mishra V, Sharma A (2015) Sarcoidosis: an update for the oral health care provider. J Cranio-Maxillary Dis 4(1):69–75. https://doi.org/10.4103/2278-9588.151908
Arkema EV, Cozier YC (2018) Epidemiology of sarcoidosis: current findings and future directions. Therapeut Adv Chronic Dis 9(11):227–240. https://doi.org/10.1177/2040622318790197
Awotedu AA, George AO, Oluboyo PO, Alabi GO, Onadeko BO, Ogunseyinde O, Aghadiuno PU (1987) Sarcoidosis in Africans: 12 cases with histological confirmation from Nigeria. Trans R Soc Trop Med Hyg 81(6):1027–1029. https://doi.org/10.1016/0035-9203(87)90387-7
Kaloga M, Gbéry IP, Bamba V, Kouassi YI, Ecra EJ, Diabate A, Kourouma S, Ahogo KC, Kouamé KA, Kassi K, Kouame K, Sangaré A (2015) Epidemiological, clinical, and paraclinic aspect of cutaneous sarcoidosis in Black Africans. Dermatol Res Pract 2015:802824. https://doi.org/10.1155/2015/802824
Morar R, Feldman C (2015) Comorbid illnesses in South African patients with sarcoidosis. Eur Respir J 46(59):839. https://doi.org/10.1183/13993003.co9ngress-2015.PA839
Morar R, Feldman C (2015) Sarcoidosis in Johannesburg, South Africa: a retrospective study. Eur Respir J 46(59):841. https://doi.org/10.1183/13993003.congress-2015
Newman LS (1998) Metals that cause sarcoidosis. Semin Respir Infect 13(3):212–220
Beijer E, Meek B, Bossuyt X, Peters S, Vermuulen RCH, Kromhout H, Veltkamp M (2020) Immunoreactivity to metal and silica associates with sarcoidosis in Dutch patients. Resp Res 21:141. https://doi.org/10.1186/s12931-020-01409-w
Denisova O, Chernogoryuk G, Baranovskaya N, Rikhvanov L, Shefer N, Chernjavskaya G, Palchikova I, Kalacheva T (2020) Trace elements in the lung tissue affected by Sarcoidosis. Biol Trace Elem Res 196(1):66–73. https://doi.org/10.1007/s12011-019-01915-z
Judson MA (2020) Environmental risk factors for sarcoidosis. Front Immunol 11:1340. https://doi.org/10.3389/fimmu.2020.01340
Culver DA, Newman LS, Kavuru MS (2007) Gene environment interactions in sarcoidosis: challenge and opportunity. Clin Dermatol 25:267–275. https://doi.org/10.1016/j.clindermatol.2007.03.005
Lacey DC, De Kok B, Clanchy FI, Bailey MJ, Speed K, Haynes D, Graves SE, Hamilton JA (2009) Low dose metal particles can induce monocyte/macrophage survival. J Orthopaed Res 27(11):1481–1486. https://doi.org/10.1002/jor.20914
Lepzien R, Liu S, Czarnewski P, Nie M, Österberg B, Baharom F, Pourazar J, Rankin G et al (2021) Monocytes in sarcoidosis are potent tumour necrosis factor producers and predict disease outcome. Eur Respir J 58(1):2003468. https://doi.org/10.1183/13993003.03468-2020
Sartwell PE, Edwards LB (1974) Epidemiology of sarcoidosis in the U.S Navy. Am J Epidemiol 99:250–257. https://doi.org/10.1093/oxfordjournals.aje.a121609
Ramos-Casals M, Kostov B, Brito-Zerón P, Sisó-Almirall A, Baughman RP (2019) Autoimmune Big Data Study Group. How the frequency and phenotype of Sarcoidosis is driven by environmental determinants. Lung 197(4):427–436. https://doi.org/10.1007/s00408-019-00243-2
Pietra R, Edel J, Sabbioni E, Rizzato GP (1988) Sarcoidosis and trace metals as investigated by neutron activation analysis. Int Nucl Inf Syst 19:23
Beghè D, Garavelli C, Pastorelli AA, Muscarella M, Saccani G, Aiello M, Crisafulli E, Corradi M, Stacchini P, Chetta A, Bertorelli G (2017) Sarcoidosis in an Italian province: prevalence and environmental risk factors. PLoS ONE. https://doi.org/10.1371/journal.pone.0176859
