Maternal factors and T1DM risk.
\r\n\tWater occupies about 71% of the surface and 93% of the planet's volume.
\r\n\tSince the beginning of its formation, about three billion years ago, the hydrosphere - as envelope of the terrestrial ellipsoid - has remained constant from a quantitative point of view, modifying only the ratio of the stretches of the planetary ocean and land and the proportion of the states of the water aggregation: gaseous, liquid and solid.
\r\n\tThe hydrological cycle trains only a portion of the hydrosphere repeats itself annually and presents itself as a huge planetary plant that for billions of years operating uninterruptedly on the basis of solar energy and gravity, providing freshwater resources for the maintenance and perpetuation of life beyond the planetary ocean.
\r\n\tLately, water resources, highly influenced by the hydrologic cycle, play a role in the agriculture economic development. As it is shown by the intergovernmental panel on climate change report, the phenomenon of changing the climate and land use is set way to exacerbate an already serious situation of water supply for various users. In this context, the scientific investigations on the issue of sustainable use of water are timely and important. Improvement of water management involves the accurate estimation of consumptive uses. Consequently, the purpose of this book is to know the achievements of scientists and academicians all over the world to promote and share new issues on various topics related to evapotranspiration.
Type 1 diabetes mellitus (T1DM) is the most common endocrinopathy in pediatric age group, due to an autoimmune process characterized by a selective destruction of insulin producing pancreatic β-cells progressing over different stages [1]. T1DM develops in genetically susceptible subjects by activation of so far uncharacterized environmental factors that trigger an inflammatory process with infiltration of pancreatic islets and subsequent loss of β-cells. Despite the growing incidence of T1DM, the causative mechanisms are not completely defined up to now, and the identification of factors triggering the immune process represents a challenge for clinical immunologists, with practical, diagnostic and therapeutic implications [2,3]. The clinical onset of T1DM is preceded by an asymptomatic period characterized on pathology grounds by insulitis, i.e. an infiltration of the pancreatic islet of Langerhans by CD4+, CD8+ T lymphocytes (both Th1 and Th2 subsets), B lymphocytes, macrophages and dendritic cells. T lymphocytes can differentiate into 2 major subsets: Th1, producing IL-2 and IFN-γ, and Th2, secreting mainly IL-4. All these cells produce cytokines which can be directly cytotoxic to β-cells or play an indirect role on β-cell destruction influencing some cells of the immune system, then resulting in either acceleration or arrest of the immune attack [4]. Worldwide T1DM incidence has grown more than two to three fold during the last decades, particularly in Finland, where T1DM incidence has increased from 12 to 63 cases per 100,00 [5]. A raising incidence has also been reported in Italy, where Sardinia Region shows an incidence rate similar to Finland, therefore is called “Hot Spot” [6,7]. Interestingly, this rise of incidence was not followed by a parallel increased frequency of the major risk genes [8]. T1DM can be defined as a polygenic disease, and the genes mainly involved include Major Histocompatibility Complex (MHC) class II (DR and DQ) on chromosome 6, responsible for 40% of genetic risk, and insulin gene located on chromosome 11. Moreover thanks to whole genome screening techniques more than 15 loci have been identified. In particular, an allele of the gene for a negative regulator of T-cell activation, i.e. Cytotoxic T Lymphocyte Antigen 4 (CTLA-4), on chromosome 2q33, and a variant of PTNP22 gene encoding LYP (a suppressor of T cell activation) and ILrRA gene are considered as other important susceptibility loci [8]. Recently, the prevalence of MHC class II genes seems to be decreasing [9]. Moreover, studies in identical twins showed a concordance rate ranging from 27 to 61%, otherwise lower in non-identical twins (3.8-12%) [10]. Despite the growing incidence of T1DM, the causative mechanisms are not completely defined up to now. The paradigm of autoimmune dysregulation has not offered a clear explanation for its raising incidence.
The reported discrepancy between higher incidence of T1DM without concomitant shift in the frequency of susceptibility genes, suggests that environmental factors play a key role in the development of the autoimmune process leading to clinical onset of the disease [11]. Moreover the shift to younger age at T1DM clinical onset is caused by environmental risk factors accelerating the on-going β-cell destructive process up to clinical disease even in children with lower levels of genetic risk otherwise exposed to such factor [12-14].
The high T1DM incidence is a phenomenon of the 20th century, even if the disease has been described already in antiquity. This increasing incidence and its difference among neighboring regions strengthens the role of multiple environmental factors in the pathogenesis of T1DM. In the present chapter the main environmental factors involved in T1DM pathogenesis according to the most relevant scientific evidence will be considered. The main topics are: perinatal and socioeconomic factors, hygiene hypothesis, dietary components both in mother and in children, gut permeability, infectious agents, vaccinations, obesity and Accelerator Hypothesis, epigenetic.
Environmental risk factors combined with genetic susceptibility are thought to contribute to the development of autoimmune destruction of pancreatic β-cells. The rapid increasing incidence of T1DM, especially in the youngest age group [15], cannot be explained by genetic factors. It has been postulated that gestational or perinatal events could trigger T1DM.
It has been reported that certain infections during pregnancy contribute to an increased risk of T1DM in the offspring. The first report of a link between infection and diabetes was the exposure to rubella in intrauterine life. Studies showed that about 20% of children born with congenital rubella develop T1DM during infancy [16,17]. Other reports describe an increased risk of T1DM if the mother has had an enterovirus infection during pregnancy [18,19]. Anyway these studies are not confirmed by all investigators [20,21] and whether enterovirus infection during the first trimester of pregnancy is associated with increased risk for T1DM in the offspring remains controversial up to now [21]. Not only congenital infections are associated with the risk of T1DM, but also perinatal infections are discussed as protective factors or triggers of the disease [22]. Certain studies reported that two infections in the first year of life seem to be protective against T1DM, while neonatal respiratory diseases are associated with a increased risk of disease [22].
To explain the growing incidence in T1DM within the first year of life, it has been hypothesized that certain dietary nutrients could be protective for islet autoimmunity. Maternal intake of vitamin D is significantly associated with a decreased risk of islet autoimmunity in offspring, independent from HLA genotype, family history of T1DM, presence of gestational diabetes mellitus and ethnicity (adjusted HR=0.37; 95% CI 0.17-0.78). Instead, vitamin D intake via supplements, ω-3 fatty acid and ω-6 fatty acids intake during pregnancy are not associated with appearance of islet autoimmunity in offspring [23]. There is also an increased interest in nutritional factors in the first months of life as risk factors for T1DM. Some authors reported that children exposed to cereals between 0 and 3 months of life were more likely to develop islet cell auto-antibodies compared to those who were exposed during the fourth through sixth month [24]. Another study showed that ingestion of gluten-containing foods before 3 months of age was associated with increased islet cell autoimmunity compared to children who received only breast milk until 3 months of life. Then other studies showed that a high intake of cow’s milk could have a protective effect [25]. On the other hand, some authors claim that milk protein carries an increased risk of T1DM [26,27]. It is also been reported a correlation between a high intake of nitrosamines, nitrites and nitrates and T1DM [25,28][Table 1].
Protective effect | \n\t\t\tVitamin D intake | \n\t\t\tHR* | \n\t\t\tCI** | \n\t\t
0.49;95% | \n\t\t\t(0.17-0.78) | \n\t\t||
Increased risk | \n\t\t\tInadequate prenatal care | \n\t\t\t0.53;95% | \n\t\t\t(0.40-0.71) | \n\t\t
Medicaid insurance | \n\t\t\t0.67;95% | \n\t\t\t(0.58-0.77) | \n\t\t|
Unmarried mother | \n\t\t\t0.79;95% | \n\t\t\t(0.69-0.91) | \n\t\t|
Mother\'s age ≥ 25 yrs | \n\t\t\t1.28;95% | \n\t\t\t(1.13-1.45) | \n\t\t|
Mother\'s BMI ≥ 30 kg/m2\n\t\t\t | \n\t\t\t1.29;95% | \n\t\t\t(1.01-1.64) | \n\t\t|
Mother\'s age ≥ 35 yrs | \n\t\t\t1,32;95% | \n\t\t\t(1.01-1.64) | \n\t\t
Maternal factors and T1DM risk.
HR*: Hazard Ratio; CI**: Confidence Interval
An association between birth weight and risk for T1DM has been postulated. A meta-analysis study of 12.807 cases of T1DM found an increased risk in children heavier at birth: children with birth weight from 3,5 to 4 Kg showed an increased risk of 6% (OR 1.06; 95% CI 1.01-1.11) (p=0.02) and children with birth weight over 4 Kg have an increased risk of 10% (OR 1.10; 95% CI 1.04-1.19) (p=0.003), compared to children weighing 3 to 3,5 Kg at birth [29]. Several studies support this link [30], while others did not find any association with T1DM [31].
Another controversial question is the role of caesarean section. A meta-analysis study of 9.938 cases reported a 20% increase in the risk of childhood-onset T1DM (adjusted OR 1.19, 95% CI 1.04-1.36, p=0.01) [32], while other authors did not find any association between caesarean delivery and risk for T1DM [33].
It is also been investigated the association between blood incompatibility and risk for T1DM: ABO incompatibility was related to an increased risk for the disease in some studies [34], while others found an association just only with Rhesus immunization [33].
A report have shown that also neonatal jaundice of unknown cause confers an increased risk for T1DM [34].
Another topic discussed is about the stress events. Some authors found an increased risk of T1DM in children diagnosed between 5 to 9 years of age who experienced stress events [25], while others showed that stressful events during the first two years of life increased the risk of the disease, probably by affecting the autoimmune pathogenetic process [35]. Finally, some investigators have reported a decreased risk for T1DM in children of prenatal smokers [36,37].
Other factors such as maternal age may contribute to increase the risk for T1DM. It is been observed an increased incidence of disease in children born to older mother [25,34,38,39]. These data are confirmed by a population-based case-control study in Washington State on children younger than 19 years from 1987 to 2005, an increased OR in children of mothers older than 25 years (age 25-34 HR=1.28; 95% CI 1.13-1.45; age≥35 HR=1.32; 95% CI 1.10-1.58) has been reported [31]. Risk for T1DM is also been related with maternal weight: mother with a BMI of 30 Kg/m2 or higher had an increased ORs for the disease (BMI≥30: OR 1.29; CI 1.01-1.64). Pregnancy-related factors also include birth order: the first-born child has the highest risk for T1DM and the risk decreases with number of children born [38,40]. Several studies have found an inverse association between increasing number of siblings and risk of T1DM [31,37,41,42]. An inverse correlation has also been observed with lower economic status or care access, such as unmarried mother (OR 0.79; 95% CI 0.69-0.91), inadequate prenatal care (OR 0.53; 95% CI 0.40-0.71), or Medicaid Insurance (OR 0.67; 95% CI 0.58-0.77) [31]. Another widely discussed topic is tobacco exposure, as influencing immune system, and represents a risk factors for T1DM. It’s been questioned if the decrease of passive smoking in children may be a predisposing factor for the increasing incidence of T1DM, in according with the hygiene hypothesis. To clarify this aspect, ABIS, a population-based prospective long term cohort study, revealed no difference in prevalence of immunological markers (GAD and IA-2 antibodies) between tobacco smoke-exposed and non-exposed children [43].
