Potential diagnostic value of a type X collagen neo-epitope biomarker for knee osteoarthritis.

OBJECTIVE: Phenotypic changes of chondrocytes toward hypertrophy might be fundamental in the pathogenesis of osteoarthritis (OA), of which type X collagen (Col10) is a well-known marker. The purpose was to develop a specific immunoassay for blood quantification of a newly identified neo-epitope of type Col10 to assess its diagnostic value for radiographic knee OA. METHODS: A neo-epitope of Col10 was identified in urine samples from OA patients. A monoclonal antibody against the neo-epitope was produced in Balb/C mice. The enzyme responsible for the cleavage was identified. Immunohistochemical detection of this neo-epitope was performed on human OA cartilage. An immunoassay (Col10neo) was developed and quantified in two clinical studies: the C4Pain-003 and the NYU OA progression study. Receiver operating characteristic curve (ROC) curve analysis was carried out to evaluate the discriminative power of Col10neo between OA and rheumatoid arthritis (RA). RESULTS: A neo-epitope specific mAb was produced. The Cathepsin K-generated neo-epitope was localized to the pericellular matrix of chondrocytes, while its presence was extended and more prominent in superficial fibrillation in the cartilage with advanced degradation. In the C4Pain study, a higher level of Col10neo was seen in subjects with greater KL grade. The group of the highest tertile of Col10neo included more subjects with KL3-4. In the NYU study, Col10neo was statistically higher in OA than control or RA. ROC curve analysis revealed area under the curve was 0.88 (95% CI 0.81-0.94). CONCLUSION: Our findings indicate that Col10neo linked to hypertrophic chondrocytes could be used as a diagnostic biochemical marker for knee OA.

ECHO: health care performance assessment in several European health systems.

BACKGROUND: Strengthening health-care effectiveness, increasing accessibility and improving resilience are key goals in the upcoming European Union health-care agenda. European Collaboration for Health-Care Optimization (ECHO), an international research project on health-care performance assessment funded by the seventh framework programme, has provided evidence and methodology to allow the attainment of those goals. This article aims at describing ECHO, analysing its main instruments and discussing some of the ECHO policy implications. METHODS: Using patient-level administrative data, a series of observational studies (ecological and cross-section with associated time-series analyses) were conducted to analyze population and patients' exposure to health care. Operationally, several performance dimensions such as health-care inequalities, quality, safety and efficiency were analyzed using a set of validated indicators. The main instruments in ECHO were: (i) building a homogeneous data infrastructure; (ii) constructing coding crosswalks to allow comparisons between countries; (iii) making geographical units of analysis comparable; and (iv) allowing comparisons through the use of common benchmarks. CONCLUSION: ECHO has provided some innovations in international comparisons of health-care performance, mainly derived from the massive pooling of patient-level data and thus: (i) has expanded the usual approach based on average figures, providing insight into within and across country variation at various meaningful policy levels, (ii) the important effort made on data homogenization has increased comparability, increasing stakeholders' reliance on data and improving the acceptance of findings and (iii) has been able to provide more flexible and reliable benchmarking, allowing stakeholders to make critical use of the evidence.

Expression of vitamin D-metabolizing enzymes in human adipose tissue -- the effect of obesity and diet-induced weight loss.