Ganeshan D, Menias CO, Luber MG, Pickhardt PJ, Sandrasegaran K, Bhalla S (2018) Sarcoidosis from head to toe: what the radiologist needs to know. Radiographics 38(4):1180–1200. https://doi.org/10.1148/rg.2018170157
Ahmadzai H, Thomas PS, Wakefield D (2013) Laboratory investigations and immunological testing in sarcoidosis. https://doi.org/10.5772/55294. https://www.intechopen.com/books/sarcoidosis/laboratory-investigations-and-immunological-testing-in-sarcoidosis . Accessed 31 Oct 2020
US NINDS (United States National Institute of Neurological Disorders and Stroke) (2014) Hereditary Spastic Paraplegia Information Page. https://web.archive.org/web/20140221102852/http://www.ninds.nih.gov/disorders/hereditary_spastic_paraplegia/hereditary_spastic_paraplegia.htm . Accessed 29 Oct 2020
US NIH (United States National Institute of Health) (2019) Hereditary Spastic Paraplegia Information Page. https://www.ninds.nih.gov/Disorders/All-Disorders/Hereditary-Spastic-Paraplegia-Information-Page . Accessed 29 Oct 2020
Mitchell JD, East BW, Harris IA, Prescott RJ, Pentland B (1986) Trace elements in the spinal cord and other tissues in motor neuron disease. J Neurol Neurosurg Psychiatry 49(2):211–215. https://doi.org/10.1136/jnnp.49.2.211
Hedera P (2016) Hereditary and metabolic myelopathies. Handb Clin Neurolol 136:769–785. https://doi.org/10.1016/B978-0-444-53486-6.00038-7
Hedera P (Updated 2018) Hereditary spastic paraplegia overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A, Eds, GeneReviews® [Internet]. Seattle (WA), University of Washington, Seattle, 1993-2021. https://www.ncbi.nlm.nih.gov/books/NBK1509/. Accessed 30 Oct 2020
Cliff J, Martelli A, Molin A, Rosling H (1984) Mantakassa: an epidemic of spastic paraparesis associated with chronic cyanide intoxication in a cassava staple area of Mozambique. 1. Epidemiology and clinical and laboratory findings in patients, Ministry of Health, Mozambique. Bull World Health Org 62(3):477–484
Taibo CLA, Cliff J, Rosling H, Hall CD, Park MM, Frimpong JA (2017) An epidemic of spastic paraparesis of unknown aetiology in Northern Mozambique. Pan African Med J 27(Supplement 1):6. https://doi.org/10.11604/pamj.supp.2017.27.1.12623
Duncan JR, Byard RW (eds) (2018) SIDS-sudden infant and early childhood death: the past, the present and the future. University of Adelaide Press, Adelaide
Müller-Nordhorn J, Schneider A, Grittner U, Neumann K, Keil T, Willich SN, Binting S (2020) International time trends in sudden unexpected infant death, 1969–2012. BMC Pediatr 20:377. https://doi.org/10.1186/s12887-020-02271-x(accessed02.02.2021)
Ogbu CN (2003) Sudden infant death syndrome (SIDS) or cot death: a review. West Afr J Med 22:1. https://doi.org/10.4314/wajm.v22i1.27988
Ndu IK (2016) Sudden infant death syndrome: an unrecognized killer in developing countries. Pediatric Health Med Therapeut 7:1–4. https://doi.org/10.2147/PHMT.S99685
Dempers JJ, Burger EH, Du Toit-Prinsloo L, Verster J (2018) A South African perspective. In: Duncan JR, Byard RW (eds) SIDS-sudden infant and early childhood death: the past, the present and the future (Chap 17). University of Adelaide Press, Adelaide
Drasch GA, Kretschmer E, Lochner C (1988) Lead and sudden infant death. Eur J Paediatr 147:79–84. https://doi.org/10.1007/BF00442618
