Global health in conflict. Understanding opposition to vitamin A supplementation in India.

Vitamin A supplementation is a public health intervention that clinical trials have suggested can significantly improve child survival in the developing world. Yet, prominent scientists in India have questioned its scientific validity, opposed its implementation, and accused its advocates of corruption and greed. It is ironic that these opponents were among the pioneers of populationwide vitamin A supplementation for ocular health. Historically, complex interests have shaped vitamin A supplementation resistance in India. Local social and nutritional revolutions and shifting international paradigms of global health have played a role. Other resistance movements in Indian history, such as those in response to campaigns for bacillus Calmette-Guérin and novel vaccines, have been structured around similar themes. Public health resistance is shaped by the cultural and political context in which it develops. Armed with knowledge of the history of a region and patterns of past resistance, public health practitioners can better understand how to negotiate global health conflicts.

On the 'discovery' of vitamin A.

Vitamin A is essential for normal growth, reproduction, immunity, and vision. The characterization of vitamin A spanned a period of about 130 years. During this long, incremental process, there is no single event that can be called the 'discovery' of vitamin A. The physiologist François Magendie conducted nutritional deprivation experiments with dogs in 1816 that resulted in corneal ulcers and high mortality - a finding similar to the common clinical situation in poorly fed, abandoned infants in Paris. In the 1880s, Nicolai Lunin showed that there was an unknown substance in milk that was essential for nutrition. Carl Socin suggested that an unknown substance for growth in egg yolk was fat soluble. Frederick Gowland Hopkins proposed in 1906 that there were 'unsuspected dietetic factors' that were necessary for life. In 1911, Wilhelm Stepp demonstrated that this essential substance in milk was fat soluble. The following year, Hopkins showed that there were 'accessory factors' present in 'astonishingly small amounts' in milk that supported life. Contrary to the dogma that all fats had similar nutritional value, in 1913, Elmer McCollum and Marguerite Davis at Wisconsin and Thomas Osborne and Lafayette Mendel at Yale showed butter and egg yolk were not equivalent to lard and olive oil in supporting the growth and survival of rats. The growth-supporting 'accessory factor' became known as 'fat-soluble A' in 1918 and then 'vitamin A' in 1920. Paul Karrer described the chemical structure of vitamin A in 1932. Harry Holmes and Ruth Corbet isolated and crystallized vitamin A in 1937. Methods for the synthesis of vitamin A came with the work of David Adriaan van Dorp and Jozef Ferdinand Arens in 1946 and Otto Isler and colleagues in 1947. Further work on the role of vitamin A in immunity and child survival continued until through the 1990s.

The discovery of the vitamins.

The discovery of the vitamins was a major scientific achievement in our understanding of health and disease. In 1912, Casimir Funk originally coined the term "vitamine". The major period of discovery began in the early nineteenth century and ended at the mid-twentieth century. The puzzle of each vitamin was solved through the work and contributions of epidemiologists, physicians, physiologists, and chemists. Rather than a mythical story of crowning scientific breakthroughs, the reality was a slow, stepwise progress that included setbacks, contradictions, refutations, and some chicanery. Research on the vitamins that are related to major deficiency syndromes began when the germ theory of disease was dominant and dogma held that only four nutritional factors were essential: proteins, carbohydrates, fats, and minerals. Clinicians soon recognized scurvy, beriberi, rickets, pellagra, and xerophthalmia as specific vitamin deficiencies, rather than diseases due to infections or toxins. Experimental physiology with animal models played a fundamental role in nutrition research and greatly shortened the period of human suffering from vitamin deficiencies. Ultimately it was the chemists who isolated the various vitamins, deduced their chemical structure, and developed methods for synthesis of vitamins. Our understanding of the vitamins continues to evolve from the initial period of discovery.

One hundred years of vitamins-a success story of the natural sciences.

The discovery of vitamins as essential factors in the diet was a scientific breakthrough that changed the world. Diseases such as scurvy, rickets, beriberi, and pellagra were recognized to be curable with an adequate diet. These diseases had been prevalent for thousands of years and had a dramatic impact on societies as well as on economic development. This Review highlights the key achievements in the development of industrial processes for the manufacture of eight of the 13 vitamins.

Bernard Strehler-inspiration for basic research into the mechanisms of aging.

