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Background & Aims: The prevalence of nutritional risk varies according to several factors. We aimed to determine the nutritional risk profile in a large Norwegian hospital population, specifically by age, disease category and hospital department., Methods: Nutritional surveys are performed routinely at Haukeland University Hospital, Norway. During eight surveys in 2008-2009, 3279 patients were categorized according to the Nutritional Risk Screening tool (NRS 2002)., Results: The overall prevalence of nutritional risk was 29%, highest in patients with infections (51%), cancer (44%) and pulmonary diseases (42%), and in the departments of intensive care (74%), oncology (49%) and pulmonology (43%). Further, nutritional risk was identified in 40% of patients aged ≥80 years compared to 21% of age <40 years and 35% of patients with emergency admissions compared to 19% with elective admissions. Related to the tool components, nutritional risk was most common in patients with low BMI (<20.5 kg/m(2)) (95%) and/or high comorbidity (>7 diagnoses) (45%). However it was also high in patients with BMI ≥25 kg/m(2) (12%) and in those with fewer than 7 diagnoses (26%)., Conclusions: Nutritional risk was most common among patients with high age, low BMI, more comorbidity, and with infections, cancer or pulmonary diseases, and patients who were discharged to nursing homes. However, the highest number of patients at nutritional risk had BMI in the normal or overweight range, were 60-80 years old, and were found in departments of general medicine or surgery. Importantly, younger patients and overweight patients were also affected. Thus, nutritional risk screening should be performed in the total patient population in order to identify, within this heterogeneous group of patients, those at nutritional risk., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Nutritional care for hospital in-patients is potentially important but challenging., Objective: To investigate the association between nutritional status and clinical outcomes., Methods: Eight prevalence surveys were performed at Haukeland University Hospital, Norway, during 2008-2009. In total 3279 patients were classified as being at nutritional risk or not according to the Nutritional Risk Screening (NRS 2002) tool. The initial four questions of NRS 2002 assess dietary intake, weight loss, body mass index (BMI) and illness severity., Results: The overall prevalence of nutritional risk was 29%. Adjusted mean days for hospitalisation was 8.3 days for patients at nutritional risk and 5.0 days for patients not at risk (p < 0.001). In adjusted models, patients at nutritional risk had increased one-year mortality (OR 4.07, 95% CI 2.90-5.70), morbidity (OR 1.59, 95% CI 1.18-2.13), and were 1.24 (95% CI 1.16-1.32) times more likely to have had a new admission during the three previous years and the one subsequent year, compared to patients not at risk. A 'positive' response to the initial four questions was associated with increased risk of morbidity and mortality. Patients with a reduced dietary intake during the last weeks had OR 1.72 (95% CI 1.03-2.85) for one-year mortality. Patients with a positive answer on all the initial four questions had ten times increased risk for mortality the following year, OR 13.0 (95% CI 4.52-37.6)., Conclusion: The four initial questions of the NRS 2002 robustly identify nutritional risk and were strong predictors of hospitalisation, morbidity and most importantly mortality among hospitalised patients. Thus, these simpler and short questions are robust indicators for subsequent poor outcomes., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Chronic opiate usage, whether prescribed or illicit, has been associated with changes in bone mass and is a recognized risk factor for the development of osteoporosis; however, the mechanism behind this effect is unknown. Here we show that lack of dynorphin, an endogenous opioid, in mice (Dyn-/-), resulted in a significantly elevated cancellous bone volume associated with greater mineral apposition rate and increased resorption indices. A similar anabolic phenotype was evident in bone of mice lacking dynorphin's cognate receptor, the kappa opioid receptor. Lack of opioid receptor expression in primary osteoblastic cultures and no change in bone cell function after dynorphin agonist treatment in vitro indicates an indirect mode of action. Consistent with a hypothalamic action, central dynorphin signaling induces extracellular signal-regulated kinase (ERK) phosphorylation and c-fos activation of neurons in the arcuate nucleus of the hypothalamus (Arc). Importantly, this signaling also leads to an increase in Arc NPY mRNA expression, a change known to decrease bone formation. Further implicating NPY in the skeletal effects of dynorphin, Dyn-/-/NPY-/- double mutant mice showed comparable increases in bone formation to single mutant mice, suggesting that dynorphin acts upstream of NPY signaling to control bone formation. Thus the dynorphin system, acting via NPY, may represent a pathway by which higher processes including stress, reward/addiction and depression influence skeletal metabolism. Moreover, understanding of these unique interactions may enable modulation of the adverse effects of exogenous opioid treatment without directly affecting analgesic responses., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)