Erickson MM, Poklis A, Gantner GE, Dickinson AW, Hillman LS (1983) Tissue mineral levels in victims of sudden infant death syndrome I. Toxic metals-lead and cadmium. Pediatr Res 17(10):779–784. https://doi.org/10.1203/00006450-198310000-00002
Steele RJ, Fogerty AC, Willcox ME, Clancy SL (1984) Metal content of the liver in sudden infant death syndrome. J Paediatr Child Health 20(2):141–142
Caddell JL (1992) Hypothesis: new concepts concerning the pathophysiology of the sudden infant death syndrome due to magnesium deficiency shock. Magnes Res 5(3):165–172
George M, Wiklund L, Aastrup M, Pousette J, Thunholm B, Saldeen T, Wernroth L, Zarén B, Holmberg L (2001) Incidence and geographical distribution of sudden infant death syndrome in relation to content of nitrate in drinking water and groundwater levels. Eur J Clin Investig 31(12):1083–1094. https://doi.org/10.1046/j.1365-2362.2001.00921.x
Deacon EL, Williams AL (1982) The incidence of the sudden infant death syndrome in relation to climate. Int J Biometeorol 26:207–218. https://doi.org/10.1007/BF02184936
Sawczenko A, Fleming PJ (1996) Thermal stress, sleeping position, and the sudden infant death syndrome. Sleep 19(10):S267–S270
Schluter PJ, Ford RP, Brown J, Ryan AP (1998) Weather temperatures and sudden infant death syndrome: a regional study over 22 years in New Zealand. J Epidemiol Community Health 52(1):27–33. https://doi.org/10.1136/jech.52.1.27
Jhun I, Mata DA, Nordio F, Lee M, Schwartz J, Zanobetti A (2017) Ambient temperature and sudden infant death syndrome in the United States. Epidemiology 28(5):728–734. https://doi.org/10.1097/EDE.0000000000000703
Goldwater PN (2017) Infection: the neglected paradigm in SIDS research. Arch Dis Child 102:767–772. https://doi.org/10.1136/archdischild-2016-312327
Goenka A, Kollmann T (2015) Development of immunity in early life. J Infect 71(Supplement 1):112–120. https://doi.org/10.1016/j.jinf.2015.04.027
Simon AK, Hollander GA, McMichael A (2015) Evolution of the immune system in humans from infancy to old age. Proc R Soc B 282(1821):20143085. https://doi.org/10.1098/rspb.2014.3085
Davies TC (2021) Recent applied geochemistry research in Africa contributes towards understanding causal cofactors of diseases of unknown aetiology. EXPLORE 190:13–25
Salzberg SL (2018) Open questions: how many genes do we have? BMC Biol 16:94. https://doi.org/10.1186/s12915-018-0564-x
Rappaport SM (2016) Genetic factors are not the major causes of chronic diseases. PLoS ONE 11(4):e0154387. https://doi.org/10.1371/journal.pone.0154387
Perera BPU, Svoboda LK, Dolinoy DC (2019) Genomic tools for environmental epigenetics and implications for public health. Curr Opin Toxicol 18:27–33
US NIEHS (National Institute of Environmental Health Sciences) (2020) Environmental epigenetics. https://www.niehs.nih.gov/research/supported/health/envepi/index.cfm . Accessed 12 Dec 2020
Kanellis VG, Dos Remedios CG (2018) A review of heavy metal cation binding to deoxyribonucleic acids for the creation of chemical sensors. Biophys Rev 10(5):1401–1414. https://doi.org/10.1007/s12551-018-0455-y
Anastassopoulou J (2003) Metal-DNA interactions. J Mol Struct 651–653:19–26. https://doi.org/10.1016/S0022-2860(02)00625-7
Dales JP, Desplat-Jégo S (2020) Metal imbalance in neurodegenerative diseases with a specific concern to the brain of multiple sclerosis patients. Int J Mol Sci 30(21–23):9105. https://doi.org/10.3390/ijms21239105