Recently, attention has been focused on lifestyle changes as a major factor in the rise of T1DM frequency, as well as other immune or allergic diseases [44]. Improved hygiene and living conditions decreased the frequency of childhood infections, leading to a modulation of the developing immune system and increasing risk for autoimmune and allergic diseases such as T1DM and asthma [45]. This theory, called “Hygiene Hypothesis”, finds its roots in the 1870 when Charles Harris Blackley noticed that aristocrats and city dwellers were more likely to get hay fever than farmers [46]. One century later, in 1966, Leibowitz and colleagues noted that in Israel the incidence of multiple sclerosis (MS) was positively related to levels of sanitation [47]. More recently, Correale et al. showed that patients with multiple sclerosis who become infected with helminths have a strikingly reduced rate of disease progression [48]. However, the term “Hygiene Hypothesis” was proposed in 1989 by Strachan, who noted that hay fever was less frequent in families with many siblings [49].
In accordance to hygiene hypothesis, several studies report the lowest incidence of T1DM in areas with poorest hygiene condition [50,31]. These data are supported by the experiments in non-obese diabetic (NOD) mice (mice that spontaneously develop a condition resembling T1DM) and in BB rats, in which caesarean delivery and isolated living conditions increased the incidence of diabetes from 40% to 80%. In humans, several studies reported a significant inverse correlation between the incidence of T1DM and certain socioeconomic index (unemployment, lack of a car, crowded housing conditions, and living in rental housing rather than purchased property) [50,51]. In the people living in Washington state from 1987 to 2005, D’Angeli and colleagues found a negative association between T1DM and some indicators of lower economic status or care access, such as an unmarried mother (OR 0.79%; 95% CI 0.69-0.91), inadequate prenatal care (OR 0.53%; 95% CI 0.40-0.71), or Medical insurance (OR, 0.67; 95% CI 0.58-0.77) [31]. Young children with older brothers and sisters and sharing the bedroom, as well as those who attended a day-care centre during the first six months of life showed a lower incidence of T1DM later in life than children who did not attend a day-care centre and who had no older siblings [52].
A topic discussion of our day is whether the reduced exposure to certain infections, as result of improving socioeconomic conditions, may be responsible for the increased incidence in diabetes and other autoimmune conditions such as systemic lupus erythematosous and multiple sclerosis [45,53-55]. As regards the rise in the disease in Western Europe and the USA during the twentieth century strikingly correlates with the decline of helminths infections, particularly E. vermicularis [56]. Experimental studies showed in Non-Obese Diabetic (NOD) mice, infected with mycobacterium or helminthes, a reduced frequency of T1DM [54,57-58]. Moreover, infection of 4-5 week-old NOD mice with Schistosoma mansoni or injection of soluble eggs (SEA) seems to prevent diabetes clinical onset. One possible explanation is that helminths antigens are able to induce either IL-10 production by dendritic cells and activation of Natural Killer T cells (NKTs) and Regulatory T cells (TRegs). Considering the role of IL-10 in delaying or inhibiting the host immune response and limiting tissue pathology [59-61], exogenous administration of IL-10 inhibits the development of diabetes in NOD mice [62]. Moreover, some bacterial infections can inhibit diabetes development in NOD mice. In mice infected with S. typhimurium the protective mechanism could be the key role of dendritic cells in modulating the trafficking of diabetogenic T cells to the pancreas [63]. Another way by which bacteria and viruses could protect against autoimmune disorders is related to Toll-Like Receptor (TLRs). In fact, when TLRs bind bacterial ligands, stimulate mononuclear cells to produce several cytokines, which down-regulate the autoimmune response. Wen and colleagues showed that Specific-Pathogen Free (SPF) NOD mice are protected from the disease when knocked-out from the MyD88 gene, encoding an adaptor for multiple TLRs [64]. Modification of the immune system in knocked out MyD88 seriously impairs the interactions between the immune system and microbiota. Due to these positive results after treatments with a mycobacterium extract [65], helminthiases treatment and probiotics [66,67] in patients with atopic dermatitis and multiple sclerosis, have recently been reported [68,69]. Instead, vaccination with bacille Calmette-Guèrin produced negative results in patient with T1DM [70,71].
Nowadays a topic discussion is about the role of gut bacteria in the control of autoimmune diseases. In fact changes in the composition of the gut flora influence the development of autoimmune and allergic diseases. It has been observed that the use of lactobacilli, derived from the gut, decreases the incidence of diabetes in NOD mice [72]. More recently, Takiishi et al. showed that treatment of NOD mice with Lactococcus lactis, a common and food-grade commensally bacterium genetically modified, which is able to secrete IL-10 and human pro-insulin auto-antigen, can revert autoimmune diabetes in newly diagnosed NOD mice, by increasing frequency of TRegs [73]. Dan Litman’s group showed that a single commensally bacteria, i.e. segmented filamentous bacteria (SFB), is able to drive the appearance of CD4+ T helper cells producing interleukin 17 (IL-17) and IL-22 (Th17 cells) in the lamina propria, thereby influencing the microbiota equilibrium [74]. On the other hand, colonization of germ-free mice with a defined intestinal flora resulted in Treg generation, expansion and activation in the lamina propria [75]. Based on these encouraging results in animal models, the use of probiotics to delay or prevent T1DM in humans has become an area of interest. The PRODIA study, currently ongoing in Finland, is investigating whether, the use of probiotics during the first 6 months of life decreases the clinical onset of T1DM in children with genetic susceptibility [76].
The T1DM is a chronic disease characterized by a preclinical phase in which environmental exposure, such as food, can contribute to the development of the autoimmune process of pancreatic β-cells destruction. Recent studies have focused upon the role of breastfeeding, introduction of cow\'s milk, wheat/cereals/gluten, vitamin D and E, ω-3 fatty acids [77]. Some studies suggest that already during pregnancy, low maternal consumption of vegetables may influence the future of the unborn [78,79].
The influence of breastfeeding on the development of diabetes remains a controversial issue; for some it seems to have a protective role, for others, a predisposing role, for others no effect [80]. Gerstein conducted in 1993 a meta-analysis of retrospective case-control studies showing that breast-feeding for short periods (<3 months) is associated with the development of T1DM, with an odds ratio (OR) of 1.43 [81]. A Finnish study has shown that early introduction of cow milk-based formula was associated with an increased risk of β-cell autoimmunity in genetically predisposed children, but the duration of breastfeeding was not associated with an increased risk of autoimmunity in children with first-degree relatives with T1DM in Germany, Australia and USA. The risk of diabetes seems to be higher in patients with first-degree relatives with T1DM, and this risk is increased in carriers of HLA genotype [82-84]. The positive correlation between short duration of breastfeeding and the development of diabetes has been studied in non-diabetic children at the age of 5 years, evaluating the presence of circulating antibodies predictive of the disease [Auto-Antibodies to Insulin (IAA), Glutamic Acid Decarboxylase Antibodies (GADA) and Protein Tyrosine Phosphatase-like (IA-2A)]. This study demonstrates the long-term increased risk of developing T1DM with the early introduction of formula milk. A protective role of breast milk which, for the presence of cytokines and growth factors, promote the maturation of the intestinal mucosa and the development of the immune system has been suggested [85]. Conflicting results can be explained by observing the many differences in feeding practices between the different countries. There is variation between countries and cultures in the proportion of babies first introduced to milk-based formula and there are differences in the kind of complementary food that infants who are not first exposed to milk-based formula [85].
It has been known as T1DM is connected with other autoimmune diseases, such as thyroiditis or celiac disease. Two prospective studies in USA and Germany showed a high risk for the development of β-cells auto-immunity when gluten’s introduction happens before the fourth month rather than after the seventh; moreover this risk is similar when gluten ingestion starts before the third month [24,86]. Several studies were aimed to explain the etiology of this phenomenon. Simpson et al. compared the levels of antibodies to a wheat storage globulin homologue of Glo-3A, which is a non-gluten component of the wheat protein matrix. They have shown that in children with islet auto-immunity, the antibody titer was directly linked to the early introduction of gluten, and inversely to breastfeeding duration [87]. Not all authors agree with this association; a prospective analysis from the DIPP study did not show a correlation between early or late introduction of gluten and subsequent development of pancreatic β-cells autoimmunity [88]. Mojibian et al. hypothesized that the passage of gliadin (a polypeptide of the wheat) through the intestinal epithelial barrier may trigger an inflammatory response, and then an autoimmune disease, in genetically predisposed individuals. The passage of protein molecules is facilitated by inflammation produced by intestinal infections. The location of an uncovering receptor for Coxsackie and Adenovirus at the level of tight junctions may explain the development of T1DM. The bowel inflammation and T-cells activation by gluten could activate and potentiate β-cell auto-immunity, like viral infections [89]. Recently a study in NOD mice demonstrated that there is a statistically significant protection from diabetes in mice that received gluten-free diet [90].
Some studies have shown an increased risk of developing diabetes in children with low intake of vitamin D. An European case-control study has quantified the reduction in risk with an OR of 0.67 (95% CI 0.53-0.86) in children supplemented with vitamin D [Table 2]. Also a Finnish study showed a protective role of vitamin D, with an OR equal to 0.12 (95% CI 0.03-0.51), comparing children who received regular doses of 2000 IU/day rather than 400 IU/day, and an OR of 3 (95% CI 1.0-9.0) comparing children with an irregular supplementation rather no supplementation with vitamin D [91,92]. Simpson et al. followed from 1993 to 2011 2,664 children at increased risk of T1DM, monitoring the intake of vitamin D and blood levels of 25(OH)D. They have shown that vitamin supplementation is not associated with an increased protection from autoimmune phenomena [93]. Vitamin D deficiency predisposes individuals to type 1 and type 2 diabetes, and receptors for its activated form 1α25-dihydroxyvitamin D3 have been identified in β-cells and immune cells. In some populations, T1DM is associated with certain polymorphisms within the vitamin D receptor gene. In studies in non-obese diabetic mice, pharmacological doses of 1α25-dihydroxyvitamin D3, or its structural analogues, have been shown to delay the onset of diabetes, mainly through immune modulation [94]. Human studies reported that vitamin D is able to modulate the immune response by suppressing pro-inflammatory cytokines and promoting the secretion of anti-inflammatory ones [23]. Therefore it seems appropriate the supplementation with vitamin D in countries with an increased risk of deficiency, especially if T1DM incidence is high. Other authors emphasized the important role of vitamin E for its antioxidant function; Vitamin E ameliorates oxidative stress in T1DM patients and improves antioxidant defense system [95].
