Omega-3 fatty acid deficiency in major depressive disorder is caused by the interaction between diet and a genetically determined abnormality in phospholipid metabolism

Omega-3 fatty acids are a type of polyunsaturated fatty acid (PUFA). A growing body of evidence suggests that this form PUFA is a useful and well tolerated treatment for major depressive disorder, a common and serious mental illness. The efficacy of omega-3 PUFA is routinely explained as being due to a deficiency caused by inadequate dietary intake of this class of fatty acid. The hypothesis considered states that low omega-3 PUFA abundance in patients with major depressive and related disorders is due to an underlying genetically determined abnormality. The hypothesis can explain why although a specific and consistent deficit in omega-3, but not omega-6, PUFA occurs in major depressive and related disorders, the literature does not consistently support the notion that this is due to deficient dietary intake. Specifically it is hypothesized that having genetically determined low activity of fatty acid CoA ligase 4 and/or Type IV phospholipase A(2) combined with the low dietary availability of omega-3 PUFA results in reduced cellular uptake of omega-3 PUFA and constitutes a risk factor for depression. The hypothesis also has important consequences for the pharmacological treatment of depression in that it predicts that administering agents which enhance phospholipid synthesis, particularly those containing ethanolamine such as CDP-ethanolamine, should be effective antidepressants especially when co-administered with omega-3 PUFA.     

Docosahexaenoic acid biosynthesis and dietary contingency: Encephalization without aquatic constraint.

Reconstructing evolutionary processes in the distant past is necessarily an inductive endeavor, typically appealing to numerous considerations thought to be relevant to the veracity of a particular conclusion. In this respect, it is essential that the considerations invoked to support hypotheses are in turn well-established truths. It is with these concerns that we sought to examine the nutritional, physiological, and archeological premises underlying the perspective that access to an aquatic diet rich in docosahexaenoic acid (DHA, 22:6n-3) was critical to human brain evolution (Carlson and Kingston [2007]: Am J Hum Biol 19:132-141). In our report investigating links between omega-3 (n-3) fatty acids and hominin encephalization, we concluded that the regular consumption of aquatic resources rich in preformed DHA may not have been essential given a varied diet of wild terrestrial foods (Carlson and Kingston [2007]). This assessment was based primarily on evidence of potential physiological adaptations in modern humans to ensure sufficient availability of DHA during critical periods of brain growth. While modern human physiology provides critical information regarding DHA as a constraint in evolving a large brain, it is also important to consistently contextualize interpretations within a framework of eclectic foraging diets rather than nutritionally limited modern agricultural populations or even modern foragers. We contend that current interpretations of Pleistocene hominin nutritional ecology do not uniquely support a shore-based foraging niche as claimed by Cunnane et al. ([2007]: Am J Hum Biol, 19:578-581). Specific issues raised in response to our article by Cunnane et al. and Joordens et al. ([2007]: Am J Hum Biol, 19:582-584) are addressed here.     

5-Lipoxygenase as a putative link between cardiovascular and psychiatric disorders

There is evidence of an association between depression and anxiety and cardio- cerebro-vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid. Production of active leukotrienes can be reduced by dietary omega-3 fatty acids, which also are beneficial in cardiac and psychiatric (e.g., depression) pathologies. Human 5-LOX and FLAP gene polymorphisms are a risk factor in atherosclerosis and cardio-cerebro-vascular pathologies; an overactive 5-LOX pathway is found in these diseases. Studies with 5-LOX-deficient transgenic mice suggest that 5-LOX activity may contribute to anxiety- and depression-like behaviors. Future research should characterize the role of the 5-LOX pathway in comorbid cardio-cerebro-vascular and psychiatric disorders and in the therapeutic actions of dietary omega-3 fatty acids.     

Homocystinuria and psychiatric disorder: a case report.

