Osteological evidence of metabolic diseases from a post medieval North Italy archaeological site.

Skeletal lesions related to metabolic diseases in children have been systematically investigated in paleopathological literature only in recent years. This work presents an infant pathological specimen from the post-medieval cemetery of the St. Mary's Nativity church (15th-18th centuries, Segno, Trento, Trentino, Northeast Italy). The bones belonged to an individual of 9 ± 3 months of age, estimated upon an assessment of the stage of dental eruption. Metabolic diseases were diagnosed with paleopathological criteria according to previous literature. Differential diagnosis of the osteological evidence indicates a disease that might be caused by the lack of vitamin D or C. Comorbidity of vitamin C and D deficiency has been widely studied in clinical literature, particularly in children between 3 months and 5 years of age. The study of ancient osteoarchaeological materials allows us to improve our knowledge on diseases' effects on bone development in children and, in this case, it represents additional evidence of the presence of metabolic diseases in a rural contest of the Italian post-medieval period.

Vitamin D: part II; cod liver oil, ultraviolet radiation, and eradication of rickets.

PURPOSE: After Glisson's description of rickets, it took two centuries to realize that rickets was due to the absence of antirachitic nutrients in the diet or lack exposure of the skin to ultraviolet rays. This bone disease caused by vitamin D deficiency was one of the most common diseases of children 100 years ago. This paper explores how the definition, diagnosis, and treatment of rickets shifted in the first decades of the twentieth century. MATERIAL AND METHODS: Although benefits of cod liver oil as food were known as early as the seventh century, cod liver oil was only proposed as medicinal for rickets in Northern Europe at the end of the eighteenth century. The relationship between rickets and nutritional deficiency was suspected and demonstrated between 1880 and 1915, at the same time of the discovery of other vital substances (vitamins) needed to prevent beriberi, scurvy, and pellagra. Understanding that the lack of photosynthesized vitamin D or the lack of dietary vitamin D was a similar risk of rickets was an important turn in the comprehension of the disease. We look at the sequence and turn of events related to the discovery of vitamin D. RESULTS: Rickets has been recognized first as a disease of urban living people. Cod liver oil had been used since 1700 as a nonspecific treatment for a range of diseases. Generations of children in cities of the north of Europe had learned to hate the taste and smell of the black oily liquid and then grown up to be parents who, in turn, hated to force it down their children's throats. Occasional papers before 1900 pointed to its efficacy for rickets, and most textbooks of the early 1900s mentioned it only as a treatment option. The discovery in the early 1900s that artificial and natural ultraviolet rays had both antirachitic activity allowed to produce antirachitic foods just by food irradiation with artificial ultraviolet irradiation. Clinical guidelines were adopted to propose exposure to sunlight or to artificial ultraviolet radiation to prevent rickets in children. By the mid-1920s, rickets was promoted as universal, at times invisible to non-experts, but present to some degree in nearly every young child regardless of race or class. It was thus used to promote the young disciplines of preventive medicine, pediatrics, and public health. Innovative advances were made in the understanding of vitamin D synthesis from 1915 to 1935. A public health campaign of the 1930s was a success to eradicate rickets, using irradiated ergosterol from yeast to enrich milk and other foods with vitamin D, ensuring that the general population was consuming sufficient vitamin D. CONCLUSION: Rickets therefore provides an excellent window into the early politics of preventive health and the promotion of targeted interventions in the world. It is also a relevant historical counterpoint for current debates over the role of risk factors (absence of light or sun) for disease (today's so-called "lifestyle" diseases).

The rachitic tooth: The use of radiographs as a screening technique.

This study investigates morphological changes in pulp chambers of living and archaeological individuals with past vitamin D deficiency. Living individuals (n=29), four with detailed medical and dental records and three groups of archaeological individuals (n=25) were radiographed; selected individuals were further evaluated histologically for the presence of incremental interglobular dentin (IIGD), indicative of deficiency (28 living; 17 archaeological). Measurements of pulp horns/chambers from radiographs were conducted to quantify morphological observations. One group had clear skeletal evidence of rickets from St. Matthew, Quebec (n=1) and St. Jacques, France (n=4); a second group had slight skeletal indicators from Bastion des Ursulines, Quebec (n=6); and a third group lacked both skeletal and radiological evidence of deficiency from St. Antoine (n=6) and Pointe-aux-Trembles (n=4). Results showed archaeological individuals with clear and slight skeletal evidence of past deficiency displayed constricted or chair shaped pulp horns. Living individuals with deficiency exhibited similar pulp chamber morphology. Radiographic pulp horn/chamber measurements corroborated morphological findings and significant differences were found in pulp horn/chamber measurements between those with and without deficiency. Results suggest that radiograph assessment of teeth can be used as a screening technique to elucidate patterns of deficiency and select individuals for microCT or histological assessment.

