Short communication: Metabolic synthesis of vitamin D2 by the gut microbiome.

The origin of vitamin D2 in herbivorous animals was investigated in vivo in sheep and in bovine as well as mouse gastrointestinal tracts. A high concentration of 25-hydroxyvitamin D2 in blood plasma of sheep both in summer and winter appeared to be incompatible with the undetectable level of vitamin D2 in the pasture on which the sheep were grazing. Studies with bovine rumen contents from a cow grazing the same pasture as the sheep, demonstrated an increased concentration of vitamin D2 on anaerobic incubation in a 'Rusitec' artificial rumen, which was further enhanced when cellulose powder was added as a fermentation substrate. The colon contents of mice that were fed from weaning on a vitamin D-free diet were found to contain vitamin D2. The results of these comparative studies in 3 animal species indicated that vitamin D2 was being generated by microbial anaerobic metabolism in the gastrointestinal tract.

Tracking Veterinary Students Who Aspire to Careers in Science.

The Cornell Leadership Program for Veterinary Students is an intensive 10-week learning experience intended to guide competitively selected scholars into careers in science and public health. It features independent research, vocational counseling, and student-directed learning modules. Program scholars are encouraged to objectively evaluate graduate training as preparation for careers promoted by the program. Prominence is given to experiential learning through research, participation in program enrichment modules, and inspirational experiences achieved through group meetings and individual interactions with established scientists. Program alumni are monitored to determine how the careers they pursue relate to their earlier-stated ambitions. In addition, subjective assessments are made of the quality of graduate training and its impact on alumni career paths. The influence of mentors, vocational counseling, and inspirational experiences on subsequent training is also subjectively assessed. Information is obtained from students' anonymous responses to questionnaires and recorded interviews. Program alumni are contacted annually to determine their current activities and career aspirations. The Leadership Program encourages program graduates to undertake careers in science and public health, yet an unanticipated number of alumni enter private veterinary practice. A factor relevant to that outcome is that many students destined for practice lack a definitive career plan. Persuading veterinary students to consider careers in research or public service is challenging but worth the effort. Critical to that connection is the need for veterinary students to objectively evaluate graduate training options because the vocations they follow appear to be strongly influenced by the experiences they choose.

In vivo measurement of strontium absorption from the rumen of dairy cows as an index of calcium absorption capacity.

Absorption of dietary calcium from the rumen is a quantitatively important process in calcium homeostasis of ruminants. In 3 separate experiments in dairy cows, we applied a technique developed in sheep to measure the rate of strontium (Sr) absorption from the rumen as an indicator of calcium absorption capacity. Absorption from the rumen after an oral dose of SrCl2 resulted in a maximum plasma concentration of Sr after 1 h, whereas absorption from the small intestine after injection of SrCl2 into the abomasum through a cannula occurred more slowly. The second experiment demonstrated that the calcium absorption capacity index of the rumen was significantly greater in 21 lactating Friesian cows (230 ± 66, mean ± SEM) than in 6 mature, nonlactating, nonpregnant heifers (101 ± 21, mean ± SEM). In a third experiment, we compared clinically normal cows at the onset of lactation with those that developed parturient paresis. In cows that developed severe hypocalcemia, plasma concentrations of 1,25(OH)2D were significantly elevated (144 ± 60 pg/mL vs. 90 ± 54 pg/mL; means ± SEM) and their rumen calcium absorption index was significantly decreased compared with that of clinically normal cows. Evidence suggested that mobilization of calcium from bone as lactation commenced was significantly depressed in paretic cows compared with those that did not show clinical signs of hypocalcemia. Moreover, ruminal stasis suppressed the absorption of calcium from the rumen. We conclude that measurement of Sr concentration in blood plasma after an oral dose of SrCl2 into the rumen can be used as an index of rumen calcium absorption capacity under different states of calcium homeostasis.

In vivo measurement of the absorption of strontium in the rumen and small intestine of sheep as an index of calcium absorption capacity.