Deficiency of cystathionine beta-synthase (CBS) is the commonest cause of primary homocystinuria. Homocysteine metabolism is intimately linked with the metabolism of folate, vitamin B12 (cobalamin) and pyridoxine. It is hypothesised that the pathogenesis of neuropsychiatric manifestations in homocystinuria, folate and cobalamin deficiencies are related to imbalance neurotransmitters in the CNS through disturbances in the pathways linking the metabolism of homocysteine and these vitamins. Although neuropsychiatric disorders are relatively common among patients with homocystinuria, it is not well recognised as the causative factor among patients presenting with neuropsychiatric disorders. A 31 year old woman presented with a three week history of delirium and inappropriate and labile affect. There was no history suggestive of drug or alcohol abuse, nutritional deficiency or organic disorders. EEG, cerebral CT, MRI and microbiological investigations did not reveal any organic causes. Because of a diagnosis of pyridoxine-responsive homocystinuria seven years previously, the possibility of homocystinuria was considered and investigated. Laboratory tests revealed macrocytosis and a high concentration of urinary total homocystine. Commencement of pyridoxine at 400 mg/day resulted in disappearance of homocystine in urine within four days with remarkable clinical improvement. Homocystinuria should be considered in the differential diagnosis of unexplained neuropsychiatric disorders in patients who have past or family history of homocystinuria, mental retardation, thromboembolic episodes, vascular diseases or clinical and laboratory features resembling folate and/or vitamin B12 deficiencies. Homocystinuria-associated neuropsychiatric disturbances can easily be treated with pyridoxine in 50% of cases.     

Are we really what we eat? Nutrition and its role in the onset of rheumatoid arthritis

Accumulating research evidence suggests that individual dietary factors and dietary patterns might be implicated in the risk of development of rheumatoid arthritis (RA). This narrative review aims to present this evidence and provide nutritional recommendations for reducing RA risk in susceptible individuals. Overall, a ‘Western’ type diet rich in energy intake, total and saturated fat, an unbalanced ratio of n-3 to n-6 fatty acids, high in refined carbohydrates and sugar and low in fiber and antioxidants might increase the risk of RA both directly through increasing inflammation and indirectly through increasing insulin resistance and obesity, with the latter being a known risk factor for RA. On the contrary, consumption of long-chain omega-3 polyunsaturated fatty acids, derived from fish and fish oil, is associated with a reduced risk of RA probably due to their anti-inflammatory properties. The Mediterranean diet (MD), rich in plant-based foods such as wholegrains, legumes, fruit, vegetables, extra-virgin olive oil and low in red meat consumption, might have the potential to reduce the risk of RA. Based on current research evidence, it is suggested that adherence to the MD enhanced with an increased consumption of fatty fish, reduced consumption of sugar-sweetened drinks and maintenance of a normal body weight, contributes to reducing the risk of RA. Further research on RA susceptibility will allow for more specific dietary recommendations to be made.     

Interaction between food antigens and the immune system: Association with autoimmune disorders

It has been shown that environmental factors such as infections, chemicals, and diet play a major role in autoimmune diseases; however, relatively little attention has been given to food components as the most prevalent modifiers of these afflictions. This review summarizes the current body of knowledge related to different mechanisms and associations between food proteins/peptides and autoimmune disorders. The primary factor controlling food-related immune reactions is the oral tolerance mechanism. The failure of oral tolerance triggers immune reactivity against dietary antigens, which may initiate or exacerbate autoimmune disease when the food antigen shares homology with human tissue antigens. Because the conformational fit between food antigens and a host's self-determinants has been determined for only a few food proteins, we examined evidence related to the reaction of affinity-purified disease-specific antibody with different food antigens. We also studied the reaction of monoclonal or polyclonal tissue-specific antibodies with various food antigens and the reaction of food-specific antibodies with human tissue antigens. Examining the assembled information, we postulated that chemical modification of food proteins by different toxicants in food may result in immune reaction against modified food proteins that cross-react with tissue antigens, resulting in autoimmune reactivity. Because we are what our microbiome eats, food can change the gut commensals, and toxins can breach the gut barrier, penetrating into different organs where they can initiate autoimmune response. Conversely, there are also foods and supplements that help maintain oral tolerance and microbiome homeostasis. Understanding the potential link between specific food consumption and autoimmunity in humans may lay the foundation for further research about the proper diet in the prevention of autoimmune diseases.     