The vitamin D receptor (VDR) mediates the effects of 1,25(OH)(2)D(3), the active form of vitamin D. The human VDRB1 isoform differs from the originally described VDR by an N-terminal extension of 50 amino acids. Here we investigate cell-, promoter-, and ligand-specific transactivation by the VDRB1 isoform. Transactivation by these isoforms of the cytochrome P450 CYP24 promoter was compared in kidney (HEK293 and COS1), tumor-derived colon (Caco-2, LS174T, and HCT15), and mammary (HS578T and MCF7) cell lines. VDRB1 transactivation in response to 1,25(OH)(2)D(3) was greater in COS1 and HCT15 cells (145%), lower in HEK293 and Caco-2 cells (70-85%) and similar in other cell lines tested. By contrast, on the cytochrome P450 CYP3A4 promoter, 1,25(OH)(2)D(3)-induced VDRB1 transactivation was significantly lower than VDRA in Caco-2 (68%), but comparable to VDRA in HEK293 and COS1 cells. Ligand-dependence of VDRB1 differential transactivation was investigated using the secondary bile acid lithocholic acid (LCA). On the CYP24 promoter LCA-induced transactivation was similar for both isoforms in COS1, whereas in Caco-2 and HEK293 cells VDRB1 was less active. On the CYP3A4 promoter, LCA activation of VDRB1 was comparable to VDRA in all the cell lines tested. Mutational analysis indicated that both the 1,25(OH)(2)D(3) and LCA-regulated activities of both VDR isoforms required a functional ligand-dependent activation function (AF-2) domain. In gel shift assays VDR:DNA complex formation was stronger in the presence of 1,25(OH)(2)D(3) than with LCA. These results indicate that regulation of VDRB1 transactivation activity is dependent on cellular context, promoter, and the nature of the ligand.

Ski-interacting protein (SKIP), a vitamin D receptor (VDR) coactivator, also functions as a repressor in Notch signalling in association with the corepressor SMRT. Here we show that SKIP bifunctionally modulates (activates or represses) Retinoid-X receptor (RXR)- and VDR-dependent gene transcription in a cell line-specific manner, with activation in CV-1 and repression in P19 cells. The coactivator function of SKIP in these cells appeared to correlate with the relative level and ratio of expression of N-CoR and p300, with greater SKIP activation in higher p300-expressing and lower N-CoR-expressing cell-lines. C-terminal deletion of SKIP (delta334-536 aa) was associated with strong activation in both CV-1 and P19 cells. The corepressors N-CoR and SMRT and the coregulator p300 interacted with SKIP through the same N-terminal region (1-200 aa). Overall these results suggest that transcriptional action of SKIP may depend on distinct functional domains and cell line-specific interactions with both corepressors and coactivators.

Background: Mortality increases after hip fractures in women and more so in men. Little is known, however, about mortality after other fractures. We investigated the mortality associated with all fracture types in elderly women and men., Methods: We did a 5-year prospective cohort study in the semi-urban city of Dubbo, Australia, of all residents aged 60 years and older (2413 women and 1898 men). Low-trauma osteoporotic fractures that occurred between 1989 and 1994, confirmed by radiography and personal interview, were classified as proximal femur, vertebral, and groupings of other major and minor fractures. We calculated standardised mortality rates from death certificates for people with fractures compared with the Dubbo population., Findings: 356 women and 137 men had low-trauma fractures. In women and men, mortality was increased in the first year after all major fractures. In women, age-standardised mortality ratios were 2.18 (95% CI 2.03-2.32) for proximal femur, 1.66 (1.51-1.80) for vertebral, 1.92 (1.70-2.14) for other major, and 0.75 (0.66-0.84) for minor fractures. In men, these ratios were 3.17 (2.90-3.44) for proximal femur, 2.38 (2.17-2.59) for vertebral, 2.22 (1.91-2.52) for other major, and 1.45 (1.25-1.65) for minor fractures. There were excess deaths (excluding minor fractures in women) in all age-groups., Interpretation: All major fractures were associated with increased mortality, especially in men. The loss of potential years of life in the younger age-group shows that preventative strategies for fracture should not focus on older patients at the expense of younger women and of men.