OBJECTIVE: Low vitamin D (VD) levels are common in obesity. We hypothesized that this may be due to metabolism of VD in adipose tissue (AT). Thus, we studied (1) whether the VD-metabolizing enzymes were expressed differently in AT of lean and obese individuals and in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and (2) whether their expression was influenced by weight loss. METHODS: Samples of SAT and VAT were analyzed for expression of the vitamin-D-25-hydroxylases CYP2R1, CYP2J2, CYP27A1 and CYP3A4, the 25-vitamin-D-1α-hydroxylase CYP27B1, the catabolic vitamin-D-24-hydroxylase CYP24A1, and the vitamin D receptor, using reverse transcriptase-PCR. Moreover, plasma 25-hydroxy-vitamin D (25OHD) level was measured and related to the expression of these enzymes. Samples of SAT and VAT from 20 lean women and 20 obese women, and samples of SAT from 17 obese subjects before and after a 10% weight loss were analyzed. RESULTS: A plasma 25OHD level <50 nmol l(-1) was highly prevalent in both lean (45%) and obese (90%) women (P<0.01). Plasma 25OHD increased by 27% after weight loss in the obese individuals (P<0.05). Expression levels of the 25-hydroxylase CYP2J2 and the 1α-hydroxylase CYP27B1 were decreased by 71% (P<0.0001) and 49% (P<0.05), respectively, in SAT of the obese. CYP24A1 did not differ between lean and obese women, but the expression was increased by 79% (P<0.05) after weight loss. CONCLUSION: Obesity is characterized by a decreased expression of the 25-hydroxylase CYP2J2 and the 1α-hydroxylase CYP27B1 in SAT, whereas the catabolic CYP24A1 does not differ between lean and obese women. However, the expression of CYP24A1 is increased after weight loss. Accordingly, AT has the capacity to metabolize VD locally, and this can be dynamically altered during obesity and weight loss.

Socioeconomic factors related to attendance at a Type 2 diabetes screening programme.

AIMS: The prevalence of diabetes is increasing, and screening of high-risk populations is recommended. A low attendance rate has been observed in many Type 2 diabetes screening programmes, so that an analysis of factors related to attendance is therefore relevant. This paper analyses the association between socioeconomic factors and attendance for Type 2 diabetes screening. METHODS: Persons aged 40-69 years (n = 4603) were invited to participate in a stepwise diabetes screening programme performed in general practitioners' offices in the county of Aarhus, Denmark in 2001. The study was population-based and cross-sectional with follow-up. The association between screening attendance in the high-risk population and socioeconomic factors was analysed by odds ratio. RESULTS: Forty-four percent of the estimated high-risk population attended the screening programme. In those with known risk for Type 2 diabetes, attenders were more likely to be older, to be unemployed and to live in the countryside than non-attenders. The risk for Type 2 diabetes was unknown for 21% of the study population; this group was younger and less likely to be cohabitant, skilled, or employed and to have middle or high income than the study population with known risk score for diabetes. CONCLUSIONS: A low attendance rate was found in this screening programme for Type 2 diabetes. No substantial socioeconomic difference was found between attenders and non-attenders in the high-risk population. Further research is needed to uncover barriers to screening of Type 2 diabetes in socioeconomically deprived persons.

Changes in Circulating BDNF in relation to Sex, Diet, and Exercise: A 12-Week Randomized Controlled Study in Overweight and Obese Participants.

Circulating BDNF is higher in women than in men and suggested to be affected by changes in food intake, body weight, and exercise. The purpose of this study was to compare BDNF concentrations in women and men during a 12-week weight loss intervention. Using a previously published 12-week randomized study, serum BDNF was assessed at baseline and after 12 weeks using an enzyme-linked immunosorbent assay method. Fifty overweight or obese but healthy individuals (26 women, mean age of 36.4 ± 7.9 years; 24 men, mean age of 38.0 ± 5.9 years) were included and allocated into three groups: exercise-only (EXO; 12 weeks of aerobic exercise and isocaloric diet), diet-only (DIO; 8 weeks of very low energy diet (VLED 600 kcal/day) followed by a 4-week weight maintenance diet), or diet and exercise (DEX; 12 weeks of aerobic exercise in parallel with 8 weeks of VLED (800 kcal/day) followed by a 4-week weight maintenance diet). At baseline, BDNF levels were 25% higher in women compared to men (p=0.006). Body weight was reduced in all intervention groups (p < 0.006). Exercise (EXO group) induced a 22% reduction in circulating BDNF in men (p=0.037) and women (p=0.080). In the DIO and DEX groups, a significant reduction in BDNF levels (29.9%; p=0.035 and 32.5%; p=0.003, respectively) was observed in women but not in men. In conclusion, circulating BDNF was significantly changed by diet alone or combined with exercise in women and only by exercise alone in men. This suggests that changes in circulating BDNF depend on weight loss methods (diet/exercise) as well as sex.