European study | \n\t\t\tVitamin D intake | \n\t\t\tHR | \n\t\t\tCI | \n\t\t
0.67;95% | \n\t\t\t(0.53-0.86) | \n\t\t||
Finnish study | \n\t\t\tVitamin D intake (2000UI/d) | \n\t\t\t0.12;95% | \n\t\t\t(0.03-0.90) | \n\t\t
Vitamin D intake (400UI/d) | \n\t\t\t3.00;95% | \n\t\t\t(1.0-9.0) | \n\t\t
Child\'s diet and T1DM risk: protective effect with Vitamin D supplementation
An observational study in children at high risk of T1DM reported that ω-3 fatty acid intake is not associated with progression to overt disease; however the protective influence of ω-3 fatty acids remains controversial. On the other hand, ω-6 fatty acids seem to exert an opposite role. It has been argued that use of cod liver oil in the first year of life reduces the risk of the disease. The case-control study DAISY [Diabetes AutoImmunity Study in the Young] demonstrates that use of ω-3 fatty acids, between 1 and 6 years, exerts a risk reduction with an hazard ratio of 0.45 [96,97]. The immunomodulatory role of ω-3 fatty acids is quite similar to the role exerted by Vitamin D. Conversely, ω-6 fatty acids like arachidonic acid promote the pro-inflammatory cytokine prostaglandin E2 with subsequent development of β-cell autoimmunity in genetically predisposed subjects [23]. Recently, an interesting case-control study of 298 Italian children aged 0-15 years (145 affected by T1DM) showed a significant association, dose-response, between frequency of T1DM and meat consumption. The association proposed by Benson et al. between T1DM and daily consumption of water containing nitrates, nitrites and nitrosamines is intriguing [98,99].
In the recent years a topic discussion is about the link between T1DM and gut. The role of gut as a regulator of T1DM was first suggested in animal studies. Changes affecting the gut immune system modulated the incidence of diabetes. In particular structural changes, such as a decreased expression of tight junctions (TJ) proteins claudin-1 and occludin, together with increased gut permeability were noted in the intestinal morphology of Bio-Breeding (BB) rats, compared with Wistar rats [100,101]. These data are supported by the observations that early onset of autoimmune diabetes in BB-rats was associated with high gut permeability [102] and in NOD-mouse increased intestinal permeability precedes the clinical onset of T1DM [103]. In humans, studies showed that gut permeability, measured by the lactulose-mannitol test, is increased in T1DM patients [104,105] and can precede clinical onset [106]. These results are supported by the discovery of high serum zonulin concentrations, a novel member of tight-junction protein that correlates with increased ratios in sugar permeability testing, in patients with T1DM [105] and in subjects at risk of T1DM i.e. β-cell autoantibody-positive individuals [106]. Based on these findings, Wats et al. showed that the administration of zonulin antagonist reduced the cumulative incidence of T1DM in diabetic-prone rats [107]. It has also been hypothesized that changes in the normal flora may contribute to the development of T1DM by affecting intestinal permeability. Duodenal administration of Lactobacillus plantarum increased the expression of epithelial TJ proteins occluding and Zo-1 in the biopsies obtained by human volunteers [108]. Moreover, antibiotic treatment that impairs intestinal bacteria, protects from autoimmune diabetes in BB-rat model [109]. In DP-rats (Diabetes-prone rats), the onset of T1DM could be delayed by the administration after weaning of Lactobacillus johnsonii, isolated from DR-rats (Diabetes Resistant Bio-Breed rats) [110]. The composition of intestinal microbiota may not only affect permeability but may also have immune-modulating effects. Recent studies suggest for intestinal microbiota an important regulator role of Th17 immunity in the gut [74]. It has been reported that Lactobacillus johnsonii enhances Th17 differentiation of T cells upon TCR stimulation [112]. The up-regulation of IL-17 immunity in the mucosal surface has been shown to activate an antimicrobial response together with mucosal repair mechanisms and support of the gut barrier [111]. Also virus, such as rotavirus and enterovirus act as promoters of the diabetogenic gut environment with high intestinal permeability, enhanced immune activation, and via the gut-pancreas link, causing activation of β-cell autoimmunity in pancreatic lymph nodes [112]. It is also discussed the role of antiviral cytokines that damage barrier function [113] or the direct effect of virus, as suggested for Rotavirus and Coxsackie viruses [114,115]. The increased gut permeability in T1DM patients may be due to the uptake of dietary antigens causing improper immune activation and intestinal inflammation. Studies suggested that early exposure to dietary wheat may trigger β-cell auto-immunity in children at genetic risk [24,86]. In vitro, gliadin-stimulation of small intestinal biopsies taken from patients with T1DM, caused increase in T-cells and their activation markers, i.e. CD-25 and ICAM-1, promoting intestinal inflammation [116]. Gliadin may also induce an increase in intestinal permeability and zonulin released by binding to the chemokine receptor CXCR3 expressed by epithelial cells and T cells [117]. It has been noted that dietary prevention of diabetes in NOD-mice with a gluten-free diet was associated with a decrease in the number of ceacal bacteria [118]. In humans, epidemiological studies suggest that the short breastfeeding time and early feeding of cow milk (CM) proteins in the infancy increase the risk of diabetes [119]. This may be due to the lack of breastfeeding role of support epithelial and immunological maturation of gut, such as the gut closure [120] and the IgA system [121]. It has been hypothesized that CM may contain diabetogenic factors, such as immunogenic bovine insulin, that could trigger insulin-specific immunity in the gut and, in the context of impaired oral tolerance, contribute to expansion of this immune response against β cells [122]. Weaning to a hydrolyzed casein formula decreased the gut permeability [102] and led to lower expression of IFN-γ [123] in islet infiltrating lymphocytes of BB-rats, resulting in a 50% reduction in the development of autoimmune diabetes [102]. In humans, recent results of the TRIGR pilot study, have showed that weaning to hydrolyzed casein decreased the risk of β-cell autoimmunity by 40% in the infants at genetic risk [124]. In the FINDIA pilot study, the use of bovine-insulin-free whey-based formula, during the first 6 months of life, decreased the appearance of β-cell auto-antibodies by 3 age [125].
Several studies in humans and animal models have supported the hypothesis that infectious agents, in particular some viruses, can be considered as one among the environmental agents able to elicit or enhance the autoimmune response characterizing T1DM [44]. On the other hand viral infections could exert a protective role against auto-immunity [126]. This opposite scenario might be explained by the type of infecting virus, the immune status of the host and the timing of infection [127]. A possible explanation could be the significant changes in human living standards (i.e. sewage treatment, availability of microbiologically pure water) during the last century, followed by reduced repeated exposure to fecal-oral transmitted agents particularly early in life.
The major obstacle in clinical research is represented by the limited availability human samples. In fact the pancreas is very difficult to access, and routine biopsy aimed to study the role of viruses in the target organ cannot be proposed, since the majority of newly-diagnosed patients are children.
However five lines of evidence link virus to T1DM [128]:
Some viruses are able to destroy β-cells and cause mononuclear infiltration
Experimental animal models report development of T1DM in mice infected with different strains of Picornaviruses
Some viral infections in humans have been followed by T1DM (i.e. congenital rubella)
Direct isolation of viruses from humans or animals with T1DM has been documented
Virus DNA or RNA are able to initiate antiviral immune response which cross-reacts with insulin or other components within or on the surface of β-cells.
Viruses can directly damage β-cells or induce a strong cellular immune response leading to progressive lack of insulin and development of clinical signs and symptoms of the disease. Besides direct cytotoxic effect, other mechanisms involved in β-cell destruction are molecular mimicry and bystander activation [129].
The hypothesis that viral infections are capable of triggering islet auto-reactivity has been proven by several evidences both in humans and in animal models. The host immune response to viruses consists of the secretion of interferon-γ, acting as initiator of inflammation. In the pancreas interferon-γ up-regulates MHC class I molecules on β-cells, making them vulnerable to autoimmune attack [130]. Up-regulation of MHC class I molecules is followed by lymphocytic infiltration in β-cells, as reported also in humans [131]. Moreover viral particles or even isolate live virus have been detected in pancreas from patients deceased at clinical onset of T1DM.
Another evidence strengthening the association between viruses and T1DM is the identification of 4 protective genetic variations of IFIH1 gene, responsible for interferon production after viral infection [132]. Individuals with IFIH1 predisposing alleles have higher IFIH1 levels, while individuals with protective alleles have lower IFIH1 levels. After a HEV infections, the predisposed group showed increased stimulating capacity of dendritic cell, with production of pro-inflammatory cytokines and development of T1DM. The opposite scenario has been reported in the protected group.
The key role of viruses as trigger of autoimmune response may result from molecular similarities between viral antigens and host cell auto-antigens, otherwise defined as “Molecular Mimicry”. These similarities are responsible for a break of the immune tolerance to endogenous auto-antigens. In particular, analogies between an epitope of Coxsackie B virus (P2-C 35-43) and an epitope of GAD 65 auto-antigen (GAD 65 258-266) has been reported also in humans [133]. Molecular mimicry is able to enhance or accelerate autoimmune process, however it does not start auto-immunity.
Another link between viruses and auto-immunity is the so called “Bystander Activation”. Pre-existing auto-reactive T-cell precursors, activated by viral infections, become auto-aggressive and induce the autoimmune response. Bystander activation has been reported in animal model infected by Coxsackie B4 virus who later develop T1DM [134]. Molecular mimicry and bystander activation are not mutually exclusive.
The direct viral infection and lysis of β-cells has been reported in the so-called “Fulminant Diabetes” (FD). FD accounts for about 20% of diabetes mellitus in Japan and is characterized by extremely rapid and severe destruction of pancreatic β-cells in absence of insulitis, but with high titers of anti-enterovirus IgA, compatible with recurrent HEV infections [135].
Several viruses have been linked to T1DM, i.e Coxsackie, Mumps, Rubella, Cytomegalovirus, Retroviruses and Rotaviruses [136-139], otherwise several evidences link enteroviruses, in particular Coxsackie B4 virus to T1DM [140].