In summary, the optimal model for the prevention of osteoporotic fractures includes maximization and maintenance of bone strength and minimization of trauma. Numerous determinants of each have been identified, but further work to develop preventative strategies based on these determinants remains to be undertaken. Physical activity is a determinant of peak BMD. There also is evidence that activity during growth modulates the external geometry and trabecular architecture, potentially enhancing skeletal strength, while during the adult years activity may reduce age-related bone loss. The magnitude of the effect of a 7% to 8% increase in peak BMD, if maintained through the adult years, could translate to a 1.5-fold reduction in fracture risk. Moreover, in the older population, appropriate forms of exercise could reduce the risk of falling and, thus, further reduce fracture risk. These data must be considered as preliminary in view of the paucity of long-term fracture outcome data from randomized clinical trials. However, current information suggests that the optimal form of exercise to achieve these objectives may vary through life. Vigorous physical activity (including weight-bearing, resistance, and impact components) during childhood may maximize peak BMD. This type of activity seems optimal through the young adult years, but as inevitable age-related degeneration occurs, activity modification to limit the impact component of exercise may become necessary. In the elderly, progressive strength training has been demonstrated to be a safe and effective form of exercise that reduces risk factors for falling and may also enhance BMD. In the frail elderly, activity to improve balance and confidence also may be valuable. Group activities such as Tai Chi may be cost-effective. Precise prescriptions must await the outcome of well-designed, controlled longitudinal studies that include fracture as an outcome. However, increased physical activity seems to be a sensible component of strategies to reduce osteoporotic fracture.

A cohort of 15 immigrant females to Australia and 7 native Australian controls were monitored on a monthly basis with high-precision lead isotopic methods during gestation and for 6 months after pregnancy to determine the extent of lead mobilization from the maternal skeleton. Quarterly environmental samples of house dust, drinking water, urban air, gasoline, and a 6-day duplicate diet were also measured. The geometric mean blood lead concentration for the immigrant females on arrival in Australia was 3.0 microg/dl (range: 1.9 to 20 microg/dl), and for the Australian controls was 3.1 gm/dl (range: 1.9 to 4.3 microg/dl). During gestation and after pregnancy, blood lead concentrations varied, with mean individual changes of -14% to 83%. For the immigrant subjects, the percentage change in blood lead concentration was significantly greater during the postpregnancy period than during the 2nd and 3rd trimesters (p < 0.001). Skeletal contribution to blood lead, based on the isotopic composition for the immigrant subjects, increased in an approximately linear manner during pregnancy. The mean increases for each individual during pregnancy varied from 26% to 99%. Skeletal lead contribution to blood lead was significantly greater (p < 0.001) during the postpregnancy period than during the 2nd and 3rd trimesters. The contribution of skeletal lead to blood lead during the postpregnancy period remained essentially constant at the increased level of lead mobilization, although the duration of breastfeeding varied from 1 week to more than 6 months. The increased contribution of skeletal lead to blood lead during the postpregnancy period is attributed to increased mobilization of lead from maternal skeletal stores during lactation. The increased contribution of skeletal lead both during pregnancy and in the postpregnancy period is consistent with increased bone resorption, and may be associated with an inadequate calcium intake observed in quarterly 6-day duplicate diets. Mobilization of skeletal lead stores represents a potentially important source of perinatal lead intake and accumulation in the developing fetus. Only two subjects consumed dietary supplements for calcium, and their mobilization of lead from the skeleton to the blood was the lowest of all the subjects. These two subjects' use of calcium supplements may have reduced mobilization of skeletal mineral stores to supply the calcium needs of pregnancy and lactation. Calcium supplementation may be an important means of limiting fetal exposure to lead.

Osteoporosis is a major health problem in virtually all societies where its incidence and impact have been studied in terms of cost, morbidity, mortality and quality of life. The major determinant of fracture risk is bone density and, presumably, bone strength. A large number of lifestyle influences and medical interventions modify bone density, but the variation and slowness of change in response to any intervention necessitates long-term follow up. The definition of genetic factors in the determination of bone mass, and possibly in the changes in bone density, over time offer important insights into the mechanisms of response to treatment. Most importantly, if genetic factors can determine response to therapy, the understanding of such factors could influence selection of optimum therapy.

Common vitamin-D-receptor (VDR) gene allelic variants predict bone mineral density. We analysed VDR alleles and rate of change of lumbar-spine bone mineral density over 18 months in 72 elderly subjects. 9 BB homozygotes lost bone mineral density but 26 homozygotes for the alternative genotype (bb) did not (mean change -2.3 [SE 1.0] vs 0.9 [0.7]% per year, p < 0.05), irrespective of calcium intake. Among 37 heterozygotes (Bb), however, change in bone mineral density correlated with calcium intake (r = 0.35, p < 0.03). This association between a genetic marker and rate of bone loss in the elderly suggests that the effect of calcium intake on maintenance of bone mass could relate to VDR gene polymorphisms.