Morris DL Jr (2014) DNA-bound metal ions: recent developments. Biomol Concepts 5(5):397–407. https://doi.org/10.1515/bmc-2014-0021
Hasani Nourian Y, Beh-Pajooh A, Aliomrani M, Amini M, Sahraian MA, Hosseini R, Mohammadi S, Ghahremani MH (2021) Changes in DNA methylation in APOE and ACKR3 genes in multiple sclerosis patients and the relationship with their heavy metal blood levels. Neurotoxicology 87:182–187
Ibrahim MM, Gabr MT (2019) Multitarget therapeutic strategies for Alzheimer’s disease. Neural Regen Res 14(3):437–440. https://doi.org/10.4103/1673-5374.245463
Balali-Mood M, Naseri K, Tahergorabi Z, Khazdair MR, Sadeghi M (2021) Toxic mechanisms of five heavy metals: mercury, lead, chromium, cadmium and arsenic. Front Pharmacol 12:643972
Singh A, Kukreti R, Saso L, Kukreti S (2019) Oxidative stress: a key modulator in neurodegenerative diseases. Molecules 24(8):1583. https://doi.org/10.3390/molecules24081583
Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283(2–3):65–87. https://doi.org/10.1016/j.tox.2011.03.001
Coppedè F, Migliore L (2015) DNA damage in neurodegenerative diseases. Mutat Res 776:84–97. https://doi.org/10.1016/j.mrfmmm.2014.11.010
Ramani S, Pathak A, Dalal V, Paul A, Biswas S (2020) Oxidative stress in autoimmune diseases: an under dealt malice. Curr Protein Pept Sci 21(6):611–621. https://doi.org/10.2174/1389203721666200214111816
Grobusch LC, Grobusch MP (2022) A hot topic at the environment-health nexus: investigating the impact of climate change on infectious diseases. Int J Infect Dis 116:7–9
Romanello M, McGushin A, Di Napoli C, Drummond P, Hughes N, Jamart L, Kennard H, Lampard P, Solano Rodriguez B, Arnell N, Ayeb-Karlsson S, Belesova K, Cai W et al (2021) The 2021 report of the Lancet Countdown on health and climate change: code red for a healthy future. Lancet 398(10311):1619–1662. https://doi.org/10.1016/S0140-6736(21)01787-6
WHO (World Health Organisation) (2021) Climate change and health, 2021. https://www.who.int/news-room/fact-sheets/detail/climate-change-and-health
Ackland ML, Bornhorst J, Dedoussis GV, Dietert RR, Nriagu JO, Pacyna JM et al (2015) Metals in the environment as risk factors for infectious diseases: gaps and opportunities. In: Nriagu JO, Skaar EP (eds) Trace metals and infectious diseases (Chap. 17). MIT Press, Cambridge
Smith KR, Woodward A, Campbell-Lendrum D, Chadee DD, Honda Y, Liu Q, Olwoch JM, Revich B, Sauerborn R (2014) Human health: ipacts, adaptation, and co-benefits. In: Field CB, Barros VR, Dokken DJ, Mach KJ, Mastrandrea MD et al (eds) Climate Change 2014: Impacts, Adaptation, and Vulnerability Part A: Global and Sectoral Aspects. Contribution of Working Group II to the Fifth Assessment Report of the Intergovernmental Panel on Climate Change. Cambridge University Press, Cambridge, pp 709–754
Hastuti AAMB, Costas-Rodríguez M, Matsunaga A, Ichinose T, Hagiwara S, Shimura M, Vanhaecke F (2020) Cu and Zn isotope ratio variations in plasma for survival prediction in hematological malignancy cases. Sci Rep 10:16389. https://doi.org/10.1038/s41598-020-71764-7
Tea I, De Luca A, Schiphorst AM, Grand M, Barillé-Nion S, Mirallié E, Drui D, Krempf M, Hankard R, Tcherkez G (2021) Stable isotope abundance and fractionation in human diseases. Metabolites 11(6):370. https://doi.org/10.3390/metabo11060370