In the present study, a method was developed for determining the alimentary tract Ca absorption capacity of ruminant animals by measuring the absorption rate of Sr after the administration of an oral dose of strontium chloride acting as a tracer analogue of Ca. A close correlation between the absorption rates of the two tracers was observed upon simultaneous administration of an oral dose of stable Sr and radioactive calcium (r 0·98). The Ca absorption capacity of the rumen and small intestine was determined separately by either directing the solution into the rumen or by diverting it into the post-ruminal tract by vasopressin-induced closure of the ruminoreticular groove. The animals were treated with 1α-hydroxyvitamin D3 administered via subcutaneously implanted mini-osmotic pumps. The effect of elevated plasma 1,25-dihydroxycholecalciferol concentrations on the Ca absorption capacity of the alimentary tract was then determined. An increased rate of Sr absorption was observed in both the rumen and small intestine of sheep after treatment, although it is unclear whether the rumen possesses the same vitamin D-dependent Ca absorption pathway as the small intestine.

Differences in peripartal plasma parameters related to calcium homeostasis of dairy sheep and goats in comparison with cows.

Recently it has been demonstrated that there are differences between sheep and goats in respect to adaptation to a calcium-restricted diet. It was the aim of the present study to evaluate whether species-specific peculiarities also occur when calcium homoeostasis is challenged by lactation. Therefore, we investigated the time courses of plasma parameters related to calcium homoeostasis (calcium, phosphate, calcitriol, the bone resorption marker CrossLaps and the bone formation marker osteocalcin) during the transition period in multiparous animals of both species and compared the results to data from a former study carried out with dairy cows. As in cows, plasma calcium and the ratio of bone formation to bone resorption decreased at parturition in goats while plasma calcitriol increased. On day 10 post partum the bone parameters of goats reached prepartum values again, which was not the case in cows. Sheep were found to experience a challenge of calcium homoeostasis already 10 d before parturition, reflected by a very low ratio of bone formation to bone resorption, which was not accompanied by an increase in plasma calcitriol. Additionally, sheep and goats which had been in milk for 3 months were sampled, dried-off and sampled again 6 weeks later. In dried-off animals there were no detectable differences in parameters of bone metabolism. In conclusion we could show that the contribution of bone mobilisation to the compensation for the enhanced calcium demand due to lactation differs between the three ruminant species.

Culture and sun exposure in immigrant East Asian women living in Australia.

In this qualitative study, researchers examined cultural and attitudinal factors that might be related to sun-exposure behaviors among East Asian women living in Australia. Researchers asked Chinese (n = 20) and Korean (n = 16) immigrant women who participated in a larger cross-sectional quantitative study of vitamin D blood levels to volunteer to participate in an in-depth interview in 2010. These women reported a number of cultural factors related to their attitudes and behaviors with regard to sun exposure. They expressed preference for fair skin, a tradition of covering skin when outdoors, and no sunbathing culture. They believed that fair skin was more beautiful than tanned skin. They reported that beauty was the reason for active avoidance of sunlight exposure. Although they reported knowledge of the need for sun avoidance due to skin cancer risk, few reported knowledge about the benefits of sun exposure for adequate vitamin D levels. These findings may provide some reasons for vitamin D deficiency previously reported in these populations. Thus, researchers recommend that these attitudes of excessive sun protection and limiting sun exposure be further investigated as they may have implications for planning and delivery of health promotion programs to this growing population of immigrants in Australia.

Differences in career paths of alumni of the Cornell Leadership Program from North American universities compared with those alumni from universities in other countries.

OBJECTIVE: To characterize and compare the careers of alumni of the Cornell Leadership Program for Veterinary Students according to the countries where they studied and obtained their veterinary qualification. The Cornell Leadership Program is a 10-week residential research experience program for veterinary students from around the world who have ambitions for research-related careers. SAMPLE: Data on the career development of all 672 alumni were collected each year over the period of 1990 to 2019. PROCEDURES: The annual career profile of each alumnus was recorded and coded in 1 of 28 different categories. The careers and postveterinary qualifications of alumni from universities in the US and Canada (referred to as North American universities) were compared with those alumni who graduated from universities in other countries. RESULTS: Analysis of this 30-year database revealed that a considerable proportion (45.7% [307/672]) of the total 672 alumni are following the traditional career path of veterinary clinical practice rather than the research-related careers they aspired to as students during the Leadership Program. Furthermore, a higher proportion of the 325 North American alumni (56% [182/325]) were in clinical practice compared with 33.6% (112/333) of the 333 alumni from other countries. CLINICAL RELEVANCE: Many veterinary schools now provide research experience programs to encourage highly talented students who have ambitions for careers in which they can advance knowledge about animal disease and contribute to solving the health problems of animals through hypothesis-based research. Comparison of the careers of the Leadership Program alumni indicates that research experience alone is not sufficient to maintain the career goals of alumni. Follow-up mentoring of alumni of such programs is recommended while they complete their veterinary studies to reinforce their career aspirations and provide advice on how to achieve research-related careers.