Osteoporotic fractures result in substantial morbidity after heart transplantation. To measure the acute effects of corticosteroids on bone after heart transplantation, we measured bone mineral density by dual energy x-ray absorptiometry and biochemical indexes of bone turnover in 25 patients (21 male, 4 female) at baseline, 6 months, and 12 months after transplantation. Two patients sustained vertebral fractures. Bone loss was rapid in the first 6 months, occurred in 24 of 25 (96%) patients, and was most marked from the lumbar spine (mean +/- SD, -7.4% +/- 4.5%). In the second 6 months little further bone loss was evident (lumbar spine, -7.8% total over 12 months) despite continuing moderate maintenance doses of corticosteroids. Serum osteocalcin and testosterone levels rose and urinary hydroxyproline:creatinine level ratio fell significantly by 6 months. Bone loss from the lumbar spine correlated inversely with serum osteocalcin level at 6 months. Serum osteocalcin level was the only significant predictor of lumbar spine bone loss by multiple regression analysis that included age, corticosteroid dose, cyclosporine dose, lean body mass, and body mass index. These data suggest that prophylactic therapy to prevent bone loss may only be necessary in the first 6 to 12 months after heart transplantation.

Calcium intake has been implicated in the etiology of age-related osteoporosis. There is evidence to suggest that many postmenopausal women consume inadequate calcium to maintain calcium balance. One of the most accurate methods of calculating dietary intake is the weighed food record; however, that method is time consuming and unsuitable for large numbers of individuals. To determine the adequacy of calcium intake in the large numbers of postmenopausal women at risk of osteoporosis, simpler methods of assessing calcium intake are required. We therefore developed a food frequency questionnaire and tested it against a 4-day weighed food record in 54 Caucasian women, between 29 and 72 years of age. Twenty-six of the women (Group 1) completed a 4-day record and questionnaire within 1 week. Another 28 women (Group 2) completed the questionnaire 1 to 12 months after completing the 4-day food diary. A good correlation (r = .79, p less than .001) was found between the two methods of calculating calcium intake for the 54 women. Independent analysis of Group 1 and Group 2 showed correlation coefficients of 0.81 and 0.78, respectively. The correlation for postmenopausal women (r = .84) was similar to that of premenopausal women (r = .79). The data show that a short, simple questionnaire can be used to rank individuals according to adequacy of calcium intake as a prerequisite to nutrition intervention.

A specific receptor for 1,25-dihydroxyvitamin D has been demonstrated in a cultured human breast cancer cell line. This is the first such demonstration in any cancer cell. It may explain the high incidence of metastatic bone destruction and hypercalcaemia in this common malignancy, and the limited success of other steroid-receptor assays in predicting the response of breast cancer to therapy.

In normal volunteers infusion of parathyroid extract raised plasma 1,25-dihydroxyvitamin D (1,25-[OH]2D) levels by 80% (peak 8--40 h after infusion) without producing any significant change in plasma calcium, phosphate, or magnesium. An oral calcium load suppressed plasma 1,25-(OH)2D to 63% of control values within 48--72 h. These responses will be useful in the diagnosis and management of disturbances of calcium and mineral metabolism in which vitamin D metabolism is abnormal.

The binding of metabolites of vitamin D and their analogs to the 3.7S chick intestinal cytosol receptor protein has been specifically studied by competitive binding techniques and polyethylene glycol precipitation of the complex. The structural requirements for the interaction between the vitamin D molecule and the receptor could be assessed without the nuclear chromatin binding step. These measurements have shown that 1,25-dihydroxyvitamin D3 and 1,25-dihydroxyvitamin D2 are equally competitive and are the most active. Of the structural features of the compounds, the 1 alpha-hydroxyl is most important followed by the 25-hydroxyl and the 3 beta-hydroxyl. The addition of a second hydroxyl near carbon 25 markedly reduces binding whether on the 26 carbon or the 24 carbon. A hydroxyl on C-24 could substitute to some degree for the 25-hydroxyl inasmuch as 24-hydroxyvitamin D3 was much more effective than vitamin D3 but less effective than 25-hydroxyvitamin D3. In general the patterns of binding affinities correlated well with the biological activity of the various analogs strongly supporting a physiological role for the 1,25-dihydroxyvitamin D3 binding protein. It also suggests that of the two-step receptor mechanism, the structural specificity is located in the initial interaction of the 1,25-dihydroxyvitamin D3 and the cytosol receptor.