Human EnteroViruses (HEV) [141] are small, non-enveloped viruses (30 nm), characterized by an icosahedric capsid consisting of 60 capsomers; one capsomer comprises 4 structural proteins (VP1, VP2, VP3, VP4). HEV belong to the Picornaviridiae family and 5 different species are recognized: Poliovirus and HEV A, B, C, D. Enteroviruses are ubiquitous and transmitted by faecal-oral route, and characterized by a great genetic variability and consequent broad spectrum of tissue tropism and pathological effects. HEV infections are usually asymptomatic or characterized by fever, malaise, sometimes respiratory involvement or cutaneous Rash. More severe diseases such as meningitis, encephalitis and pericarditis have been reported.
Six different serotypes characterize Coxsackie virus B (CVB 1-6); the B4 serotype is defined “diabetogenic” [142]. Affected patients harbor enterovirus RNA homologous to that of Coxsackie B4 in peripheral blood mononuclear cells [143], and in small intestine samples, suggesting a persistent enterovirus infection [144].
Recently direct evidence of Coxsackie B4 enterovirus infection in human β-cells with reduced insulin secretion and islet inflammation mediated by natural killer cells has been provided [145-147].
It has been reported a protective role of viral infection in the development of T1DM. Studies in animal models report a protective effect of enterovirus infections when contracted precociously, before weaning, which disappears if the infection occurs thereafter [148]. A virus with protective effect exerts a inflammatory profile very different if compared to diabetogenic one, with opposite consequences on autoimmune reaction. The kind of virus, its β-cell affinity, and the timing of infection play a crucial role in T1DM occurrence. In fact proliferation virus-induced auto-reactive T cells after recurrent infections with protective viruses determine protection from β-cell autoimmune destruction with deviation of the auto-inflammatory response, a trafficking of auto-reactive T cells and a stimulation of Treg cells [127].
The role of vaccine in the development of T1DM has been matter of debate. In fact there is a temporal association between increased incidence of the disease after improvement of living conditions and reduction of infectious diseases in childhood, thanks to the widespread use of vaccines. Moreover, some vaccines prevent or induce T1DM in animal models. Furthermore, it has been postulated that only early vaccinations (i.e. within the first month of life) could prevent T1DM [149]. The same author reported a clusters of cases of T1DM 2-4 years post-immunization with pertussis, MMR, and BCG vaccine, but it remains to define the link between the haemophilus-vaccine and T1DM [150]. On the other hand, a large epidemiological study on all children born in Denmark from 1990 and 2000, for whom correct information about vaccine schedule and clinical diagnosis of T1DM 2 to 4 years after vaccination, revealed no significant association between vaccines and development of T1DM. Moreover, no evidence of any clustering of cases after vaccination with any kind of vaccine [151]. This nationwide cohort, together to the prospective and independent ascertainment of vaccination history and the time of T1DM diagnosis overcame the risk of selection bias and recall bias [151]. De Stefano et al., in a case-control study, didn’t support an association between any of the recommended childhood vaccines and increased risk of T1DM [152]. Similar results have been reported in a retrospective cohort study in active components of US Military between 2002-2008 [153]. Another retrospective cohort study in Sweden examining the risk of autoimmune and neurological disorders in people vaccinated against pandemic influenza A demonstrated no changes in the frequency of several autoimmune diseases, including T1DM [154].
The possibility that vaccination may increase the risk of T1DM has been evaluated in a few epidemiologic studies. Classen has provided the only evidence of a possible increased risk, but the nature of the evidence is strictly ecological, involving comparisons between countries or between different time periods in the same country. Such comparisons, however, may be influenced by many factors unrelated to vaccination, i.e. genetic predisposition. Moreover, similar ecological analyses did not found significant correlations between diabetes and BCG, pertussis, and mumps vaccine.
Recently, in Japan a case of fulminant T1DM has been reported after influenza vaccination [155]. On the other hand the absence of autoimmunity in this form of diabetes is recognized. The role of vaccinations in T1DM deserves attention. Even if vaccinations are not triggers of autoimmune process leading to overt diabetes, it is otherwise possible that in genetically predisposed subjects vaccine exposure could anticipate the clinical symptoms and therefore being associated to T1DM.
In the past decades a worldwide rising incidence of the disease has been reported [157], with a significant trend toward earlier age at diagnosis than previously observed [158]. This shift to a younger age at T1DM diagnosis could be explained by exposure to higher doses of several environmental factors, like viral infections, polluted air, and more recently, sedentary lifestyle [159-160]. In particular, physical inactivity results in obesity, whose incidence within pediatric age is dramatically rising [156,160,161]. In younger children obesity-induced insulin resistance exerts in metabolic β-cells up-regulation, accelerating their loss through glucotoxicity, and can potentially bring forward the earlier age of diabetes clinical onset, according to the so-called Accelerator Hypothesis [162].
The Accelerator Hypothesis, firstly postulated by Wilkins, argues that diabetes mellitus is a unique disorder of insulin resistance set against different genetic backgrounds, rather than two distinct diseases (type 1 and type 2), and focuses on the tempo of β-cell loss [162]. Therefore the concept of tempo might explain the commonality between type 1 and type 2 diabetes, which are distinguished only by the rate of β-cell loss and by the specific accelerator involved [163]. Three main accelerators play a pathogenetic role: the first is the intrinsic potential for β-cell apoptosis, a necessary but insufficient step in the development of diabetes. The second accelerator is insulin resistance secondary to obesity, and represents the link between type 1 and type 2 diabetes. Insulin resistance increases insulin secretory demands on β-cells and may trigger damage in these metabolically up-regulated cells by increasing antigen presentation. Insulin resistance is characterized by a decreased ability of insulin to stimulate the use of glucose by the muscle and adipose tissue, where the suppression of lipase controlled by insulin is impaired [164]. The consequent excessive supply of free fatty acids further affects glucose transportation in the skeletal muscles, and inhibits insulin activity [165]. In the liver, insulin resistance leads to increased hepatic glucose production, initially compensated by increased insulin secretion. If the process persists, glucotoxicity can occur, leading to chronic hyperglycemia and clinical diabetes [166]. The third accelerator is genetic susceptibility, predisposing to β-cell autoimmunity [167]. Several studies support the role of the Accelerator Hypothesis, showing that BMI increasing and precocious weight gain are inversely related to age at diagnosis of T1DM [168-173]. Noteworthy, other reports don’t agree with the primary pathogenic role of obesity [174,175]. Recently another study in a large cohort of patients from the Mediterranean area makes this theory controversial and unproven up to now [176].
In our previous report in a limited cohort of 174 Italian patients from Genoa (northern Italy) we demonstrated that obesity is not a common finding in younger children at T1DM diagnosis [177].
In particular, the obesogenic environment, i.e. sedentary lifestyle, which promotes insulin resistance and other metabolic consequences deserves attention.
On the other hand, some studies don’t support the role of Accelerator Hypothesis. In fact, data from UK compared BMI at T1DM diagnosis with age at diagnosis in South Asian and white children and did not find significant differences. The authors concluded that BMI could be too crude as indicator of insulin resistance, and that other specific indicators should be considered [178].
In a large cohort of Mediterranean patients diagnosed with T1DM between 1990 and 1994 BMI-SDS has not significantly increased. In addition a positive association between BMI-SDS and age at diagnosis has been also reported [176].
It is plausible that Accelerator Hypothesis does or not does become manifest because of the genetic background and environmental factors, including the prevalence of overweight and obesity.
All studies include children BMI to define obesity; however, this measurement seems to be a too crude measure of insulin resistance, as well as of percentage fat mass and its distribution and for the critical variable of cardiovascular fitness, which is the major determinant of insulin sensitivity.
The study of epigenetic in the pathogenesis of autoimmune diseases represents a new challenge and a fascinating field for clinicians and researchers, particularly as regards T1DM. It is recognized that genetic background is only one aspect in T1DM pathogenesis, and the role of environment, gender and aging deserves equally attention. In fact genetic background is responsible for susceptibility or protection from clinical onset of the disease. Moreover, genome wide association studies discovered significant associations underlying immune tolerance breakdown only in a relatively small group of patients, leading to the concept of “Missing Heritability” [179]. Furthermore the low concordance rate of T1DM in monozygotic twins reinforces the concept that external additional factors play a crucial role, and the link between genetic susceptibility and environment as trigger of auto-immunity can be represented by epigenetic [180].
In contrast to genetic alterations, epigenetic changes determine and/or perpetuate an heritable change in gene expression without a change in DNA sequence. Epigenetic mechanisms are involved in eukaryotic gene regulation through modification in chromatin structure in part packaging DNA, in part as modulating gene expression. Epigenome can be defined as a cell specific and stable pattern of gene expression determined by epigenetic mechanisms. Epigenetic mechanisms are involved in cell type development and function, since they are able to determine stable gene expression or repression. Another important feature of epigenetic mechanisms consists of determining metabolic plasticity to cells, with subsequent adaptation to environmental modifications [181].
The main epigenetic abnormalities include DNA methylation and histone modifications, leading to spatial and temporal changes in gene regulation. Studies in identical twins showed that the appearance of epigenetic differences increase with age and the most significant epigenetic differences have been occurred in those twins who spent less time together [182].
As regards T1DM pathogenesis, epigenetic role is by modulating lymphocyte maturation and cytokine expression, both involved in the development of autoimmune attack to β-cells [183]. In particular T-helper lymphocyte differentiation is under epigenetic control [184]. Another mechanism by which epigenetic modifications play a role in T1DM pathogenesis is by influencing β-cell development and repair. In fact glucose and insulin regulate methylation process which takes place in the cell via elevated homocysteine and homocysteine re-methylation, with a concomitant reduced capacity to remove homocysteine by means of transulfuration processes [185]. Homocysteine can be re-methylated to form methionine. The maintenance of methylation patterns in DNA and histone are linked to cellular methyl group metabolism, which is influenced by nutritional intake of folate [185]. Maternal nutrition state can influence newborn metabolic phenotype through epigenetic modifications. In fact the relationship between nutritional status and epigenetic is crucial during embryogenesis, intrauterine life and perinatal period, influencing offspring’s pancreas vascularisation and development [186]. Furthermore Dutch people exposed to famine during intrauterine life in the years of the Second World War experienced higher frequency of type 2 diabetes and cardiovascular risk in adulthood [187]. As regards a direct epigenetic involvement in T1DM pathogenesis few data are available. On the other hand a possible contribution is represented by food intake, for methyl donors (i.e. methionine and choline) and cofactors (i.e. folic acid and vitamin B12) which are important for DNA and histone methylation.
Even if diabetes mellitus is a condition described in the ancient Egypt, no specific etiologic factor has been defined up to now. Fascinating case reports and large multicenter studies demonstrated the complexity of pathogenetic events characterizing autoimmune diseases.