Serum 1,25-dihydroxyvitamin D levels in the diagnosis and pathogenesis of nutritional rickets - a multivariable re-analysis of a case-control study.

BACKGROUND: A multivariable logistic regression model resulting from a case-control study of nutritional rickets in Nigerian children suggested that higher levels of serum 25(OH)D may be required to prevent nutritional rickets in populations with low-calcium intakes. OBJECTIVES: This current study evaluates if adding serum 1,25-dihydroxyvitamin D [1,25(OH)2D] to that model shows that increased levels of serum 1,25(OH)2D are independently associated with risk of children on low-calcium diets having nutritional rickets. METHODS: Multivariable logistic regression analysis was used to model the association between serum 1,25(OH)2D and risk of having nutritional rickets in cases (n = 108) and controls (n = 115) after adjusting for age, sex, weight-for age z-score, religion, phosphorus intake and age began walking and the interaction between serum 25(OH)D and dietary calcium intake (Full Model). RESULTS: Serum 1,25(OH)2D levels were significantly higher (320 pmol/L vs. 280 pmol/L) (P = 0.002), and 25(OH)D levels were lower (33 nmol/L vs. 52 nmol/L) (P < 0.0001) in children with rickets than in control children. Serum calcium levels were lower in children with rickets (1.9 mmol/L) than in control children (2.2 mmol/L) (P < 0.001). Dietary calcium intakes were similarly low in both groups (212 mg/d) (P = 0.973). In the multivariable logistic model, 1,25(OH)2D was independently associated with risk of having rickets [coefficient = 0.007 (95% confidence limits: 0.002-0.011)] after adjusting for all variables in the Full Model. CONCLUSIONS: Results confirmed theoretical models that in children with low dietary calcium intake, 1,25(OH)2D serum concentrations are higher in children with rickets than in children without rickets. The difference in 1,25(OH)2D levels is consistent with the hypothesis that children with rickets have lower serum calcium concentrations which prompt the elevation of PTH levels resulting in an elevation of 1,25(OH)2D levels. These results support the need for additional studies to identify dietary and environmental risks for nutritional rickets.

In contrast to sheep, goats adapt to dietary calcium restriction by increasing intestinal absorption of calcium.

Many studies aimed at understanding calcium homeostasis in the cow use sheep or goats as ruminant models. However, the comparability of relevant homeostatic processes between ruminant species has not been assessed. Therefore, we investigated whether the mechanisms of maintaining calcium homeostasis are similar in different ruminant species. Dietary calcium of goats was restricted along with treatment with calcitriol in a similar protocol to that in a recent study with sheep. Plasma calcium and phosphate and parameters of bone metabolism were analysed. Gastrointestinal calcium transport was characterised in vitro in Ussing chambers. The expression of apical epithelial calcium channels, calbindin-D(9K), and the basolateral plasma membrane Ca(2+)-ATPase was determined by quantitative RT-PCR and Western blot analysis. In contrast to sheep, the goats were able to compensate for low dietary calcium supply by increasing active calcium absorption in the small intestine, especially in the jejunum. As in sheep, the observed ruminal calcium transport of goats was affected neither by the calcium restricted diet nor by the calcitriol treatment, thus indicating the presence of an alternative, vitamin D-independent mechanism of calcium transport in the forestomachs. These results demonstrate that mechanisms for maintaining calcium homeostasis differ significantly between ruminant species.