Bernard Strehler, who passed away recently, has provided inspiration and intellectual guidance for a generation of scientists interested in the biology of aging. My own career in this field was launched in large part by the ideas and concepts discussed by Dr Strehler in his book, Time, Cells, and Aging. Much of my scientific career has been devoted to studying one aspect of the aging process-the intracellular accumulation of autofluorescent lysosomal storage bodies (lipofuscin) during senescence. Work in my laboratory has contributed to the elucidation of the molecular mechanisms that underlie formation of lipofuscin in the retinal pigment epithelium of the eye. The challenge for the work on lipofuscin, and for much of the current research on aging, is to determine whether specific age-related changes such as lipofuscin accumulation, are involved in determining maximum life span. Bernard Strehler's eloquent statement of this challenge will hopefully continue to inspire new research to further our understanding of the aging phenomenon.

Professor Toshio Ito: a clairvoyant in pericyte biology.

Ito cells are liver-specific pericytes which were first described as Fett Speicherung Zellen, the fat-storing cells encircling outside sinusoidal endothelial cells, in 1951 by the late professor Toshio Ito. His pioneering approaches for morphological characterization of the cells stimulate investigators to further examine their functional roles in liver homeostasis: a body of evidence has been accumulated in recent years showing that the cells play a crucial role in storage and delivery of vitamin A, regulation of sinusoidal tone and local blood supply, and tissue repair and fibrosis. It is now widely accepted that microvascular pericytes including Ito cells serve as a key player that controls angiogenesis. Furthermore, recent studies support a concept that Ito cells constitutes a bridging apparatus mediating bidirectional metabolic interactions between sinusoids and hepatocytes, utilizing prostanoids and/or gaseous mediators such as nitric oxide and carbon monoxide as signaling molecules. This article reviews researches on this liver-specific pericyte and its leading roles in recent development of pericyte biology.

Eduard Schwarz, a neglected pioneer in the history of nutrition.

An account of the journey around the world by the Austrian ship's doctor Eduard Schwarz on a sailing ship from 1857 to 1859, his successful cure of nightblindness among the sailors, and how he was maligned by some of the Viennese medical press for his view that nightblindness is a nutritional disorder.

[Historical milestones in the treatment of night blindness]. / Geschichtliche Meilensteine in der Behandlung der Nachtblindheit.

Most cases of night-blindness (nyctalopia or hemeralopia) do occur without an apparent organic eye-disease. In the past one spoke of essential or epidemic night-blindness. It is caused by a vitamin deficiency, and is a result of failing dark adaptation; it may lead to xerophthalmia, and finally to a complete permanent blindness, if not treated in time with vitamin A or vitamin A containing food (butter, egg-yolk, fish-liver oil). From time immemorial the healing effects of the intake of liver from fish and various animals for night-blindness has been reported from countries all over the world. In medical literature it has been recommended in the Papyrus Ebers (ca. 1500 B.C.), by the old Greek writers, from Hippocrates to Galen, and later to Oribasius and others. In the early sixteenth century Jac. Bontius (1592-1631) learned this therapy from empiric folk-medicine and advocated shark-liver as a specific medicine. Notwithstanding scattered reports of the dramatic favourable result of liver-treatment in patients with night-blindness, it would last until experimental research with a fat-poor diet led to the discovery (1913) and identification of vitamin A in our century, and the high vitamin A content of liver was established. Thus recognizing the value of the old liver-treatment, finally vitamin A was introduced in official ophthalmology. So an age-old, nearly universal favourable experience of empiric medicine had been neglected to the detriment of countless sufferers of night-blindness. Today systematic administration in cases of impending blindness, especially in some Asiatic areas, has already prevented the development of lasting blindness on a large scale.

Preventing blindness and saving lives: the centenary of vitamin A.

Within 20 years of its discovery 100 years ago, vitamin A was recognized as critical to normal eyes, growth, and survival. Clinical interest subsequently contracted to its importance in preventing xerophthalmia, until this ophthalmologist stumbled, quite accidently, on its role in fighting life-threatening infections. Repeated, large-scale randomized clinical trials eventually convinced (and reminded) the pediatric and nutrition communities of its importance for child survival. Vitamin A distribution programs are now credited with saving the sight and lives of nearly half a million children every year.

Chapter 29: historical aspects of the major neurological vitamin deficiency disorders: overview and fat-soluble vitamin A.