Moynier F, Borgne ML, Laoud E, Mahan B, Mouton-Ligier F, Hugon J, Paquet C (2020) Copper and zinc isotopic excursions in the human brain affected by Alzheimer’s disease. Alzheimer’s Dementia 12(1):e12112. https://doi.org/10.1002/dad2.12112
Moynier F, Foriel J, Shaw AS, Le Borgne M (2017) Distribution of Zn isotopes during Alzheimer’s disease. Geochem Perspect Lett 3:2. https://doi.org/10.7185/geochemlet.1717
Sauzéat L, Bernard E, Perret-Liaudet A, Quadrio I, Vighetto A, Krolak-Salmon P, Broussolle E, Leblanc P, Balter V (2018) Isotopic evidence for disrupted copper metabolism in amyotrophic lateral sclerosis. iScience 6:264–271. https://doi.org/10.1016/j.isci.2018.07.023
Nicholson LB (2016) The immune system. Essays Biochem 60(3):275–301. https://doi.org/10.1042/EBC20160017
Galask R, Larsen B, Ohm MJ (2008) Infection in maternal-fetal medicine: an overview. Welfare of Women, Global Health Programme. Global Library of Women’s Medicine. https://doi.org/10.3843/GLOWM.10173. https://www.glowm.com/section-view/heading/infection-in-maternal-fetal-medicine-an-overview/item/173#.YTNRPp0zY2w. Accessed 04 Sept 2021
Smith T (1934) Parasitism and disease. Princeton University Press, Princeton
Failla ML (2003) Trace elements and host defense: recent advances and continuing challenges. J Nutr 133(5):1443-1447S. https://doi.org/10.1093/jn/133.5.1443S
Keen CL, Uriu-Adams JY, Ensunsa JL, Gershwin ME (2004) Trace elements/minerals and immunity. In: Gershwin ME, Nestel P, Keen CL (eds) Handbook of nutrition and immunity. Humana Press, Totowa, pp 117–140
Plumlee GS, Ziegler TL (2006) The medical geochemistry of dusts, soils, and other earth materials. In: Sahai N, Schoonen MAA (eds) Reviews in mineralogy and geochemistry. US Geological Survey, Denver
Plumlee G, Mormon SS, Ziegler TL (2006) The toxicological geochemistry of earth materials: an overview of processes and the interdisciplinary methods used to understand them. In: Sahai N, Schoonen MAA (eds) Reviews in mingralogy and Geochemistry, 64, 7. US Geological Survey, Denver
Chaplin DD (2010) Overview of the immune response. J Allergy Clin Immunol 125(2):3–23. https://doi.org/10.1016/j.jaci.2009.12.980
Winans B, Humble MC, Lawrence BP (2011) Environmental toxicants and the developing immune system: a missing link in the global battle against infectious disease? Reprod Toxicol 31(3):327–336. https://doi.org/10.1016/j.reprotox.2010.09.004
Marshall JS, Warrington R, Watson W, Kim HL (2018) An introduction to immunology and immunopathology. Allergy Asthma Clin Immunol 14:49. https://doi.org/10.1186/s13223-018-0278-1
Paludan SR, Pradeu T, Masters SL, Mogensen TH (2020) Constitutive immune mechanisms: mediators of host defence and immune regulation. Nat Rev Immunol 21:137–150
El-Zayat SR, Sibaii H, Mannaa FA (2019) Micronutrients and many important factors that affect the physiological functions of toll-like receptors. Bull Natl Res Centre 43:123. https://doi.org/10.1186/s42269-019-0165-z
Thurnham DI (2004) An overview of the interactions between micronutrients and of micronutrients with drugs, genes and immune mechanisms. Nutr Res Rev 17(2):211–240. https://doi.org/10.1079/NRR200486
Ermakov VV, Jovanović LN (2022) Biological role of trace elements and viral pathologies. Geochem Int 60:137–153. https://doi.org/10.1134/S0016702922020045