Omega-3 fatty acids upregulate adult neurogenesis

Omega-3 fatty acids play crucial roles in the development and function of the central nervous system. These components, which must be obtained from dietary sources, have been implicated in a variety of neurodevelopmental and psychiatric disorders. Furthermore, the presence of omega-6 fatty acids may interfere with omega-3 fatty acid metabolism. The present study investigated whether changes in dietary ratios of omega-3:omega-6 fatty acids influence neurogenesis in the lobster (Homarus americanus) brain where, as in many vertebrate species, neurogenesis persists throughout life. The factors that regulate adult neurogenesis are highly conserved among species, and the crustacean brain has been successfully utilized as a model for investigating this process. In this study, lobsters were fed one of three diets that differed in fatty acid content. These animals were subsequently incubated in 5-bromo-2′-deoxyuridine (BrdU) to detect cells in S-phase of the cell cycle. A quantitative analysis of the resulting BrdU-labeled cells in the projection neuron cluster in the brain shows that short-term augmentation of dietary omega-3 relative to omega-6 fatty acids results in significant increases in the numbers of S phase cells, and that the circadian pattern of neurogenesis is also altered. It is proposed that the ratio of omega-3:omega-6 fatty acids may alter neurogenesis via modulatory influences on membrane proteins, cytokines and/or neurotrophins.     

Genetic studies of neuropsychiatric disorders in Costa Rica: a model for the use of isolated populations

The importance of genetics in understanding the etiology of mental illness has become increasingly clear in recent years, as more evidence has mounted that almost all neuropsychiatric disorders have a genetic component. It has also become clear, however, that these disorders are etiologically complex, and multiple genetic and environmental factors contribute to their makeup. So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003). For this reason, alternative approaches are being attempted, including studies in genetically isolated populations. Because isolated populations have a high degree of genetic homogeneity, their use may simplify the process of identifying disease genes in disorders where multiple genes may play a role. Several areas of Latin America contain genetically isolated populations that are well suited for the study of neuropsychiatric disorders. Genetic studies of several major psychiatric illnesses, including bipolar disorder, major depression, schizophrenia, Tourette Syndrome, alcohol dependence, attention deficit hyperactivity disorder, and obsessive-compulsive disorder, are currently underway in these regions. In this paper we highlight the studies currently being conducted by our groups in the Central Valley of Costa Rica to illustrate the potential advantages of this population for genetic studies.     

Nutritional assessment in intravenous drug users with HIV/AIDS

Studying metabolic, endocrine, and gastrointestinal (MEG) disorders in drug abuse and HIV infection is important. Equally important, however, are the tools we use to assess these disorders. Assessment of nutritional status may include any combination of biochemical and body composition measurements, dietary intake assessment, and metabolic studies. Each method has its strengths and weaknesses and there is no perfect tool. When assessing nutritional status in injection drug users (IDU) and in HIV-infected people, the decision on which method or methods to use becomes even more complex. A review of studies reported during the XII World Conference on AIDS reveals that of 64 abstracts on the topic of nutrition in HIV-infected adults, only 11 assessed diet, 41 assessed anthropometry, and 24 assessed some form of biochemical measure. The most commonly reported methods for dietary intake included 24-hour recalls, food records, and food frequencies. The commonest methods used for measuring body composition included height, weight, bioimpedance, and dual-energy x-ray absorptiometry (DEXA). Biochemical measurements included various blood nutrients, lipids, and albumin. Methods varied greatly between studies, and caution should be taken when trying to compare results across studies, especially among those using different methods. Currently, few studies deal with the development of methods that can be used for research in HIV-infected and IDU populations. We need to work toward better tools in dietary intake assessment, body composition, and biochemical measurements, especially methods that will allow us to track changes in nutritional status over time.     

Tannins, salivary proline-rich proteins and oesophageal cancer

No single dietary factor or ingested substance has been implicated in the aetiology of oesophageal carcinoma especially in high-risk areas of the world. Although not well defined, there is heavy consumption of tannin-rich foods, particularly sorghum, by populations at high risk for carcinoma. The carcinogenic properties of tannins and extracts of tannin-rich plants have been demonstrated experimentally. It is proposed herein that salivary proline-rich proteins (PRPs) by binding ingested tannins protect the oesophagus from the carcinogenic effects of the latter. It is also possible that genetic variants of PRPs may influence the incidence of oesophageal cancer in different populations.     