Several environmental factors, old and new, play a crucial role in the development of T1DM, being as protective as dangerous, and their interplay with genetic susceptibility can explain the difficulty to find a single causative agent [188].
On the other hand the study of environmental factors increases the knowledge of natural history of the disease, and allows the recognition and knowledge of those protective agents which can delay the clinical onset of the disease and represent the basis for primary prevention programs.
Chromosomic instability is characterized by aneuploidy, allelic losses, and the consecutive accumulation of chromosomal abnormalities [1].
Aneuploidy is widely acknowledged as a leading cause of miscarriage and birth defects in humans and is generally known to be deleterious to the survival of individual cells. However, aneuploidy is also ubiquitous in cancer and is thought to arise as an adaptive response in certain contexts given the technical difficulties to study it and the poor understanding of the involved processes. This dichotomy of aneuploidy has attracted the interest of researchers for over a century, but many studies have reached conflicting conclusions [2] which reflect how difficult it is to understand billions of years of evolution. The emergence of new technology apparently has allowed scientists to revisit the aneuploidy problem and has fueled several recent studies aimed at understanding the effects of aneuploidy on cell physiology with frustrating results. Therefore, the reviewing of those studies, considering previous observations and knowledge, specifically focusing on the effects of aneuploidy on cellular homeostasis, chromosome stability, and adaptation, gives notably fewer useful conclusions than the expected.
Under normal conditions, genomic integrity is given by chromosomes that are assembled by the DNA sequence and proteins, such as histones that play essential structural and functional roles in the transition between active and inactive chromatin states [3]. Histones have a high degree of conservation regarding maintaining the overall structure of the nucleosomal octameric core.
The DNA is hierarchically packed in the nucleus with the aid of proteins forming a complex called chromatin. Histone variants and posttranslational modifications and interactions with chromatin remodeling complexes influence DNA replication, transcription, repair, and recombination.
The study of the chromatin has been focused in the structural aspect only. And even this type of analysis faces, so far, formidable technical challenges. But it’s not simple or even possible to find articles about the flow of energy through the nucleus, nor works on the absence of mitochondria and ATP in the cell nucleus.
Despite the progress in structural studies, we cannot yet answer the question of who controls who. Does chromatin control histones or vice versa or both or other genetic or epigenetic factors?
Eukaryotic chromatin is a highly dynamic macromolecular assembly, which means that it requires energy expenditure continuously, not only to carry out its functions but also to preserve the shape of each component, beginning with the covalent bonds and other types in every molecule, and so on until it reaches to the macromolecule. Most eukaryotic organisms have multiple copies of histone gene; thereby, they are highly conserved in evolution.
The highly complex histone interactions with the nucleosomal core particle are processes that happen in amazing accurate way. All histone domains share a similar structural motif; they form interfaces with each other in several unique ways. This interface specificity is consistent across many variant histone sequences, demonstrating the flexible and adaptable architecture of histone complexes. These are extraordinarily complex biochemical processes that repeat in the same way since the beginning of time.
So far, it is not clear if chromatin inactivation is due to an enzymatic activity and/or a steric block that impedes access by transcription factors or the chromatin remodeling machinery [4]. However, there is an unexpected actor that has not been studied at least in detail: the generation and distribution or flow of energy (from melanin) across the cell nucleus.
It is relatively easy to reverse core histone tails, i.e., by acetylation, methylation, ubiquitination, and phosphorylation, among others [5]. So it is interesting the evolution could happen relatively fast. Evolution is not a process of trial and error, because in that way it would have required time lapse greater than the age of the universe.
Thereby it is possible that the generation and distribution of energy coming from melanin not only releases energy but also is giving information.
CIN is a form of genomic instability in which chromosomes are uneven, such that either whole chromosomes or fractions of chromosomes are duplicated or deleted. The inadequate distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy (the correct number of chromosomes) leading to aneuploidy (incorrect number of chromosomes). The daughter cells do not have the same number of chromosomes as the cell they originated from.
In solid and hematological cancers, chromosomal instability is a common occurrence [6], involving gain or loss of whole chromosomes or fraction of chromosomes [7]. Chromosomal instability is thought to be an early event during tumorigenesis or furthermore is involved in tumor initiation.
Cancers result from the accumulation of inherited and somatic mutations in oncogenes and tumor suppressor genes [8]. Supposedly, these genes encode proteins that function in growth regulatory and differentiation pathways. Mutations in those genes increase the net reproductive rate of cells. Mutations in genes increase the rate at which whole chromosomes or large parts of chromosomes are lost or gained during cell division.
Chromosomal instability causes an imbalance in chromosome number (aneuploidy) and an enhanced rate of loss of heterozygosity, which seems as an important mechanism of inactivating tumor suppressor genes. Thereby, cancer results if normal regulatory mechanisms of cell birth and death are disrupted [9].
Maintenance of chromosomal stability requires a statistically nonsignificant gene mutation. Many cancers, if not all, are characterized by a high degree of aneuploidy, result of chromosomal instability mainly. However, linear analysis of chromosomal instability with mathematical models suggests that it does not arise simply because it allows a faster accumulation of carcinogenic mutations. Instead chromosomal instability must arise because other reasons, such as environmental factors, epigenetic events, or as direct consequence of a tumor suppressor gene inactivation. The increased variability alone is not enough explanation for the presence of chromosomal instability in most cancers [10].
The characteristics of cancer cells as aneuploidy, and multiple chromosomal anomalies including gain or loss of whole chromosomes or transposed chromosomal fragments [11], suggest that many cell processes are failing at the same time. The above is compatible with a generalized failure, which is characteristic of energy problems.
The prior intracellular conditions necessary to induce substantive mutations in the genes as well as aneuploidy, which are considered necessary conditions for neoplastic transformation; they are like widespread chaos inside the cell. And in a biological system as evolved as the eukaryote, cell is difficult to explain, unless we take energy into account.
Maybe, so far, the investigation did not consider the energy flow required by the cell nucleus because it does not have mitochondria or ATP. And perhaps that’s why you might think it does not require energy; but the cell nucleus is the largest intracellular organelle, so its energy needs are expected to be substantive; and on the other hand, let us remember that the cell uses energy in many ways, not only to impel each and every one of the amazingly accurate biochemical reactions that make up what we call life, which happen in the same way, with the same sequence, with the same temporality, with the same molecules, with the same location, and in similar proportions since the beginning of the time.
We can think that the eukaryotic cell knows his work perfectly, because he has done it millions of years, millions of times. But the astonishing perfection and characteristic coordination of living entities requires a source of energy that possesses similar characteristics, which are so different from the ATP energy currency prevalent theory.
The cell, therefore, requires energy for many things, not only to carry out the extraordinarily complex biological functions that we are far from understanding but even to preserve the form and stability.
The biochemical processes involved with the hematopoiesis are extraordinarily complex and surprisingly accurate, since they have been repeated in the same way continually since the beginning of time. They can be disturbed by physicochemical alterations in some of their foremost components, for example, the water viscosity is one of the characteristics that is altered with greatest ease.
The bone marrow produces an average of 2.5 million erythrocytes per second, which requires prodigious amounts of precursors of organic molecules and energy. And the production of such a quantity of blood-forming elements requires great and fast coordination between the different and highly biochemical processes involved, since they must happen with an astonishing exactitude, but their main requirement is, without a doubt, energy.
Hematopoiesis in the bone marrow turns ineffective when the biochemical steps that make up and that happen at a staggering speed suffer some alteration due to the presence of contaminants in water, in the air, or in food such as pesticides, herbicides, fertilizers, metals, plastics, solvents, industrial waste, drugs, anesthetic agents, alcohol, drug addiction, extreme climates (cold, heat) etc.
This perturbed hematopoiesis in the bone marrow can lead to cytopenias in the blood and predisposition to acute myeloid leukemia (AML) [12]. There is a delicate interplay between the hematopoietic stem and progenitor cells, stromal cells, and cytokines or chemokines secreted within the microenvironment that is needed to maintain hematopoiesis. Thereby, this microenvironment is at the same time highly complex and highly dynamic, requiring enough available chemical energy at any moment.
The bone marrow is separated into vascular and nonvascular sections. The vascular section contains blood vessels that supply the bone with nutrients and transport CO2, blood stem cells, and mature cells away from the bone and into circulation. The nonvascular sections of the bone marrow are where the hematopoiesis or blood cell formation occurs.
It is contradictory that in nonvascular section of bone marrow, hematopoiesis takes place. Supposedly, the current deep-rooted dogma says that our body can get the energy and mass precursors through a single molecule, this is glucose. However, glucose requires to be transported through blood stream, and surprisingly, the bone marrow section with the highest metabolic rate has no blood vessels at all.
Something similar happens in human retina, where the rod and cone layer, with a metabolic rate almost ten times greater than cerebral cortex, under normal conditions, it has no blood vessels at all.
Bone marrow stromal cells are progenitors of skeletal tissue components such as the bone, cartilage, the hematopoiesis-supporting stroma, and adipocytes and possibly can also form neural and myogenic cells [13].
In average, there are 2.5 trillion of red blood cells in your body at any moment. To maintain this number, under normal conditions, about two and a half million new ones need to be produced every second by your bone marrow. Considering all the tissues and cells in our body, 25 million new cells are being produced each second. We give birth to over 200 billion red cells every day.
Hypoxia or low oxygen availability is a prominent molecular feature of the bone marrow that contributes to both normal and malignant hematopoiesis. Relative to most tissues, the bone marrow microenvironment resides in a particularly hypoxic microenvironment. Oxygen tensions within the bone marrow cavity range from 0.6% to 4.2%, whereas oxygen tensions in most other adult tissues range from 2 to 9% O2 [14]. But because each cell can dissociate the molecule from water, thanks to melanin, then oxygen levels are an indirect indicator of molecular hydrogen levels in tissues.
The purely structural analysis of bone marrow, as it has been to date, confronts, at least two important challenges: (1) substantive technical limitations due to the complex anatomy and biochemistry of the area to study and (2) researchers are trying to decipher 4 billion years of evolution without considering the generation and flow of energy.
Glucose is (supposedly) an important fuel that is used by nearly all organisms through a common set of metabolic pathways. The knowledge of glucose metabolism that is prevalent until today, dates to 1860, with the identification of glycolysis with Louis Pasteur and thereafter in 1937, with the work of Gustav Embden and Otto Fritz Meyerhof [15]. Also, in 1937, the foundations of citric acid cycle were provided by Albert Szent-Gyorgyi, Hans A. Krebs, and William A. Johnson [16]. Two decades later, Peter D. Mitchell hypothesized a chemiosmotic mechanism that supposedly led to the elucidation of the electron transport chain and oxidative phosphorylation [17]. Thereby, at least apparently, the pathway for aerobic glucose metabolism and ATP generation was completed.