Analysis of patterning in the occurrence of skeletal lesions used as indicators of vitamin D deficiency in subadult and adult skeletal remains.

Paleopathological investigations of conditions linked to vitamin D deficiency have increased in the last twenty years, and a suite of skeletal lesions has been established to aid in the diagnosis of vitamin D deficiency disease in subadults and adults. This paper analyzes the occurrence of these lesions in a large skeletal series comprising 3541 Roman period individuals (1st-6th century AD). Sixteen lesions reported in rickets in subadults, and 13 associated with residual rickets and osteomalacia in adults, were analyzed. Among subadults, there were clear associations among post-cranial lesions. Porotic cranial changes were associated with each other, but not with post-cranial lesions. A range of conditions could have produced the cranial lesions. There was a general paucity of correlations between indicators found in adults, and the difficulty in recording bending deformities was clear. Pseudofractures appear to provide a useful means of investigating osteomalacia in adults. In general, a simple algorithmic approach using presence or absence of lesions is unlikely to provide an adequate means of diagnosing vitamin D deficiency in paleopathology. Knowledge and consideration of the underlying physiological mechanisms involved in lesion formation, combined with individual judgement, will be required to differentially diagnose cases.

Osteological evidence for juvenile vitamin D deficiency in a 19th century suburban population from Surrey, England.

Vitamin D deficiency rickets was considered endemic in the industrialized cities of 19th century England, but was rarely reported in more rural and suburban areas. The commercial excavation of St. John's Church, Redhill, Surrey, UK provided an opportunity to examine to what extent suburban children were affected by rickets and the factors responsible for its development. Seventy-nine non-adults (0-17 years) from St. John's Church were subjected to macroscopic and radiographic analysis to identify skeletal manifestations of vitamin D deficiency. Rachitic lesions were identified in 14/79 individuals (17.7%) aged from six months to six years. Active cases occurred from six months to two years of age with healed cases observed from three to six years. One seven month old infant also displayed healed lesions. The age-specific pattern of active and healed rickets suggests the population was vulnerable to the seasonal restriction of sunlight hours, with the considerably low vitamin D content of the infant diet unable to provide sufficient amounts to maintain metabolic functions. This research demonstrates that rickets was not simply a disease of industrialization but that a variety of factors contributed to its development in groups previously considered to be low risk.

Gender-related vitamin D deficiency in a Dutch 19th century farming community.

The most common cause of vitamin D deficiency is inadequate dermal exposure to sunlight. Residual rickets is nonadult vitamin D deficiency still evident in an adult individual, whereas osteomalacia occurs in adulthood. Previous research on the Beemster population, a 19th century rural community in the Netherlands, identified rickets in 30.4% of the nonadults between the ages of two and four years (n=7/23). Because the sex of these nonadults was not known it was not possible to determine if there were differences between boys and girls. To overcome this gap in our knowledge, the aim of this paper is to determine if there are gender related differences in vitamin D deficiency in the Beemster skeletal collection, based on adults with residual rickets and osteomalacia. Out of 200 adults (100 females; 100 males) no cases of osteomalacia were detected. However, there were 29 cases of residual rickets (14.5%), with 21 of those cases in females (21.0%; 21/100). A complex interplay of multiple factors is proposed to have affected vitamin D levels in nonadults, including sociocultural variables such as gender-based labour norms. This research highlights the importance of continuing to explore gender-based health differences in past populations.

Rare paleopathological insights into vitamin D deficiency rickets, co-occurring illnesses, and documented cause of death in mid-19th century London, UK.