Beck MA (1999) Trace minerals, immune function, and viral evolution. In: Beck M (ed) Military strategies for sustainment of nutrition and immune function in the field, Chapter 16. Committee on Military Nutrition Research, Institute of Medicine. National Academies Press, New York
Finkelman RB, Orem WH, Plumlee GS, Selinus O (2018) Applications of geochemistry to medical geology. In: DeVivo B, Belkin HE, Lima A (eds) Environmental geochemistry: site characterization, data analysis and case histories, Chap 17, 2nd edn. Elsevier, Amsterdam, pp 435–465
Hasan SE (2020) Medical geology. Ref Module Earth Syst Environ Sci B. https://doi.org/10.1016/B978-0-12-409548-9.12523-0
Danks DM (1985) Inborn errors of trace element metabolism. Clin Endocrinol Metab 14(3):591–615. https://doi.org/10.1016/s0300-595x(85)80008-6
Ferreira CR, Gahl WA (2017) Disorders of metal metabolism. Transl Sci Rare Dis 2(3–4):101–139. https://doi.org/10.3233/TRD-170015
Nriagu JO, Skaar EP (eds) (2015) Trace metals and infectious diseases. MIT, New York
Kakuschke A, Prange A (2007) The influence of metal pollution on the immune system: a potential stressor for marine mammals in the North Sea. Int J Comp Psychol 20:179–193
Cabassi E (2007) The immune system and exposure to xenobiotics in animals. Veterinary Res Commun 31:115–120. https://doi.org/10.1007/s11259-007-0074-8
Theron A, Tintinger GR, Anderson R (2012) R: Harmful interactions of non-essential heavy metals with cells of the innate immune system. J Clin Toxicol. https://doi.org/10.4172/2161-0495.S3-005
Descotes (2004) Definition, history, and scope of immunotoxicology. In: Descotes J (ed) Immunotoxicology of drugs and chemicals: an experimental and clinical approach (Chap. 1), vol 1. Elsevier, Amsterdam, pp 1–18
Smith DA, Germolec DR (1999) Introduction to immunology and autoimmunity. Environ Health Perspect 107(Suppl 5):661–665. https://doi.org/10.1289/ehp.99107s5661
Watad A, Azrielant S, Bragazzi NL, Sharif K, David P, Katz I, Aljadeff G, Quaresma M, Tanay G, Adawi M, Amital H, Shoenfeld Y (2017) Seasonality and autoimmune diseases: the contribution of the four seasons to the mosaic of autoimmunity. J Autoimmun 82:13–30. https://doi.org/10.1016/j.jaut.2017.06.001
Vojdani A, Vojdani E (2021) The role of exposomes in the pathophysiology of autoimmune diseases I: toxic chemicals and food. Pathophysiology 28:513–543. https://doi.org/10.3390/pathophysiology28040034
Zhang Y, Lawrence DA (2016) Metals and autoimmune disease. In: Vohr HW (ed) Encyclopedia of immunotoxicology. Springer, Berlin
Rowley B, Monestia M (2005) Mechanisms of heavy metal-induced autoimmunity. Mol Immunol 42(7):833–838. https://doi.org/10.1016/j.molimm.2004.07.050
Bolon B (2012) Cellular and molecular mechanisms of autoimmune disease. Toxicol Pathol 40(2):216–229. https://doi.org/10.1177/0192623311428481
Getts DR, Spiteri A, King NJC, Miller SD (2020) Microbial infection as a trigger of t-cell autoimmunity. In: Rose N, Mackay I (eds) The autoimmune diseases, 6th Edition, Chapter 21. Academic Press, New York, pp 363–374
Faber S, Zinn GM, Kern JC 2nd, Kingston HM (2009) The plasma zinc/serum copper ratio as a biomarker in children with autism spectrum disorders. Biomarkers 14(3):171–180. https://doi.org/10.1080/1354750090278374
Bahi GA, Boyvin L, Méité S, M’Boh GM, Yeo K et al (2017) Assessments of serum copper and zinc concentration, and the Cu/Zn ratio determination in patients with multidrug resistant pulmonary tuberculosis (MDR-TB) in Côte d’Ivoire. BMC Infect Dis 17:257. https://doi.org/10.1186/s12879-017-2343-7