However, glucose is the universal precursor of any organic matter in the human body, but it cannot provide the energy that its own metabolism requires. Our circumstantial finding in human retina, during an observational study about the three main worldwide causes of blindness, about the unsuspected intrinsic property of melanin to dissociate the water molecule, like chlorophyll in plants [18], constitutes a disruptive discovery because it destroys existing dogmas deeply rooted and allows to open new ways to knowledge (Figure 1).
Schematic representation of the way in which melanin (center) dissipates the energy it absorbs, dissociating the water molecule, that is, hydrogen and molecular oxygen (H2 and O2), which are released in the form of growing spheres of energy that follow the laws of simple diffusion. The difference in color of the spheres is to remark that a sphere contains higher concentration of H2 and O2, result of the dissociation of the water; the next sphere would contain higher quantity of electrons of high energy, as melanin generates four electrons of high energy for every two molecules of water that is reassociated.
Glucose and ATP have biological functions related mainly to biomass metabolism and not so much with energy. The unexpected intrinsic property of melanin to transform photon energy into chemical energy through the dissociation of water molecule, a role performed supposedly only by chlorophyll in plants, seriously questions the sacrosanct role of glucose and thereby mitochondria and ATP as the primary source of energy for the cells (Figure 2). Furthermore, increased glycosylation has been linked to increased apoptosis [19].
General outline of the very first step in photosynthesis in plants and humans. In plants the chlorophyll dissociates irreversibly the water molecule by expelling the oxygen to the atmosphere. In humans, melanin dissociates the water molecule in reversible form, and for every two water molecules that are reformed, four high-energy electrons are generated.
If we accepted by a moment that our body is able to take energy from the light thanks to the melanin, then the absence of blood vessels in anatomical structures with very high metabolic rate such as photoreceptors of the retina and the avascular region of the bone marrow is now explainable, and it is congruent with the fact that the blood vessels are not able to transport energy (Figures 3 and 4).
When the amount of sunlight is abundant, as in the tropics, the amount of melanin in the skin is higher to regulate the quantity of light that must penetrate the inside of the organism, because even the bone marrow requires luminous energy continuously. It is not surprising that leukemia in white people is more frequent than in dark-skinned people.
When the amount of sunlight is lower, as in cold countries, the amount of melanin in the skin decreases to allow for a greater passage of light, and in that way, the final quantity of light that the body inside needs will remain the right one. The amount of melanin in the skin is determined by the amount of light in the environment where people inhabit.
The absence of capillaries in anatomical regions with a high metabolic cup is explained, at least, for two reasons:
Blood cannot carry on energy. The bloodstream only transports metabolites and their intermediaries. Considering the discovery of the unsuspected bioenergetic role of melanin, the main gas that the blood transports is the CO2. Recall that unknowns about blood are important and numerous, for example, albumin formula is not yet known, and by other side, the similitudes of hemoglobin and chlorophyll molecules are substantive, thereby cannot be discarded that hemoglobin can also dissociate the water molecule, irreversible, like chlorophyll.
If all the capillaries in the human body were lined up in a single file, the line would stretch over 100,000 miles. It’s been estimated that there are 40 billion capillaries in the average human body.
The circulatory system has a complex design and is very extensive, and not all capillaries are permeable at the same time, supposedly something less than half is closed at a given time, otherwise, the volume of circulating blood would not reach to fill them all at the same time.
The intricate circulatory system and its highly complex blood content have functions related to the biology of the structure or mass mainly, but anyway energy expenditure is constantly required, thereby, our body or the cell itself, can capture it from visible and invisible light, and it is transduced into chemical energy by melanin, throughout the dissociation of the water molecule, like chlorophyll in plants and hemoglobin in blood.
Melanin absorbs the full electromagnetic spectrum, visible and invisible light, from radio waves to gamma rays; thereby, the process of transduction is quite similar during night and day, the products being molecular hydrogen (H2) from water dissociation and high-energy electrons (e-) from reformatted water.
The cells are energetically independent, because melanin is found in every one of them, mainly placed in the perinuclear space; therefore, each cell can generate its own energy by dissociating the water molecule (Figure 5).
Melanin is usually not represented in the eukaryotic cell models available in the different sources of information.
The fact is surprising that in the different schemes of the cell, melanin passes unnoticed, very seldom or never depicted in the drawings of the eukaryotic cell. It is necessary to add the melanosomes in the perinuclear space, its main location (Figure 6).
Drawing of eukaryotic cell to which the melanosomes have been added in their most usual location, the perinuclear space, from releasing the energy symmetrically, in all directions, following the laws of simple diffusion. The melanosomes surround the cell nucleus, enveloping it in its entirety, thus constituting a constant source of energy for the largest intracellular organelle, since it contains neither mitochondria nor ATP.
On the other hand, the rarely noticed absence of mitochondria and ATP in the cell nucleus, the largest organelle of the eukaryotic cell, now has a coherence with the presence of melanosomes in the perinuclear space, which surround the nucleus, while they provide it with the energy necessary for its functions (Figure 7).
Schematic representation of the cell nucleus (deep blue) and some melanosomes (black dots) of which emanate the growing spheres (light blue) composed of molecular hydrogen (H2), which transports the energy that is released by dissociating the molecule of water. Molecular hydrogen easily crosses any membrane or barrier inside the cell, so the growing spheres provide energy to both the inside of the cell nucleus and the rest of the organelles located outer of the nucleus by inside cell membrane. That molecular hydrogen does not combine with water is a crucial physic-chemical of hydrogen characteristic that explains the normal displacement of molecular hydrogen (H2) along cytoplasm.
Hence the importance of water in living beings, because it is the perfect substrate for melanin that must always be available and accessible so that the cell can obtain the energy it requires incessantly throught water dissociation.
The water content of the cells is very high, 77% by weight and 94.54% by number of molecules, and the constant need for water (and energy) explains the cerebral caesuras, because in this way the water of the cerebrospinal fluid (CSF) can circulate quickly and deeply, reaching up to the neuron furthest from the ventricles and the subarachnoid space.
Although the discussion of water, so far, is largely focused on its properties as a solvent, it also serves as a ligand. For example, in both hemoglobin and cytochrome oxidase, the binding and subsequent release of water molecules is critical to their proper function and now in ahead with need to add a new possibility: water as substrate to energy production.
The amount of chemical energy in the form of H2 and high-energy electrons that eukaryotic cells need at any moment is surprisingly accurate, and when water or melanin physic-chemical properties are altered by pollution of the surroundings (pesticides, herbicides, fertilizers, metals, plastics, solvents, industrial waste, anesthetic agents, drugs, alcohol, variations in climate, cold, heat; etc.), the cell seems as it goes into imbalance, experiencing a turning-point in evolution.
It is a sequence of chemicals that form information that control how humans are made and how they work. It is a digital-like code, but it is not binary, but quaternary with four distinct items: adenosine (A), cytosine (C), guanine (G), and thymine (T).
These four substances are the fundamental “bits” of information in the genetic code and are called “base pairs” because there are actually two substances per “bit.” Everything else is built on top of this basis of four DNA digits.
However, life origin cannot be explained arising from DNA. The sequence in melanin about dissociation and reformation of water, this is, liquid → gas → liquid → gas → liquid → gas, and so on, can be reduced to 0 (liquid) and 1 (gas), a kind of binary code and a binary code that gives origin and therefore also regulates a quaternary code has room to explain the origin and evolution of life.
The genetic code is not an autonomous system, as any other chemical process, nevertheless complicated, requires energy to be created, to replicate, to carry out their functions, and even to preserve the shape, because the water of the cytoplasm tend to separate the molecules.
The human genome is about 3 billion bases in total, and every human being has 2 copies of this code; one copy from each parent, thereby a human’s cell DNA contains around 6 billion bases.
These 6 billion base pairs are split among 46 chromosomes. Each person gets 2 pairs of chromosomes, 23 from each parent, to total 46 chromosomes per human cell. A chromosome is the largest form of a DNA molecule, with a large sequence of DNA codes, of differing lengths, usually hundreds of millions of base pairs in each chromosome.
Chromosomes are independent molecules of DNA, with the typical double helix, a start and end, but no cycles. Each chromosome has subsequences of DNA bases that encode features, and these are called “genes.” All genes have different lengths. The total number of distinct genes in the human genome is believed to be around 30,000 genes.
Most genes clearly encode the data sequence representing a specific protein that would be synthesized in the precise moment, right temporality, exact amount, and accurate location; therefore, a gene, besides constant energy supply, also requires detailed information to adequately carry out its highly complex functions. All the genes together are only a small part of DNA code. The 30,000 odd genes in human DNA might only make up 4% of human DNA.
The structure of DNA and RNA are very similar, but RNA uses uracil (U) instead of thymine (T). Proteins are a base-20 code using the 20 amino acids. DNA represents a protein that has an ordered sequence of base-4 triplets, using 64 possible values to 20 amino acids.
The following phrase “Chronic Myeloid Leukemia (CLL) is a genetic disease, but not a hereditary disease” is confusing because in any disease some degree of altered gene expression can be expected. Therefore, most leukemia patients have no family history of the disease, and there is no evidence that it can be passed on to the children of someone living with the disease. Occasionally, there are families that may have other members living with leukemia, however, without taking in account the role of toxic compounds capable to perturb the generation and distribution of energy, never was and never will conclusive genetic evidence that family members are predisposed to develop leukemia.
There are diseases that are difficult to classify, i.e., the CLL that is a B-cell lymphoproliferative disorder and is one of the most common adult leukemias [20]. Although the cause remains unknown, a family history of the disease is one of the best characterized risk factors, but more for familial exposure to external toxic compounds than for theoretical minute punctual mutations or loci that cannot be found yet or even less to probe.
This is a long-lasting observation that is congruent with the fact that the genetic code is as perfect as everything else, instead what we see are groups of people (family members or factory workers) exposed to similar toxics.
The family groups share the same customs, the same food, the same house, the same trades or professions, the same environment, etc.
In fact, familial aggregation of the disease has been observed for decades, with multiple reports in the literature of families in whom the occurrence of CLL is greatly enriched with what appears to be almost Mendelian inheritance [21], and worst, there are environmental toxicants so persistent that can be transmitted from parents to child, for instance, through mother’s milk.