Effects of dietary supplementation with a combination of fish oil, bilberry extract, and lutein on subjective symptoms of asthenopia in humans

The aim of this study was to determine the effects of dietary supplementation with a combination of fish oil, bilberry extract, and lutein on subjective symptoms of asthenopia in humans by a double- blind, randomized, parallel-group, and placebo-controlled trial. In the Active group, eleven subjects ingested a supplement containing omega-3 fatty acid-rich fish oil (docosahexaenoic acid 783 mg/day, eicosapentaenoic acid 162 mg/day), bilberry extract (anthocyanidin 59 mg/day), and lutein (17.5 mg/day) in soft gel capsule form, every day for 4 weeks. In the Placebo group, nine subjects ingested placebo capsules. Before and after supplementation, subjects completed a questionnaire to determine their asthenopia symptoms and were also assessed for mental fatigue symptom by the visual analog scale (VAS) test. Asthenopia symptoms such as "stiff shoulder, low back pain", "frustration", "dry-eye", and "stuffy head" were improved in the Active group. Furthermore, a score of mental fatigue was improved after 4 weeks of supplementation, and no side effects were observed after the 4-week supplementation and a 2-week washout period in the Active group. These results suggest that dietary supplementation with the combination of omega-3 fatty acid-rich fish oil, bilberry extract, and lutein may safely improve subjective symptoms of asthenopia and mental fatigue in humans.     

How eating affects mood

IOAKIMIDIS I, M. ZANDIAN, F. ULBL, C. BERGH, M LEON, AND P. S?DERSTEN. How eating affects mood. PHYSIOL BEHAV 2011 (000) 000-000. We hypothesize that the changes in mood that are associated with eating disorders are caused by a change in eating behavior. When food is in short supply, the rhythm of the neural network for eating, including orbitofrontal cortex and brainstem, slows down and we suggest that this type of neural activity activates a partially overlapping neural network for mood, including dorsal raphe serotonin projections to the orbitofrontal and prefrontal cortex. As a consequence, people who restrict the amount of food that they consume, either by choice or by their limited access to food, become preoccupied with food and food-related behavior. Most eating disorders emerge from a history of dietary restriction and we suggest that disordered eating consequent upon food restriction produces the altered mental state of patients with eating disorders. Based on the present hypothesis, eating disorders are not the result of a primary mental disorder. Rather, this notion suggests that the patients should be treated by learning to eat an appropriate amount of food at an appropriate rate.     

Cognitive reserve in neuropsychiatry

BACKGROUND: The idea that superior cognitive function acts as a protective factor against dementia and the consequences of head injury is well established. Here we suggest the hypothesis that cognitive reserve is also important in neuropsychiatric disorders including schizophrenia, bipolar disorder and depression. METHOD: We review the history of passive and active models of reserve, and apply the concept to neuropsychiatric disorders. Schizophrenia is used as an exemplar because the effects of premorbid IQ and cognitive function in this disorder have been extensively studied. RESULTS: Cognitive reserve may impact on neuropsychiatric disorders in three ways: by affecting the risk for developing the disorder, in the expression of symptoms within disorders, and in patients' functional outcome. Cognitive failure below a certain threshold may alone, or in combination with common psychiatric symptoms, produce neuropsychiatric syndromes. CONCLUSIONS: Consideration of cognitive reserve may considerably improve our understanding of individual differences in the causes and consequences of neuropsychiatric disorders. For these reasons, the concept of cognitive reserve should be incorporated in future studies of neuropsychiatric disorder. It may be possible to enhance cognitive reserve through pharmacological or non-pharmacological means, such as education, neurocognitive activation or other treatment programmes.     

Nutritional treatment for inborn errors of metabolism: Indications, regulations, and availability of medical foods and dietary supplements using phenylketonuria as an example

Medical foods and dietary supplements are used to treat rare inborn errors of metabolism (IEM) identified through state-based universal newborn screening. These products are regulated under Food and Drug Administration (FDA) food and dietary supplement statutes. The lack of harmony in terminology used to refer to medical foods and dietary supplements and the misuse of words that imply that FDA regulates these products as drugs have led to confusion. These products are expensive and, although they are used for medical treatment of IEM, third-party payer coverage of these products is inconsistent across the United States. Clinicians and families report termination of coverage in late adolescence, failure to cover treatment during pregnancy, coverage for select conditions only, or no coverage. We describe the indications for specific nutritional treatment products for IEM and their regulation, availability, and categorization. We conclude with a discussion of the problems that have contributed to the paradox of identifying individuals with IEM through newborn screening but not guaranteeing that they receive optimal treatment. Throughout the paper, we use the nutritional treatment of phenylketonuria as an example of IEM treatment.     