Growing evidence suggests that vitamin D supports immune responses to infections, autoimmune conditions and cancers, although evidence from large-scale studies is limited. There is scope to better understand how vitamin D deficiency interacted with other diseases to affect health in past groups. This study investigated paleopathological evidence and documentary records of individual cause of death to examine disease co-occurrence in a group of mid-19th century child burials from London, UK. Twenty-one percent of children had vitamin D deficiency rickets (138/642) and 36 children with rickets had an identified cause of death. Cyclical episodes of metabolic and nutritional deficiencies (rickets and scurvy) had occurred during childhood. Active rickets co-occurred with respiratory and gastrointestinal infections in a small number of children, likely reflecting vitamin D's role in supporting immune function. Consideration of the stage of the vitamin D deficiency showed that the majority of children were affected by chronic disease loads indicative of multiple episodes of illness. Reconstructions of the wider health consequences of vitamin D deficiency in past groups are dependent on recognising whether the deficiency was active or healed. The variability of diseases identified illustrates the high disease burden that affected children in this socially disadvantaged group.

The discovery and synthesis of the nutritional factor vitamin D.

Although vitamin D deficiency was first recognized as rickets/osteomalacia in the early 1600s, it was only a century ago that vitamin D, the nutritional factor responsible, was discovered. This discovery was made difficult by the fact that the substance could be synthesized in human skin by exposure to UV light and could also be present in the diet in animal-derived (D3) and plant-derived forms (D2). Prior to 1920, the frequency of vitamin D deficiency in the general population of industrialized cities was high. The discovery of vitamin D led to the widespread fortification of foods e.g. milk and the virtual eradication of rickets in developed nations. Vitamin D3 was first chemically synthesized in the 1930s and its metabolism to the active form 1,25-dihydroxyvitamin D3 and its mode of action in calcium and phosphate homeostasis were elucidated in the latter half of the 20th century. Synthetic vitamin D analogs that mimic the physiological effects of vitamin D are now used therapeutically in diseases such as bone disease, chronic kidney disease and psoriasis. Thus, a wide range of disciplines played critical roles in the rich history of vitamin D and these are described in this short historical overview.

Latitude, urbanization, age, and sex as risk factors for vitamin D deficiency disease in the Roman Empire.

OBJECTIVES: The aims of the study are to investigate the effects of latitude, settlement type, age, and sex on the prevalence of vitamin D deficiency disease in the Roman Empire using human skeletal remains from cemetery sites (1st to 6th cent. AD). MATERIALS AND METHODS: Data from 2,787 individuals (1,143 subadults, 1,644 adults) from 18 cemeteries associated with 15 different settlements in the Mediterranean and north-western Europe were analyzed. Vitamin D deficiency disease (rickets, osteomalacia) was identified using standard paleopathological criteria. Multivariate statistical analysis was used analyze the effects of the variables of interest on the prevalence of vitamin D deficiency. RESULTS: The overall prevalence of rickets in subadults (<20 years) was 5.7%, and 3.2% of adults showed osteomalacia and/or residual rickets. There was a positive association between rickets in subadults and latitude, with numerous cases of rickets among infants. There was no general association with sex or settlement type, although an elevated prevalence of rickets was observed at a cemetery associated with a settlement (Ostia, Italy), which had multi-storey buildings. DISCUSSION: The association of rickets with latitude may reflect care practices that, in more northerly locations where solar radiation is less intense, placed infants at increased risk of insufficient sunlight exposure to permit adequate vitamin D biosynthesis. The elevated level of vitamin D deficiency at Ostia may reflect, at least in part, the lack of sunlight due to dense occupation of multi-storey blocks that prevented direct sunlight from reaching living quarters and the streets between these closely spaced buildings.

Endochondral growth disruption during vitamin D deficiency rickets in a mid-19th century series from Bethnal Green, London, UK.

OBJECTIVES: Vitamin D affects many aspects of cartilage and skeletal development. Inconsistent findings currently exist regarding the impact of vitamin D deficiency on childhood growth. This study aims to evaluate the impact of vitamin D deficiency on childhood skeletal development by exploring long bone growth in children with healed and active rickets. MATERIALS AND METHODS: Forty-four known-age children (2 months to 12 years) with rickets and 99 without rickets were compared with modern reference data from North America. Diaphyseal lengths of children with active rickets (34.1%, 15/44), healed rickets (65.9%, 29/44), and without rickets (99/143, 69.2%) were expressed as a percentage of expected length and an average percentage value was calculated across all available long bones. RESULTS: Combined data for all six long bones revealed that children with active rickets had achieved only 75.3% of their expected size whereas, on average, children with healed rickets had achieved 81.6% of their expected size. On average, children without skeletal evidence of rickets had achieved 83.7% of their expected size. Children with severe skeletal manifestations of active rickets had a lower average percentage of expected size (70.4%) than the remainder of children affected by the condition. DISCUSSION: Pronounced growth faltering existed in children with active rickets and affected the upper and lower limb, indicating systemic growth failures during the deficiency. Poor maternal health, early weaning and inadequate infant feeding, and lack of sunlight exposure likely contributed to the development of rickets. Complex interactions between pathological conditions, nutritional deficiencies and vitamin D deficiency may have exacerbated growth impacts.