Author Correction: Egyptian metallic inks on textiles from the 15th century BCE unravelled by non-invasive techniques and chemometric analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Egyptian metallic inks on textiles from the 15th century BCE unravelled by non-invasive techniques and chemometric analysis.

The development of black inks has enabled writing to become an established method of communication in history. Although a large research effort has been devoted to the study of pigments and dyes used in ancient Egypt to decorate burial walls and furnishings, or to write on papyrus, to date little attention has been paid to the nature and technology of inks used on ritual and daily-use textiles, which may have fostered the transfer of metallic ink technology onto papyrus and parchment supports. We report about inks from 15th century BCE Egyptian textiles by combining non-invasive techniques, including ultraviolet (UV) reflected imaging, near-infrared reflectography (NIRR), X-ray fluorescence (XRF) spectroscopy, Raman spectroscopy and prompt-gamma-activation-analysis (PGAA). It is argued that the inks are related to the family of iron gall inks, whose introduction is commonly attributed to the third century BCE. This interpretation frames the technology of writing on fabrics, used by the ancient Egyptians, in a different time, thus providing new information on the genesis of mordant inks in the ancient Mediterranean cultures. We anticipate our study to be a starting point for further and more sophisticated investigations of textiles, which will clarify the origin of metallic ink in the ancient world.

MEAD: an interdisciplinary study of the marine effects of atmospheric deposition in the Kattegat.

This paper summarises the results of the EU funded MEAD project, an interdisciplinary study of the effects of atmospheric nitrogen deposition on the Kattegat Sea between Denmark and Sweden. The study considers emissions of reactive nitrogen gases, their transport, transformations, deposition and effects on algal growth together with management options to reduce these effects. We conclude that atmospheric deposition is an important source of fixed nitrogen to the region particularly in summer, when nitrogen is the limiting nutrient for phytoplankton growth, and contributes to the overall eutrophication pressures in this region. However, we also conclude that it is unlikely that atmospheric deposition can, on its own, induce algal blooms in this region. A reduction of atmospheric nitrogen loads to this region will require strategies to reduce emissions of ammonia from local agriculture and Europe wide reductions in nitrous oxide emissions.

Magnetic resonance imaging as a monitor of kidney enlargement and regression in experimental diabetes in rats.

The aim of the present study was to use magnetic resonance imaging as a non-invasive measure of renal enlargement and regression in experimental diabetes in rats. Rats were randomized into three groups: (1) non-diabetic control animals, (2) diabetic animals, untreated for 30 days after streptozotocin treatment and (3) diabetic animals treated with insulin from day 21 to day 30 after streptozotocin administration. Magnetic resonance images were obtained from anaesthetized rats and kidney, cortex, medulla and pelvis volumes were calculated throughout the experiment until day 30. In untreated diabetic animals, a marked increase in kidney volume was seen 4 days after the induction of diabetes (P < 0.05) and after 30 days this increase amounted to 73%, with similar increases in the cortex (63%) and medulla (69%). No change was seen in the pelvis volume. Insulin administration on day 21 to untreated diabetic rats abruptly reduced kidney volume by 21%, cortex volume by 27% and medulla volume by 18%, and after 4 days all three parameters were similar to those seen in non-diabetic controls. In conclusion, the present study has demonstrated the applicability of magnetic resonance imaging as a non-invasive measure of renal enlargement and regression in experimental diabetes in rats. In untreated hyperglycaemic diabetic rats, with manifest diabetic renal enlargement, acute regression in renal volume was observed concomitant with insulin-induced normoglycaemia.

Typing of Pasteurella multocida from haemorrhagic septicaemia in Danish fallow deer (Dama dama).