Physiological significance of vitamin D produced in skin compared with oral vitamin D.

Since the discovery of vitamin D, it has been accepted that its physiological supply is either from food or by endogenous synthesis in skin exposed to solar UV light. Yet vitamin D is a component of very few foods and its supply as a natural nutrient is unable to maintain good vitamin D status for human populations. One aspect of vitamin D physiology that has been ignored is that the mechanisms for its transport and processing from these two sources are quite different. Excess intake of vitamin D causes hypercalcaemic toxicity. However, experiments with different animal species have shown that long-term supply of oral vitamin D in apparently non-toxic amounts causes atherosclerosis in large arteries. A mechanism for this toxicity is proposed. Alternative strategies for addressing widespread vitamin D deficiency by food fortification should be considered in light of the angiotoxicity caused by oral vitamin D in animal experiments.

Diabetes prevalence is associated with serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in US middle-aged Caucasian men and women: a cross-sectional analysis within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Hypovitaminosis D may be associated with diabetes, hypertension and CHD. However, because studies examining the associations of all three chronic conditions with circulating 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)(2)D) are limited, we examined these associations in the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (n 2465). Caucasian PLCO participants selected as controls in previous nested case-control studies of 25(OH)D and 1,25(OH)(2)D were included in this analysis. Diabetes, CHD and hypertension prevalence, risk factors for these conditions and intake of vitamin D and Ca were collected from a baseline questionnaire. Results indicated that serum levels of 25(OH)D were low (< 50 nmol/l) in 29 % and very low (< 37 nmol/l) in 11 % of subjects. The prevalence of diabetes, hypertension and CHD was 7, 30 and 10 %, respectively. After adjustment for confounding by sex, geographical location, educational level, smoking history, BMI, physical activity, total dietary energy and vitamin D and Ca intake, only diabetes was significantly associated with lower 25(OH)D and 1,25(OH)(2)D levels. Caucasians who had 25(OH)D ≥ 80 nmol/l were half as likely to have diabetes (OR 0·5 (95 % CI 0·3, 0·9)) compared with those who had 25(OH)D < 37 nmol/l. Those in the highest quartile of 1,25(OH)(2)D (≥ 103 pmol/l) were less than half as likely to have diabetes (OR 0·3 (95 % CI 0·1, 0·7)) than those in the lowest quartile (< 72 pmol/l). In conclusion, the independent associations of 25(OH)D and 1,25(OH)(2)D with diabetes prevalence in a large population are new findings, and thus warrant confirmation in larger, prospective studies.

Vitamin D toxicity related to its physiological and unphysiological supply.

Vitamin D is defined as a nutrient despite its rare occurrence in food. Vitamin D status is determined mainly by solar UV light action in skin. However, the strategy to combat vitamin D deficiency has been to increase oral intake of vitamin D in greater amounts than could be obtained from food. Persistent large intakes of vitamin D can cause hypercalcaemic toxicity. Although the amounts recommended to prevent deficiency are far less than those causing such toxicity, the possibility of other toxic actions from increased intake of vitamin D has been ignored. Animal experiments have demonstrated that moderate amounts of oral vitamin D over time result in atherosclerosis. Differences in the fate of vitamin D could explain this angiotoxicity.

The association between dietary protein intake and bone mass accretion in pubertal girls with low calcium intakes.

To assess the association between protein intakes and bone mass accrual in girls, data were analysed for 757 pre-pubertal girls (mean age 10.1 years) in urban Beijing, China, who participated in a 5-year study including 2 years of milk supplementation (intervention groups only) and 3 years of follow-up study. At 0, 12, 24, 48 and 60 months from the baseline, bone mass of the proximal or distal forearm (PF or DF) and total body (TB) was measured with dual energy X-ray absorptiometry; dietary intakes were assessed by a 3-d food record (including two weekdays and one weekend day). Linear mixed models were used and continuous variables were logarithm transformed. The mean longitudinal Ca intake (432-675 mg/d on average) positively influenced bone mineral content (BMC) at TB, PF and DF after controlling for baseline bone mass and other possible confounders. However, negative associations were observed between protein intake (55.9-61.0 g/d on average) and BMC accrual at TB, PF or DF (beta = - 1.92, - 10.2 or - 4.82, respectively, P < 0.01) after adjustment. When protein intake was considered according to animal or plant food sources, protein from animal foods, particularly meat, had significant negative effects on BMC accrual at DF or PF after adjustment. It was concluded that higher protein intake, especially from animal foods, appeared to have a negative effect on bone mass accrual in Chinese pubertal girls with low Ca intakes.