Kazi Tani LS, Gourlan AT, Dennouni-Medjati N, Telouk P, Dali-Sahi M, Harek Y, Sun Q, Hackler J, Belhadj M, Schomburg L, Charlet L (2021) Copper isotopes and copper to zinc ratio as possible biomarkers for thyroid cancer. Front Med 8:698167. https://doi.org/10.3389/fmed.2021.698167
Böckerman P, Bryson A, Viinikainen J, Viikari J, Lehtimäki T, Vuori E, Keltikangas-Järvinen L, Raitakari O, Pehkonen J (2016) The serum copper/zinc ratio in childhood and educational attainment: a population-based study. J Public Health 38(4):696–703. https://doi.org/10.1093/pubmed/fdv187
Büchl A, Hawkesworth CJ, Ragnarsdottir KV, Brown DR (2008) Re-partitioning of Cu and Zn isotopes by modified protein expression. Geochem Trans 9:11. https://doi.org/10.1186/1467-4866-9-11
Erickson KL, Medina EA, Hubbard NE (2000) Micronutrients and innate immunity. J Infect Dis 182(Supplement 1):5–10. https://doi.org/10.1086/315922
Osredkar J, Sustar N (2011) Copper and zinc, biological role and significance of copper/zinc imbalance. J Clin Toxicol. https://doi.org/10.4172/2161-0495.S3-001
Chandra RK (1990) Trace element regulation of immunity and infection. In: Tomita H (ed) Trace elements in clinical medicine. Springer, Tokyo
Chaturvedi UC, Shrivastava R, Upreti RK (2004) Viral infections and trace elements: a complex interaction. Curr Sci 87(11):1536–1554
Djoko KY, Ong CL, Walker MJ, McEwan AG (2015) The role of copper and zinc toxicity in innate immune defense against bacterial pathogens. J Biol Chem 290(31):18954–18961. https://doi.org/10.1074/jbc.R115.647099
Kehl-Fie TE, Chitayat S, Hood MI, Damo S, Restrepo N, Garcia C, Munro KA, Chazin WJ, Skaar EP (2011) Nutrient metal sequestration by calprotectin inhibits bacterial superoxide defense, enhancing neutrophil killing of Staphylococcus aureus. Cell Host Microbe 10(2):158–164. https://doi.org/10.1016/j.chom.2011.07.004
Lahr J, Kooistra L (2010) Environmental risk mapping of pollutants: state of the art and communication aspects. Sci Total Environ 408(18):3899–3907. https://doi.org/10.1016/j.scitotenv.2009.10.045
Whitty CJ, Watt FM (2020) Map clusters of diseases to tackle multimorbidity. Comments Nat 579:494–496. https://doi.org/10.1038/d41586-020-00837-4
Pinto MMSC, da Silva EAF, Silva MMVG, Melo-Gonçalves P, Candeias C (2014) Environmental risk assessment based on high-resolution spatial maps of potentially toxic elements sampled on stream sediments of Santiago, Cape Verde. Geosciences 4:297–315. https://doi.org/10.3390/geosciences4040297
Darnley AG, Björklund A, Bølviken B, Gustavsson N, Koval PV, Plant JA, Steenfelt A, Tauchid M, Xie X, Garrett RG, Hall GEM (1995) A global geochemical database for environmental and resource management: final report of IGCP Project 259. Earth Sciences, 19. UNESCO, Paris, p 122
Wang X, Zhang Q, Zhou G (2007) National-scale geochemical mapping projects in China. Geostand Geoanal Res 31(4):311–320. https://doi.org/10.1111/j.1751-908X.2007.00128.x
Xie X, Wang X, Zhang Q, Zhou G, Cheng H, Liu D, Cheng Z, Xu S (2008) Multi-scale geochemical mapping in China. Geochemistry 8:333–341. https://doi.org/10.1016/j.gexplo.2013.06.003
Cheng Z, Xie X, Yao W, Feng J, Zhang Q, Fang J (2014) Multi-element geochemical mapping in Southern China. J Geochem Explor 139(100):183–192. https://doi.org/10.1016/j.gexplo.2013.06.003