Effects of food processing on the thermodynamic and nutritive value of foods: literature and database survey

One of the goals of our society is to provide adequate nourishment for the general population of humans. In the strictness sense, the foodstuffs which we ingest are bundles of thermodynamic energy. In our post-industrial society, food producers provide society with the bioenergetic content of foods, while stabilizing the food in a non-perishable form that enables the consumer to access foods that are convenient and nutritious. As our modern society developed, the processing of foodstuffs increased to allow consumers flexibility in their choice in which foods to eat (based on nutritional content and amount of post-harvest processing). The thermodynamic energy content of foodstuffs is well documented in the literature by the use of bomb calorimetry measurements. Here, we determine the effects of processing (in most cases by the application of heat) on the thermodynamic energy content of foods in order to investigate the role of processing in daily nutritional needs. We also examine which processing procedures affect the nutritive quality (vitamin and mineral content) and critically assess the rational, advantages and disadvantages of additives to food. Finally, we discuss the role of endogenous enzymes in foods not only on the nutritive quality of the food but also on the freshness and flavor of the food. Our results show that a significant decrease in thermodynamic energy content occurs in fruits, vegetables, and meat products upon processing that is independent of water content. No significant change in energy content was observed in cereals, sugars, grains, fats and oils, and nuts. The vitamin content of most foods was most dramatically decreased by canning while smaller effects were observed upon blanching and freezing. We found that most food additives had very little effect on thermodynamic energy content due to their presence in minute quantities and that most were added to preserve the foodstuff or supplement its vitamin content. The endogenous food enzymes while aiding in digestibility of some foods (yogurt or grains) also helped some foods have a more palatable taste. Our conclusions are there is some scientific merit to the idea that enzymes in food can act synergistically with those in the human body to facilitate maximum nutritive value of foods.     

Health consequences of postsocialist transition: dietary and lifestyle determinants of plasma lipids in Yakutia.

The rapid social and cultural changes introduced by the collapse of the Soviet Union have resulted in important differences in cardiovascular health for indigenous Siberians. This study investigated diet and lifestyle determinants of plasma lipids in the Yakut, an indigenous Siberian herding population. The study used a cross-sectional design with data on 201 subjects in three urbanized towns and three rural communities in northeastern Siberia. Data on sociodemographic characteristics, dietary intake, and material lifestyle were collected, and lipids were analyzed from venous whole blood. Diet was analyzed using patterns of dietary intake based on principal components analysis of a dietary intake (food frequency) questionnaire. We identified three diet patterns: a traditional subsistence diet, a market foods diet, and a mixed diet. The effect of lifestyle on cardiovascular risk factors was measured using an ethnographically defined lifestyle index, with two orthogonal dimensions: subsistence lifestyle and modern lifestyle. Total cholesterol (TC) and low-density lipoprotein (LDL) were significantly higher among those consuming a traditional subsistence diet of meat and dairy products. A modern lifestyle was associated with lower TC and LDL but higher adiposity and higher risk of obesity. LDL and TC were higher in rural communities and lower in urbanized towns. The significantly higher lipid levels associated with a subsistence diet and indirectly with a subsistence lifestyle indicate the emergence of a significant health problem associated with the social and cultural changes occurring in Yakutia today. These findings underscore the need for dietary modification and promotion of physical activity among those most at risk for cardiovascular disease (CVD). Moreover, these results differ from those commonly seen in "modernizing" populations, in that elements of subsistence lifestyle are associated with an elevated rather than reduced risk of CVD. Such variable responses to lifestyle change emphasize the need to better understand the distinct social and historical events that may influence health changes among populations in transition.     