The vitamine doctrine: Although diseases resulting from vitamin deficiencies have been known for millennia, such disorders were generally attributed to toxic or infectious causes until the "vitamin doctrine" was developed in the early 20th century. In the late-19th century, a physiologically complete diet was believed to require only sufficient proteins, carbohydrates, fats, inorganic salts, and water. From 1880-1912, Lunin, Pekelharing, and Hopkins found that animals fed purified mixtures of known food components failed to grow or even lost weight and died, unless the diet was supplemented with small amounts of milk, suggesting that "accessory food factors" are required in trace amounts for normal growth. By this time, Funk suggested that deficiencies of trace dietary factors, which he labeled "vitamines" on the mistaken notion that they were "vital amines," were responsible for such diseases as beriberi, scurvy, rickets, and pellagra. Vitamin A deficiency eye disease: Night blindness was recognized by the ancient Egyptians and Greeks, and many authorities from Galen onward advocated liver as a curative. Outbreaks of night blindness were linked to nutritional causes in the 18th and 19th centuries by von Bergen, Schwarz, and others. Corneal ulceration was reported in 1817 by Magendie among vitamin A-deficient dogs fed for several weeks on a diet limited to sugar and water, although he erroneously attributed this to a deficiency of dietary nitrogen (i.e. protein). Subsequently, corneal epithelial defects, often in association with night blindness, were recognized in malnourished individuals subsisting on diets now recognizable as deficient in vitamin A by Budd, Livingstone, von Hubbenet, Bitot, Mori, Ishihari, and others. During World War I, Bloch conducted a controlled clinical trial of different diets among malnourished Danish children with night blindness and keratomalacia and concluded that whole milk, butter, and cod-liver oil contain a fat-soluble substance that protects against xerophthalmia. Early retinal photochemistry: In the 1870s, Boll found that light causes bleaching of the retinal pigment, and suggested that the outer segments of the rods contain a substance that conveys an impression of light to the brain by a photochemical process. Shortly thereafter, Kühne demonstrated that the bleaching process depends upon light, and was reversible if the retinal pigment epithelium was intact. Kühne proposed an "optochemical hypothesis," a prescient concept of photochemical transduction, attributing vision to a photochemical change in visual purple (rhodopsin) with resulting chemical products stimulating the visual cells and thereby conveying a visual image. Vitamin A: In 1913, Ishihara proposed that a "fatty substance" in blood is necessary for synthesis of both rhodopsin and the surface layer of the cornea, and that night blindness and keratomalacia develop when this substance is deficient. That year McCollum and Davis (and almost simultaneously Mendel and Osborne) discovered a fat-soluble accessory food factor (later called "fat-soluble A") distinct from the water-soluble anti-beriberi factor (later called "fat-soluble B"). By 1922 McCollum and colleagues distinguished two vitamins within the fat-soluble fraction, later named vitamins A and D. In 1925 Fridericia and Holm directly linked vitamin A to night blindness in animal experiments using rats, and in 1929 Holm demonstrated the presence of vitamin A in retinal tissue. In the 1930s, Moore, Karrer, Wald, and others established the provitamin role of beta-carotene. Karrer and colleagues isolated beta-carotene (the main dietary precursor of vitamin A) and retinol (vitamin A), and determined their chemical structures. In 1947, Isler and colleagues completed the full chemical synthesis of vitamin A. Modern retinal photochemistry: Beginning in the 1930s, Wald and colleagues greatly elaborated the photochemistry of vision, with the discovery of the visual cycle of vitamin A, demonstration that rhodopsin is decomposed by light into retinal (the aldehyde form of vitamin A) and a protein (opsin), elaboration of the enzymatic conversions of various elements in the rhodopsin system, and discovery that the rhodopsin system is dependent on a photoisomerization of retinal. In 1942, Hecht and colleagues demonstrated that a single photon could trigger excitation in a rod. In 1965, Wald suggested that a large chemical amplification was necessary for this degree of light sensitivity, likely by a cascade of enzymatic reactions. Later studies elaborated this cascade and found that an intermediary in the photoisomerization of retinal interacts with transducin, a G-protein, to activate phosphodiesterases that control cyclic GMP levels, which in turn modulate the release of neurotransmitter from the rod cell. Public health: Although the availability of vitamin A through food fortification and medicinal supplements virtually eliminated ocular vitamin A deficiency from developed countries by the second half of the 20th century, vitamin A deficiency remains a serious problem in developing countries as indicated by global surveys beginning in the 1960s. Millions of children were shown to be vitamin A deficient, with resultant blindness, increased susceptibility to infection, and increased childhood mortality. Beginning in the 1960s, intervention trials showed that vitamin A deficiency disorders could be prevented in developing countries with periodic vitamin A dosing, and in the 1980s and 1990s, large randomized, double-blind, placebo-controlled clinical trials demonstrated the marked efficacy of vitamin A supplementation in reducing childhood mortality.