Rawlins BG, McGrath SP, Scheib AJ, Breward N, Cave M, Lister TR, Ingham M, Gowing C, Carter S (2012) The advanced soil geochemical Atlas of England and Wales. British Geological Survey, Keyworth
Reimann C, de Caritat P (2017) Establishing geochemical background variation and threshold values for 59 elements in Australian surface soil. Sci Total Environ 578:633–648. https://doi.org/10.1016/j.scitotenv.2016.11.010
Angelé-Martínez C, Goodman C, Brumaghim J (2014) Metal-mediated DNA damage and cell death: mechanisms, detection methods, and cellular consequences. Metallomics 6(8):1358–1381. https://doi.org/10.1039/c4mt00057a
Hegde ML, Hegde PM, Rao KS, Mitra S (2011) Oxidative genome damage and its repair in neurodegenerative diseases: function of transition metals as a double-edged sword. J Alzheimer’s Dis 24(2):183–198. https://doi.org/10.3233/JAD-2011-110281
Amarasekera M, Prescott SL, Palmer DJ (2013) Nutrition in early life, immune-programming and allergies: the role of epigenetics. Asian Pac J Allergy Immunol 31(3):175–182
Jain N (2020) The early life education of the immune system: Moms, microbes and (missed) opportunities. Gut Microbes 12(1):1824564. https://doi.org/10.1080/19490976.2020.1824564
Scanlon ST (2020) The immune system’s first Steps. Science 368(6491):598–599. https://doi.org/10.1126/science.abc3140
Acknowledgements
Part of this work was done during the tenure of a research fellowship at the Institute of Geosystems and Bioindication (IGeo), Technical University of Braunschweig, Germany, sponsored by the Alexander von Humboldt Foundation. Manuscript compilation was done at the Mangosuthu University of Technology and the conference offices of the Gooderson Tropicana Hotel (GTH) in Durban, South Africa. Dr. Beth McClenaghan (Geological Survey of Canada) is thanked for rekindling my interest in the ‘unknown aetiologies’ theme. Finally, my thanks go to the anonymous reviewers whose insightful critiques and suggestions helped produce a much improved manuscript.
Funding
Funding provided by the Alexander von Humboldt Foundation during the tenure of a research fellowship at the Technical University of Braunschweig, Germany, assisted with the preparation of this manuscript.
Author information
Authors and Affiliations
Contributions
All contributions to the manuscript were made by the sole author.
Corresponding author
Ethics declarations
Competing interest
The author declares he has no other relevant financial or non-financial interests to declare.
Ethical approval
No ethical approval was required for this study since no human participants, their data or biological materials were involved. No experimental work involving animals was conducted in this study.
Consent to participate
The work reported in this manuscript did not involve human subjects, and informed consent to participate was not required.
Consent to publish
The work reported in this manuscript did not involve human subjects, and informed consent to publish was not required.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Davies, T.C. The position of geochemical variables as causal co-factors of diseases of unknown aetiology. SN Appl. Sci. 4, 236 (2022). https://doi.org/10.1007/s42452-022-05113-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s42452-022-05113-w