The role of omega-3 fatty acids contained in olive oil on chronic inflammation

Nowadays, people have been eating lots of unhealthy dietary excesses, that make them have chronic inflammatory diseases or known as chronic diseases. Countless millions of people worldwide can not help eating selectively massive quantities of unhealthy foods, until they become sick, often mortality. The omega-6 fatty acids account for the majority of PUFA (Poly Unsaturated Fatty Acids) in the food supply. They are the pre-dominant PUFA in all diets, especially the western diets, which produce pro-inflammatory metabolic products. The persistent antigenic or cytotoxic effects will lead to chronic inflammation. Olive tree is native to the Mediterranean basin and parts of Asia Minor. Its compression-extracted oil from the fruit has a wide range of therapeutic and culinary applications. It had been used as aphrodisiacs, emollients, laxatives, nutritives, sedatives, and tonics. In the later part of the 20th century, several studies had revealed that the olives in the Mediteranian diet is linked to a reduced incidence of degenerative diseases. It is one of phytomedicine which has omega-3 fatty acid as its constituent, may inhibit inflammation composing chronic inflammatory process in many chronic diseases, such as coronary artery disease, rheumatoid arthritis, hypertension, and even cancer.     

Treatment of chronic fatigue syndrome by dietary supplementation with omega-3 fatty acids--a good idea?

Minor alterations of immune, neuroendocrine, and autonomic function may be associated with the chronic fatigue syndrome. omega-3 fatty acids decrease the production of putative mediators of inflammation, including interleukin-1, and tumor necrosis factor. Since interleukin-1 and tumor necrosis factor are the principal polypeptide mediators of immunoregulation, reduced production of these cytokines by dietary supplementation with omega-3, may be a possible mechanism for the treatment of chronic fatigue syndrome.     

Does modification of olfacto-gustatory stimulation diminish sensory-specific satiety in humans?

Alimentary sensory pleasure is an important factor in ingestive behavior. Renewal of olfacto-gustatory pleasure by introducing new foods or through seasoning of previously consumed food might increase intake. OBJECTIVES: To explore whether sensory-specific satiety (SSS) for a food could be modulated, either by introducing a novel food or by a modification of sensory stimulation via seasoning the food just eaten. METHODS: 180 out of 242 subjects were distributed over 3 experiments involving ad libitum intake of one of 6 fresh foods (cucumber, tomato, pineapple, banana, peanut, pistachio). Blindfolded subjects reported their sensations for the foods on 3 parameters before and after intake of an olfactorily chosen food: Olfactory pleasure (OP), Specific appetite (SA) and Stimulus-Induced Salivation (SIS). EXP. 1: One chosen food was repeatedly presented orthonasally and rated before and after it was eaten. EXP. 2: A second food was olfactorily chosen and ingested after the first one. EXP. 3: The same food was offered again after seasoning. RESULTS: 2 min after ingestion, food intake was limited by SSS. OP, SA, SIS correlated with each other for eaten and non-eaten foods. OP for non-eaten foods increased (p<0.01) after ingestion of the chosen food to specific satiety. When the food just eaten was seasoned, OP increased (p<0.01) and led to additional intake (80% of first intake). CONCLUSION: A reduction in SSS after introduction of a new flavor or after seasoning an ingested food was observed. Such a reduction has not previously been reported. This could hint at how food sensory variation leads to over-consumption.     

Ecology fo the health and nutrition in Ecuadorian Amazonia (province of Napo). II. Colonists of the petroleum zone

The amazonian region of Ecuador is the site of a powerful migratory influx for colonizing new lands. 1/3 of the settlers come from the coastal part of the country and 2/3 from the andean part (Sierra). To cope with their new situation, people carry out cash crop cultivations and adopt stereotyped food consumption patterns. Though they do not suffer from any important food shortages, the dietary quality of foods is poor and nutritional deficiencies are observed. Prevalence rate of parasitic infestation is high and infectious diseases are common. About 10% of the children are moderately undernourished and more than 50% denote growth retardation. The extent of growth retardations varies according to the geographical origin of families. Children from the coast having a faster growth than their andean counterparts. The differences could be explained by the fact that coastal families, coming from an area with ecological and climatic characteristics closed to those encountered in Amazonia, are less out of their element than the Sierra's. It seems that fortune of settlers improve with time, however the evolution of the colonization process and its consequences on the health status of populations is almost unknown. The magnitude of this phenomenon, the number of countries involved and people concerned emphasize the need for more substantial research on the scope.