“Along with its antibodies, enzymes and general goodness, breast milk also contains dozens of compounds that have been linked to negative health effects,” bisphenol A (BPA, a plastic component), PBDEs (used in flame retardants), perchlorate (used in rocket fuel), perfluorinated chemicals (PFCs, used in floor cleaners and nonstick pans), phthalates (used in plastics), polyvinyl chloride (PVC, commonly known as vinyl), organochlorine pesticides, dioxin, benzene (a known human carcinogen [22]), and the heavy metals cadmium, lead, and mercury as leading offenders [23].
Risk of childhood leukemia is increased for benzene exposures of > 10 μg/m3 associated with traffic [24] and auto repair garages and gasoline stations [25].
Human milk serves as a valuable biological matrix for the assessment of public and environmental health. The more lipophilic the chemical is, the more likely it is to be found in human milk. By the way, the bone marrow has a high content of lipids.
Family predisposition should be understood as epigenetic predisposition, as external factors such as contaminated air, contaminated water, polluted air, contaminated food, pesticides, herbicides, fertilizers, metals, plastics, solvents, industrial waste, shocks, addiction drugs, emotional strains, etc.
Such factors are common to the group of people we define as family; these are father, mother, siblings, and sometimes close relatives who live in the same house.
The exposure to exogenous factors in factory employees is called professional risk, as is the newly sounded case of leukemia in Samsung employees. And the difference between one and another example is only the name that we put, because both in the families and in the factories, the effect of the toxins is similar as they alter the delicate balance between mass and energy in the processes that make up the life, in this case in the complex functions of the bone marrow.
Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome [26].
But such external factors only modify the genetic expression in one way or another, but they do not have an effect that we could call direct on the DNA chains or their components. In fact, what is importantly affected is the generation and distribution of energy that emanates from melanin, and hence, general failures, characteristic of disturbances in the generation, and distribution of energy begin to happen, as it happens in any system.
So, it is to date, the identification of genes that predisposes to chronic familial leukemia has been unsuccessful in real terms, which is attributed to various factors, such as the small number of affected individuals susceptible to being studied and technological limitations or maybe because there are many genes affected and each contributes a little [27].
Farming-related exposure and occupational chemicals increase risk of CLL. This is congruent with population-based studies and cohorts that have shown significant family aggregation in CLL and related conditions such as non-Hodgkin lymphoma and other lymphomas; and on the other hand, the absolute risk of a first-degree family member for the development of CLL or a similar disease is very low.
Thereby, linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility, but no gene mutations have yet been identified by this method.
The accumulation of small, mature-appearing lymphocytes in the bone marrow, blood, and lymphoid tissues in CLL indicates that many germ cells are altered, as well as the daughter cells that are produced. The possibilities that a point mutation (loci) or the joint failure of several genes occurs in a significant portion of the germ cells and that such dysfunction is also expressed in the daughter cells is so unlikely that it has not been able to prove much least explain.
On the contrary, a failure in the generation and distribution of energy from melanin that is repeated in numerous cells both germs and daughters is so feasible that it can easily be demonstrated, as is the case of the experiment described in Section 2.4.
Incidence rates in men are nearly twice as high as in women that can be explained due to men are exposed to environmental toxics more often than women. Although advanced age, white ancestry (less melanin equal to less water dissociation) and family history of hematologic malignancies are risk factors; the etiology of CLL is still not understood more than unknown [28].
In any system, when the failure is widespread, energy is the usual or main cause. And in the case of the eukaryotic cell, alterations are diffuse, so they can be found at any level, including genes, histones, chromosomes, etc. The study of cellular structures separately from the flow of energy leads to biased conclusions, because the mass and the energy are inseparable in the real world.
Any structural alteration of the cell is preceded and accompanied by a disturbance in the flow of energy that comes from the dissociation of the water, which happens inside the melanin. The name of the affected structures or substances (protein, histone, amino acid, nucleotide, gene, chromosome, etc.), does not have more relevance, because the cell ignores it; there is simply an imbalance between mass and energy.
The cell uses the energy in many ways, and it does in a surprisingly exact way, leaving almost nothing at random; as it has done since the beginning of time. When the amount of chemical energy available in the form of molecular hydrogen (H2) and high-energy electrons(e-) is not enough to fill the energy needs of the cell, then the role of chance begins to be significant, so the clinical manifestations also depend on chance, but the basic problem is still the same: balance between mass and energy.
Leukemia is cancer that starts in the tissue that forms blood. Most blood cells develop from cells in the bone marrow called stem cells. In a person with leukemia, the bone marrow makes abnormal white blood cells. The abnormal cells are leukemia cells. Unlike normal blood cells, leukemia cells do not die when they should. These may crowd out abnormal white blood cells, red blood cells, and platelets. This makes it hard for normal blood cells to do their work. The four main types of leukemias are acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).
The risk factors already described in leukemia are genetic disorders, radiation exposure, physical and chemical exposures, and chemotherapy.
The greater incidence of leukemia per 100,000 persons is in white races, with 17.5/10.7 (male/female), and in black race, the incidence per 100,000 persons is 12.9/8.0, suggesting that a greater amount of melanin in the skin or body is a protective factor.
Supposedly, a clone of invasive cells may arise at any stage of cell maturation and specialization in the lymphoid, myeloid, or pluripotential stage. The cause of this apparent clonal development is quite unknown in most cases; it appears to involve the rearrangement of sequence of bases on DNA molecules or chromosomal instability syndrome.
External and internal factors such as ionizing radiation and chemicals favor chromosomal anomalies. These random DNA changes will lead to an uncontrollable mitosis of cells.
These leukemic blasts show abnormal behavior infiltrating into the bone marrow, altering, by means of diverse mechanisms, the astonishing accuracies of the normal processes of hematopoiesis (formation of cellular components of blood).
The abnormal cells eventually infiltrate into other organs as such as the spleen, the eye, or the liver, also disrupting the astonishing accuracy of their regular processes.
The blood becomes unable to carry out its functions, and the individual affected will experience within a few days or weeks increased fatigue and infections and will bruise and bleed more easily than they usually would have.
The clinical findings of leukemia, such as thrombocytopenia, anemia, severe infections widespread, bone pain, arthralgias, and involvement of the liver, spleen, thymus, lymph nodes, skin, gums, eye, head (CNS), and neck; it is compatible with a generalized system failure, which is typical of problems in the generation and distribution of energy (from light/melanin/water).
The experiment that we describe below points in that direction (Figures 8–28).
Bone marrow, control group (A), H&E, 5X.
Bone marrow, exposed group (B) to arsenic. H&E, 5X.
Bone marrow. Group C exposed to arsenic and treated at the same time. H&E, 5X.
Bone marrow, control group (A). H&E, 10X.
Bone marrow. Exposed group (B) to arsenic in water. H&E, 10X.
Bone marrow. Group C exposed to arsenic in water and treated at the same time. H&E, 10X.
Bone marrow, control group (A). H&E, 40X.
Bone marrow. Exposed group (B) to arsenic in water. H&E, 40X.
Bone marrow. Group C exposed to arsenic in water and treated at the same time. H&E, 40X.
Bone marrow. Control group A. H&E, 100 X.
Bone marrow. Group B exposed to arsenic in water. H&E, 100X.
Bone marrow. Group C exposed to arsenic in water and treated at the same time. H&E, 100X.
Peripheral blood smear. Control group A. Giemsa stain. 10X.
Peripheral blood smear. Group B exposed to arsenic in water. Giemsa stain, 10X.
Peripheral blood smear. Group C exposed to arsenic in water and treated at the same time. Giemsa stain, 10X.
Peripheral blood smear. Control group A. Giemsa stain, 40X.
Peripheral blood smear. Group B exposed to arsenic in water. Giemsa stain, 40X.
Peripheral blood smear. Group C exposed to arsenic in water and treated at the same time. Giemsa stain, 40X.
Peripheral blood smear. Control group A. Giemsa stain, 100X.
Peripheral blood smear. Group B exposed to arsenic in water. Giemsa stain, 100X.
Peripheral blood smear. Group C exposed to arsenic in water and treated at the same time. Giemsa stain, 100X.
It is a metalloid with atomic number 33, atomic mass of 74.92, and oxidation number: ± 3, 5. It alters multiple metabolic pathways by supposedly uncoupling oxidative phosphorylation. Its effect is not specific; it attacks several organs and is tasteless and odorless. The ingestion of arsenic induces a general failure of the organism, suggesting that arsenic acts by disturbing the amazingly accurate generation and distribution of energy.
Arsenic binds the cofactor sulfhydryl, dihydrolipoate, which inhibits the oxidative metabolic pathway of pyruvate and succinate. The body also replaces arsenic with phosphorus, which inhibits oxidative phosphorylation, but the most significant alteration seems to be the inhibition of sulfhydryl.
Arsenic pentavalent is well absorbed by the GI tract, and it is initially located in blood, coupled with globulin; thereafter, redistribution occurs within following 24 hours mainly to the liver, lungs, intestine, and spleen. Arsenic replaces the phosphorus of the bone, where it remains 30 years or more.
Arsenic, when decoupling the oxidative phosphorylation, induces a significant decrease in the availability of energy of the cell. However, arsenic affects the melanin itself, because they have great affinity with each other, so arsenic (As) not only damages the complex energy distribution system arising from the dissociation of the water molecule by melanin but damages the melanin itself, disturbing the generation of energy, so the damage is widespread.
Arsenic in small doses stimulates the generation and distribution of energy from melanin, so it is, in the seventeenth and eighteenth century, was used by the aristocracy in France to rejuvenate the skin of the face.
Furthermore, in the fifteenth century, William Withering, who discovered digitalis, was a strong proponent of arsenic-based therapies [29]. He argued, “Poisons in small doses are the best medicines; and the best medicines in too large doses are poisonous”.
Thomas Fowler compounded a potassium bicarbonate-based solution of arsenic trioxide (As2O3) and was used empirically to treat a variety of diseases during the eighteenth, nineteenth, and early twentieth centuries [30]. In 1910, Nobel Laureate and Paul Ehrlich developed Salvarsan, an organic arsenical for treating syphilis and trypanosomiasis.
But in higher doses, the opposite effect occurs; therefore, chronic exposure is a serious with arsenic public health problem in some parts of the world [31]. Intoxication by this heavy metal can result from breathing sawdust, workplace air, or arsenic-preserved wood or from ingesting contaminated water, food, or soil [32].
Contamination of groundwater happens by naturally occurring arsenic, also by widespread use of arsenic-containing herbicides and pesticides; its incorporation into feed as a substance to promote the growth of livestock and poultry and its industrial use has caused the environmental arsenic dispersion.
Biomagnification of arsenic is observed in many species of fish and shellfish. Sadly, the average daily human intake of arsenic is approximately 300 μg, mainly ingested with food and water. The World Health Organization (WHO) safe limit for arsenic in drinking water is 0.01 mg/L.