Medical diagnostic methods applied to a medieval female with vitamin D deficiency from the north of Spain.

Vitamin D deficiency is a pathological condition that affects bone metabolism by preventing proper mineralization, which eventually leads to bone deformities and other pathological conditions such as osteoporosis, increased bone fragility and fractures. The aim of this study is to present a case of vitamin D deficiency, but also to note how the application of several complementary techniques is a fundamental step in the establishing an accurate diagnosis. These techniques range from classical palaeopathological analysis to modern clinical practice. After the macroscopic examination of a medieval female skeleton from Palencia (Spain), where various bone deformations were observed, a differential diagnosis could not establish a definitive cause. Radiological, bone density, and histological studies were carried out, finally allowing to confirm a vitamin D deficiency suffered in both childhood and adulthood. This is a clear example, with practical applications, of the importance of interdisciplinarity to reveal insights about the life history and physical health of ancient individuals.

The pathology of vitamin D deficiency in domesticated animals: An evolutionary and comparative overview.

Although vitamin D is critical to calcium/phosphorus homeostasis, bone formation and remodeling, there is evolution-based variation between species in vitamin D metabolism and susceptibility to rickets and osteomalacia. Most herbivores produce vitamin D3 in response to sunlight, but dogs and cats have generally lost the ability as carnivore diets are rich in vitamin D. Nutritional deficiencies and/or poor exposure to sunlight can induce rickets in birds, swine, cattle and sheep, but horses are less susceptible as they have evolved a calcium homeostasis that is quite different than other animals. Adaptations to specific environments also affect disease incidence: llamas/alpacas out of their natural high altitude intense solar radiation environments are highly susceptible to vitamin D deficiency. The pathology of rickets/osteomalacia is similar across species, however fibrous osteodystrophy is more common and may also be present. Rickets/osteomalacia were likely more common in animals before the advent of commercial diets, but can be difficult to definitively diagnose especially in single archeological specimens. Consideration of species susceptibility, location - especially in terms of latitude, and any available information on diet, season of occurrence, husbandry practices or descriptions of affected animals can support the diagnosis of metabolic bone disease in animals.

Smaller long bone cross-sectional size in people who died of tuberculosis: Insights on frailty factors from a 19th and early 20th century Finnish population.

There is little research on how individuals suffering from tuberculosis may differ from those not infected in terms of overall skeletal morphology. Tuberculosis was endemic in 19th and early 20th century Finland making documented skeletal collections of Finns ideal to study effects of the disease on bone. The present study compares long bone cross-sectional total area between individuals who died of tuberculosis and those with another recorded cause of death in a Finnish sample. Adult male individuals (N = 105) were selected for analysis. Complete humeri (N = 56), femora (N = 66) and tibiae (N = 64) were 3D scanned using a laser scanner and total cross-sectional areas calculated with AsciiSection software. Individuals who died of tuberculosis (N = 24, 15 humeri, 14 femora, 13 tibiae) had, when standardized for body size, significantly smaller total cross-sectional femoral and humeral, but not tibial, areas. The mechanisms behind the observed relationship may reflect a combination of biological 'frailty' in terms of susceptibility to infection, reduced childhood activity and/or vitamin D deficiency, which possibly influenced both subperiosteal development during adolescence and, later, susceptibility to contracting and dying of TB. Due to the relatively small sample future studies are needed to further investigate the relationship between TB and bone cross-sectional size.

Increment of fatigue, depression, and stage fright during the first year of high-level education in music students.