Is it reasonable to ignore vitamin D status for musculoskeletal health?

Severe vitamin D deficiency-25-hydroxyvitamin D (25OHD) concentrations below around 25-30 nmol/L-may lead to growth plate disorganization and mineralization abnormalities in children (rickets) and mineralization defects throughout the skeleton (osteomalacia) and proximal muscle weakness. Both problems are reversed with vitamin D treatment. Apart from this musculoskeletal dysfunction at very low vitamin D levels, there is apparent inconsistency in the available data about whether concentrations of 25OHD below around 50 nmol/L cause muscle function impairment and increase the risk of fracture. This narrative review provides evidence to support the contention that improving vitamin D status, up to around 50 nmol/L, plays a small causal role in optimizing bone and muscle function as well as reducing overall mortality.

Skeletal Muscle and the Maintenance of Vitamin D Status.

Vitamin D, unlike the micronutrients, vitamins A, E, and K, is largely obtained not from food, but by the action of solar ultraviolet (UV) light on its precursor, 7-dehydrocholesterol, in skin. With the decline in UV light intensity in winter, most skin production of vitamin D occurs in summer. Since no defined storage organ or tissue has been found for vitamin D, it has been assumed that an adequate vitamin D status in winter can only be maintained by oral supplementation. Skeletal muscle cells have now been shown to incorporate the vitamin D-binding protein (DBP) from blood into the cell cytoplasm where it binds to cytoplasmic actin. This intracellular DBP provides an array of specific binding sites for 25-hydroxyvitamin D (25(OH)D), which diffuses into the cell from the extracellular fluid. When intracellular DBP undergoes proteolytic breakdown, the bound 25(OH)D is then released and diffuses back into the blood. This uptake and release of 25(OH)D by muscle accounts for the very long half-life of this metabolite in the circulation. Since 25(OH)D concentration in the blood declines in winter, its cycling in and out of muscle cells appears to be upregulated. Parathyroid hormone is the most likely factor enhancing the repeated cycling of 25(OH)D between skeletal muscle and blood. This mechanism appears to have evolved to maintain an adequate vitamin D status in winter.

Low vitamin D status has an adverse influence on bone mass, bone turnover, and muscle strength in Chinese adolescent girls.

Our goal in this cross-sectional study was to investigate the influence of low-vitamin D status on bone mass, bone turnover, and muscle strength in 301 healthy Chinese adolescent girls. Blood plasma 25-hydroxyvitamin D [25(OH)D] was measured by RIA and plasma and urine biomarkers of bone turnover were measured. Bone mineral content (BMC) and density and bone area for the whole body and the distal and proximal forearm were measured by dual energy X-ray absorptiometry. When vitamin D deficiency was defined as a serum 25(OH)D concentration of < or =50 nmol/L and severe deficiency as <25 nmol/L, 57.8% of subjects were vitamin D deficient and 31.2% were severely deficient. Multivariate analysis shows that girls with adequate vitamin D status had higher size-adjusted BMC for the whole body (P < 0.001), distal forearm (P < 0.001), and proximal forearm (P < 0.01) than those with poorer vitamin D status after adjusting for body size, handgrip strength, physical activity, and dietary intakes of calcium and vitamin D. Similar results were also found for handgrip muscle strength. Participants with adequate vitamin D status had significantly lower concentrations of bone alkaline phosphatase in plasma and deoxypyridinoline:creatinine ratio in urine compared with those of the vitamin D-deficient girls. Adolescent girls with adequate vitamin D status had significantly higher bone mass and muscle strength compared with those with poor vitamin D status. This may be attributed in part to a lower rate of bone remodeling with adequate vitamin D status. These findings suggest that adequate vitamin D status during adolescence is important for optimizing bone mass, which may lead to higher peak bone mass at maturity. Poor vitamin D status also compromises forearm muscle strength.