Isolates of Pasteurella multocida ssp. multocida (n = 31) from a Danish population of fallow deer which succumbed to haemorrhagic septicaemia during 1992 1993 and isolates from the palatine tonsils of apparently healthy fallow deer from the same area (n=6) were typed and compared with P. multocida from other sources. Plasmids were net observed in the fallow deer strains and one unique pattern was observed by ribotyping using HindIII and by pulsed-field gel electrophoresis using SanlI as restriction endonuclease. All Danish fallow deer isolates belonged to serotype B:3,4. On restriction endonuclease analysis using HhaI as restriction endonuclease, all had a profile identical to that of a fallow deer isolate from the United Kingdom: profile 0033 of Wilson et al. On restriction endonuclease analysis using HpaII as restriction endonuclease, the Danish fallow deer isolates had a unique profile, designated 0062, which differed slightly from that of a fallow deer isolate from the United Kingdom. P. multocida from other animal species were genotypically different from the fallow deer isolates. It is concluded that a specific clone of P. multocida was responsible for the outbreak of haemorrhagic septicaemia among Danish fallow deer. A carrier rate of 27% was demonstrated among apparently normal animals from the same population.

Heparin anticoagulation during cardiopulmonary bypass in an antithrombin-III deficient patient. Implications relative to the etiology of heparin rebound.

A case of antithrombin-III (AT-III) deficiency was diagnosed on the basis of a diminished anticoagulant effect following the administration of heparin for cardiopulmonary bypass. The clinical evaluation and interpretation of a diminished response to heparin is discussed, as are considerations relative to the treatment of AT-III deficient persons whose disorder is not manifest until they are already anesthetized for cardiovascular bypass. The implications of AT-III deficiency relative to the mechanism of heparin rebound are also discussed.

The pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN703, a novel orally active growth hormone secretagogue in healthy male volunteers.

The aim of the present study was to investigate the pharmacodynamics, pharmacokinetics, safety and tolerability of a single dose of NN703 (tabimorelin), a growth hormone secretagogue in healthy male subjects. The study design was double blind, randomized and placebo-controlled, with eight escalating dose levels (0.05-12 mg/kg bodyweight (BW)). NN703 was well tolerated by the subjects. The GH area under the curve (AUC) (0-24 h) was significantly higher when compared to placebo for the three highest dose levels (3.0 mg/kg: P = 0.027, 6.0 mg/kg: P = 0.0023, 12 mg/kg: P< 0.0001), and for GH maximal concentration C(max)the four highest dose levels were also significantly higher when compared to placebo (1.5 mg/kg: P = 0.04, 3.0 mg/kg: P = 0.0143, 6.0 mg/kg: P = 0.0053, 12 mg/kg: P = 0.0007). Furthermore, there was a significant increase in IGF-1 levels when compared to placebo for the 6.0 and 12.0 mg/kg BW dose levels (P< 0. 0001). Statistical analysis comparing the AUC (0-24 h) of the NN703 (four highest dose levels) and placebo-treated groups showed no significant increases following NN703 for ACTH, LH, FSH, TSH, prolactin, and cortisol, however, subtle individual changes were noted in ACTH, cortisol and prolactin at doses above 3.0 mg/kg. In conclusion, NN703 is a promising potential candidate for treatment of GH deficiency/insufficiency.

The pharmacokinetics, pharmacodynamics, safety and tolerability following 7 days daily oral treatment with NN703 in healthy male subjects.