In a recent Letter to the Editor, Grant and Pilz propose the hypothesis of a contribution of very low serum 25-hydroxyvitamin D levels to provoke Wolfgang Amadeus Mozart's death. Mozart died on the 5th of December, 1791, aged 35, probably due to an infection which, very likely, had low vitamin D levels as an important risk factor. According to Grant and Pilz, the lack of vitamin D is to be attributed, in the case of Mozart's, to insufficient exposure to sunlight, because he "did much of his composing at night, so would have slept during much of the day." Historical evidence, however, disproves the nocturnal habits of the Austrian composer.

Theobald palm and his remarkable observation: how the sunshine vitamin came to be recognized.

The seminal discovery that sunlight was important in the prevention of nutritional rickets was made in 1890 by Theobald A. Palm, a medical missionary who contrasted the prevalence of rickets in northern European urban areas with similar areas in Japan and other tropical countries. He surmised that exposure to sunlight prevented rickets. Over the next 40 years his observation led to an understanding of ultraviolet irradiation and its role in vitamin D synthesis. This opened a new era of appreciation for the curative powers of the sun and "the sunshine vitamin". While Palm's observations were in some ways obscure, they had a potent effect on the development of photobiology.

Old wine in new bottles: vitamin D in the treatment and prevention of tuberculosis.

Tuberculosis (TB) is a major cause of mortality, responsible for 1·68 million deaths worldwide in 2009. The global prevalence of latent Mycobacterium tuberculosis infection is estimated to be 32%, and this carries a 5-20% lifetime risk of reactivation disease. The emergence of drug-resistant organisms necessitates the development of new agents to enhance the response to antimicrobial therapy for active TB. Vitamin D was used to treat TB in the pre-antibiotic era, and its active metabolite, 1,25-dihydoxyvitamin D, has long been known to enhance the immune response to mycobacteria in vitro. Vitamin D deficiency is common in patients with active TB, and several clinical trials have evaluated the role of adjunctive vitamin D supplementation in its treatment. Results of these studies are conflicting, reflecting variation between studies in baseline vitamin D status of participants, dosing regimens and outcome measures. Vitamin D deficiency is also recognised to be highly prevalent among people with latent M. tuberculosis infection in both high- and low-burden settings, and there is a wealth of observational epidemiological evidence linking vitamin D deficiency with increased risk of reactivation disease. Randomised controlled trials of vitamin D supplementation for the prevention of active TB have yet to be performed, however. The conduct of such trials is a research priority, given the safety and low cost of vitamin D supplementation, and the potentially huge public health consequences of positive results.

Early animal models of rickets and proof of a nutritional deficiency hypothesis.

In the period between 1880 and 1930, the role of nutrition and nutritional deficiency as a cause of rickets was established based upon the results from 6 animal models of rickets. This greatly prevalent condition (60%-90% in some locales) in children of the industrialized world was an important clinical research topic. What had to be reconciled was that rickets was associated with infections, crowding, and living in northern latitudes, and cod liver oil was observed to prevent or cure the disease. Several brilliant insights opened up a new pathway to discovery using animal models of rickets. Studies in lion cubs, dogs, and rats showed the importance of cod liver oil and an antirachitic substance later termed vitamin D. They showed that fats in the diet were required, that vitamin D had a secosteroid structure and was different from vitamin A, and that ultraviolet irradiation could prevent or cure rickets. Several of these experiments had elements of serendipity in that certain dietary components and the presence or absence of sunshine or ultraviolet irradiation could critically change the course of rickets. Nonetheless, at the end of these studies, a nutritional deficiency of vitamin D resulting from a poor diet or lack of adequate sunshine was firmly established as a cause of rickets.

Sir Edward Mellanby (1884-1955) GBE KCB FRCP FRS: nutrition scientist and medical research mandarin.

Edward Mellanby used the experimental method to investigate medical problems. In 1918, working at King's College for Women, London, he provided conclusive evidence that rickets is a dietary deficiency disease due to lack of a fat-soluble vitamin [D]. In Sheffield he demonstrated that cereals, in an unbalanced diet, produced rickets due to the phytic acid content reducing the availability of calcium. Mellanby became Secretary of the Medical Research Council (1933-49) but continued his research by working at weekends. In the 1930s he campaigned for the results of nutritional research to be used for the benefit of public health. During World War II he acted as a scientific adviser to the War Cabinet and had a strong influence on the food policy which maintained successfully the nutrition of the population during the shipping blockade. Mellanby was a formidable person but with sagacity he promoted new research and guided the expansion of the organization.