The Role of Skeletal Muscle in Maintaining Vitamin D Status in Winter.

The status of vitamin D is determined mainly by its formation in skin by the photochemical action of solar UVB light (wavelength 290-320 nm) on the precursor 7-dehydrocholesterol. Because of seasonal variation in intensity of solar UV light, vitamin D status falls in winter and rises in summer. It has been presumed that there is no functional store of vitamin D. Thus, to avoid deficiency, a nutritional supply would be required in winter. However, there is now evidence that the main circulating metabolite of vitamin D, 25-hydroxyvitamin D, accumulates in skeletal muscle cells, which provide a functional store during the winter months. The mechanism is mediated by muscle cell uptake of circulating vitamin D-binding protein (DBP) through a megalin-cubilin membrane transport process. DBP then binds to cytoplasmic actin to provide an array of high-affinity binding sites for 25-hydroxyvitamin D [25(OH)D]. The repeated passage of 25(OH)D into and out of muscle cells would account for its long residence time in blood.

Acquainting veterinary students with careers in the pharmaceutical industry.

Careers in the pharmaceutical industry were revealed in modules facilitated by senior scientists from companies that sponsor the Cornell Leadership Program for Veterinary Students. One module was structured as a series of interviews for different positions in industry, the other as a competition between hypothetical companies created by students. The interview-based module stimulated wide-ranging discussion of the activities and responsibilities of veterinarians employed in a discovery-intensive pharmaceutical firm and of the characteristics such companies seek in prospective employees, from both professional and personal perspectives. The second module explored the drug discovery and development process from the perspective of animal-health companies that are competitors in the market for animal health care products. The exercise provided insights into the manner in which companies discover new chemical entities, screen candidate drugs, allocate resources, and pursue the development of products through testing, licensing, and distribution.

Growth, bone mass, and vitamin D status of Chinese adolescent girls 3 y after withdrawal of milk supplementation.

BACKGROUND: A 2-y school milk intervention trial showed that 330 mL of a dietary milk supplement (fortified with calcium alone or with both calcium and vitamin D) enhanced the growth and bone mineral accretion of Chinese girls aged 10 y at baseline. Girls who received milk fortified with both calcium and vitamin D also had better vitamin D status than did girls who received nothing or girls who received milk fortified only with calcium. OBJECTIVE: The aim was to evaluate whether these effects were sustained 3 y after supplement withdrawal. DESIGN: Anthropometric measures and dietary intake were reassessed in 501 of the 698 girls whose data had been studied at the end of the intervention. As in the intervention phase, total-body bone mineral content and bone mineral density and serum 25-hydroxyvitamin D concentrations were measured in half of these subjects. RESULTS: At follow-up, 99% of girls had reached menarche, at a mean (+/-SD) menarcheal age of 12.1 +/- 1.1 y. No significant differences in the timing of menarche were observed between the 3 groups (P = 0.6). No significant differences in the changes of total-body bone mineral content and bone mineral density since baseline were observed between the groups. The group receiving calcium-fortified milk had significantly greater gains in sitting height (0.9 +/- 0.3%; P = 0.02) than did the control group. The group that received calcium- and vitamin D-fortified milk had 17.1 +/- 6.7% lower serum 25-hydroxyvitamin D concentrations than did the control group (P = 0.04), but the difference was attenuated by additional adjustment for physical activity level (14.2 +/- 6.7%; P = 0.08). CONCLUSION: Milk supplementation during early puberty does not have long-lasting effects on bone mineral accretion.

Promoting science-based careers through student-directed learning.

Student-directed learning has been featured in a program aimed at promoting the entry of veterinary students into science-based careers. Pursuant to that objective, students participated in workshops and role-playing exercises calculated to enhance self-confidence and the development of leadership, teamwork, and communication skills. Insights into research careers and the optimal sequencing of graduate training were also gained through self-study and simulated interviews for research or service positions in industry. The modules were well received by students, who found them enjoyable and relevant to their career aspirations.