Acute and chronic poisoning of arsenic can be confused with hemorrhagic gastroenteritis, cardiac arrhythmias, and psychiatric disease. In 1878, Boston City Hospital described the effect of Fowler’s solution on the reduction of white blood cells in two normal people and one patient with “leukocythemia” [33].
Subsequently, As2O3 was administered as a primary antileukemic agent until it was replaced by radiation therapy. In 1930, the hematologic use of arsenic experienced a resurgence in popularity, when its efficacy was reported in patients with chronic myelogenous leukemia [34].
Until supplanted by modern chemotherapy, arsenic trioxide after radiation was considered the most effective treatment for CML and other types of leukemia. Recently, reports from China have described the induction of clinical and hematological responses by arsenic trioxide in patients with de novo and relapsed acute promyelocytic leukemia (APL) [35]. This is an important observation, since around 20–30% of patients with this form of acute myelogenous leukemia relapse despite treatment with all-trans retinoic acid and combination chemotherapy.
Arsenic treatment was not associated with bone marrow suppression and produced only limited side effects. Thereby, arsenic trioxide (Trisenox®) was approved for the treatment of relapsed or refractory APL by the US Food and Drug Administration in September 2000.
It is interesting that the therapeutic application of arsenic in low dose is widely used. Due to generalized systemic effects, so far, a clear explanation about its therapeutic effects is not available. It is possible that other similar therapies, based in toxic compounds as all-trans retinoic acid and daunorubicin/doxorubicin/epirubicin/idarubicin, an anthracycline-related compounds [36], are altering gene expression (genotoxic agents) through different pathways; thereby their effect is generalized, so it can be expected that it also affects the generation and flow of energy from melanin.
Arsenic, all trans-retinoic acid, and anthracycline-related compounds, when it is used at very high doses, then the amazingly accurate process of generation and distribution of energy, from the dissociation of the water molecule by melanin, stops almost completely, so death occurs in minutes.
Therefore, the administration of arsenic in laboratory animals is an easy way to induce general dysfunction or failure, as we are altering a fundamental process of life as is the generation and distribution of melanin energy.
Our working hypothesis was to induce widespread failure in rats and to study the effects on different tissues, such as the lung, kidney, liver, etc. [37]. The results in kidney and liver were published already. This is the first publication of results in the bone marrow.
There were 3 groups of 10 Wistar rats each one, all males, adults. Group A was control. Group B was the exposed group to arsenic in water. The administration of pentavalent arsenic was 0.50 mg/L in the water and administered ad libitum. Group C was the group exposed to arsenic in the same way as group B and treated at the same time with a novel formula that restores the balance between mass and energy.
The results of the experiment were according to what was expected. The administration of pentavalent arsenic was 0.50 mg/L in the water. Arsenic is a toxic and a carcinogen; among the noncarcinogenic harmful effects of this metalloid, the most common associated with its ingestion are those presented in the skin, hyperpigmentation, agent hypopigmentation, and hyperkeratosis, damage to the cardiovascular system; renal and hepatic alterations, development of peripheral neuropathies and encephalopathies; and its capacity of endocrine disruptor related to the development of diabetes. The relationship between the presence of arsenic in water in several regions and the increase in the presence and mortality of the bladder, lung, kidney, and hepatic cancer has been recognized in the potentially exposed populations.
As described in literature and as we observed in the histological slides of the group of animals exposed to arsenic (group B), the damage is generalized. It would be necessary to elaborate multiple conjectures to try to explain the diffuse impairment to organs and systems that are produced from the ingestion of arsenic in the water. However, the significant disturbance caused by arsenic in the generation and distribution of energy derived from melanin, it could explain the different levels of microscopic alterations observed in the histological stains of the lung, kidney, liver, spleen, bone marrow, etc.
According to the adage that good experiments are those with few animals, many results are obtained; group B was constituted with only ten animals, and the size of the effect of arsenic was substantive. On the other hand, it fulfilled the observed fact that in any system, when the fault is widespread, we must think first of energy.
So, we can think that, in this experiment, we could induce and thereby demonstrated in a reasonable way that the widespread failure caused by arsenic ingestion is due to the perturbations of the generation and distribution of energy derived from melanin.
The findings of group C—exposed and treated at the same time—cast better than expected findings, because on the one hand, the generalized toxicity of arsenic manifested itself again, but significantly decreased by the simultaneous administration of the therapeutic drug. And on the other hand, we could demonstrate the usefulness of our therapy to prevent and treat the general failure of organs and systems that is induced with the ingestion of arsenic that also gives a real hope for the many patients in similar situation.
The improvement with the treatment was also manifested in the different tissues studied, which is consistent with the fact that, by reducing the alteration in the generation and distribution of energy, the improvement is detectable at the microscopic level and it is also a general improvement.
The induced changes during the experiment with the exposure and treatment mean widespread effects, positive and negatives. The size of the effect is noticeable in both cases, exposure and treatment. And the magnitude of the effect was similar in other tissues in which biopsy was taken.
The observable findings under the microscope are very interesting, as they involve numerous variables such as cell size, shape, color changes, etc. But there are so many changes that are hard to explain based only in analysis of observable structures.
The improvement in group C (treated and exposed) is notorious. Thereby, two hypotheses were tested with one experiment, few animals, and many results, a good experiment. The way melanin releases energy, symmetrically and in all directions, in the manner of growing spheres that follow the laws of simple diffusion, flooding of molecular hydrogen cytosol, allows the vast majority of chemical reactions to be driven by these hydrogen molecules, which are not combined with water, so they only move through it reaching until the last corner of the eukaryotic cells with its precious energy charge and its powerful antioxidant effect.
Therefore, when the generation and distribution of energy that comes from melanin is altered or at least disturbed by environmental factors, of a chemical or physical nature, many biochemical processes are randomly affected by the decrease in energy levels.
We must not forget that intracellular biochemical processes are surprisingly accurate in every one of their physical and chemical characteristics, as they have been since the beginning of time. But the exact chemical reactions require in turn to be driven by an exact amount of energy. And only a molecule as wonderful as melanin has the necessary bioenergetic capacity.
The multiple tissue changes observable in the histological images of the rat and arsenic experiment underpin the concept of the unsuspected bioenergetic role of melanin. The structural changes susceptible to being observed in the light microscope and stains Giemsa, in the case of the smears, and hematoxylin and eosin, in the case of histological cuts, allow to glimpse that the number of factors involved is vast.
And analyzing one by one from a structural point of view, without considering the incessant flow of energy, would lead us to the same errors that we currently observe in the literature. It is a fact that the cell uses energy in many ways, and in studying cell biology, we must be aware that even to study ultrastructure alone, our technological resources are relatively limited.
The changes that we observed in the experiment are very interesting and highly significant, it would be very difficult to explain them based on genes, since genes are not autonomous, because they depend on the energy and surrounding cell scaffolding to replicate, express themselves and even to preserve the form, stability and function. They are also immersed in a highly complex biological system, with which they interact in a way that is not yet understood, but all the components of this highly complex system depend entirely on the energy that emanates from the melanin, so that by restoring the generation and Energy distribution, which it is so fundamental, then it is possible to explain the positive and negative changes that we could observe under the light microscope.
Characteristically, energy failures produce widespread alterations, we can say otherwise, when the problem of energy is improved or corrected, then many processes are in turn restored, which can be detected by microscopically examining the cellular structure, which is all what we can value, being an indirect indicator of the flow of energy.
Simplistically, if the ultrastructure is altered, the generation and distribution of energy is indeed disturbed, in a directly proportional form, and vice versa. That is why, despite many efforts, trying to explain diseases such as leukemia, based on purely observations of the structure, for example genes, histones or chromosomes, has given so far poor results, it is necessary to consider at the same time the highly dynamic generation and distribution of energy.
The current medicine is ensnared in the dogma that a single molecule, glucose, provides energy and mass at the same time; furthermore it also considers that only the chlorophyll of plants can transform the luminous energy into chemical energy by means of the dissociation of the water molecule. On the other hand, analyzing in a separate way the microstructure (mass) and the energy flow in the cells has led to important biases since the mass and energy are inseparable in the real world.
Trying to find the cause or explanation of diseases, based merely on the study of observable of micro or ultrastructural alterations has produced very limited results, because the cell is a highly dynamic living entity, in which the flow of energy and mass are incessant and inseparable. The optimal thing would be to study both phenomena (mass and energy) at the same time and in real time, which is not currently feasible.
During the study of biological phenomena, we must keep in mind that the size of the effect should be large [38]; otherwise, when the size of the effect is small, we end up studying in detail some prevalent bias. Bias is defined as the combination of various design, data, analysis, and presentation factors that tend to produce research findings when they should not be produced. There is an increasing concern that most current published research findings are false. The extremely large studies may be more likely to find a formally statistically significant difference for a trivial effect that is not meaningfully different from the null hypothesis [39].
It is likely that current unawareness of physicians about the human body’s ability to take light energy and the impoverishment of it by environment toxicants is a significant factor of the poor performance of health systems. For instance, in the USA, 225000 annual deaths are estimated due to unnecessary surgeries, errors in patient medication, errors of different types in hospitals; nosocomial infections, and adverse effects of medications [40]. Most of the data are derived from studies in hospitalized patients, thereby are estimates of death only and do not include adverse effects associated with disability or discomfort.
Therefore between 4% and 18% experience adverse effects in outpatient settings, with 116 million extra physician visits, 8 million hospitalizations, 3 million long-term admissions, 199.000 additional deaths, and $77 billion in extra costs [41].
The specific alterations of the genes cannot explain the diseases called genetic or hereditary, because the influence of genes is relatively limited and highly complex, i.e., the cystic fibrosis gene, codify to almost 600 proteins. Furthermore, disturbances in the generation and distribution of energy from melanin can manifest—structurally—as alterations in the genes, since the replication and the expression of chromosomes require an astonishing accurate source and level of available energy in the form of molecular hydrogen (H2) and high-energy electrons (e-).
And if we consider the effects of energy flow not only in the cell nucleus, histones, genes, and chromosomes but also in the scaffolding around them, things become even more incomprehensible to us; but to have understood that the energy of the cell comes from the light-melanin-water triad in order of abundance in the universe, and that it does not come from glucose, represents a critical advance in the knowledge, which can be translated in an expedited way to the clinic, for the benefit of the patient, especially if we take into account the role of environmental toxins and their detrimental and generalized effects on the amazingly accurate process of generation and distribution of energy by melanin.
This work was supported by Human Photosynthesis® Research Center, Aguascalientes 2000, México.
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