The aim of the present study was to assess the safety, pharmacokinetics and pharmacodynamics (including specificity) of NN703 (tabimorelin), a growth hormone (GH) secretagogue, in healthy male subjects following treatment for 7 days once-daily. This was a randomized, double-blind and placebo-controlled study with four active dose levels: 1.71, 3.0, 4.5 and 6.86 mg/kg body weight. There was a dose-related increase for GH area under the curve (AUC) (0-12 h) and GH C(max)(0--12 h); these were significantly higher on both days 1 and 7 as compared with placebo treatment (P = 0.04 to P< 0.0001); however, an overall significant decrease in GH release was found from day 1 to day 7 (P< 0.001). Insulin-like growth factor-I (IGF-I) and IGF binding protein 3 (IGFBP-3) increased at all dose levels (including placebo); however, a significantly higher increase as compared with placebo treatment was observed at the three highest dose levels for IGF-I (P = 0.04--0.0006) and at the highest dose level for IGFBP-3 (P = 0.03). There was no statistically significant increase in AUC (0-5 h) for follicle-stimulating hormone, luteinizing hormone and cortisol between active and placebo treatment for day 1 or 7. On day 1 only, a statistically significant increase in AUC (0--5 h) was found for prolactin at 1.71 and 6.86 mg/kg (P< 0.05), for thyroid-stimulating hormone (TSH) at 3.0 mg/kg (P< 0.01) and for adrenocorticotrophic hormone (ACTH) at 4.5 mg/kg (P< 0.05); however, no dose--response relationship was observed for TSH or ACTH. In addition, a statistically significant decrease in AUC (0--5 h) for ACTH (3.0 and 6.86 mg/kg) and cortisol (1.71 mg/kg) was observed on day 7 (P< 0.05). Thus, NN703 is a promising candidate for treatment of absolute or relative GH deficiency.

Accuracy of magnetic resonance imaging in the diagnosis of deep vein thrombosis in asymptomatic patients with injuries of the lower extremity. A pilot study.

This is a prospective comparative study of magnetic resonance imaging (MRI) of the deep veins versus contrast venography in consecutive patients treated for various injuries to their lower extremities, showing no clinical symptoms of deep vein thrombosis. The majority of examinations referred to in this study were performed according to the following methodology: First, the patient was subjected to MRI. Subsequently, within a 24-h interval, he/she was subjected to contrast venography. The acquired results were compared in a blinded manner. The diagnostic indices for MRI were calculated on the assumption that the results of contrast venography were sure to give an accurate indication of either presence or absence of thrombosis. Thirty-six patients were included in the study, of which 27 (15 males) completed it. The overall incidence of distal deep venous thrombosis (DVT) was 22% (6/27). One patient showed extension of a crural thrombus into the popliteal vein. MRI did not detect any of the thrombi. This lack of result was ascribed to failure to fully demonstrate all segments of the crural veins. However, MRI did show three proximal thrombi in the superficial femoral vein, which were not shown by the venograms. Thus, both the sensitivity and specificity of MRI were 0%, so MRI proved to be of no value in the diagnosis of asymptomatic deep venous thrombosis in this study.

Equity in the delivery of health care: some international comparisons.

This paper presents the results of an eight-country comparative study of equity in the delivery of health care. Equity is taken to mean that persons in equal need of health care should be treated the same, irrespective of their income. Two methods are used to investigate inequity: an index of inequity based on standardized expenditure shares, and a regression-based test. The results suggest that inequity exists in most of the eight countries, but there is no simple one-to-one correspondence between a country's delivery system and the degree to which persons in equal need are treated the same.

Equity in the finance of health care: some international comparisons.

This paper presents the results of a ten-country comparative study of health care financing systems and their progressivity characteristics. It distinguishes between the tax-financed systems of Denmark, Portugal and the U.K., the social insurance systems of France, the Netherlands and Spain, and the predominantly private systems of Switzerland and the U.S. It concludes that tax-financed systems tend to be proportional or mildly progressive, that social insurance systems are regressive and that private systems are even more regressive. Out-of-pocket payments are in most countries an especially regressive means of raising health care revenues.

Equity in the delivery of health care in Europe and the US.

This paper presents a comparison of horizontal equity in health care utilization in 10 European countries and the US. It does not only extend previous work by using more recent data from a larger set of countries, but also uses new methods and presents disaggregated results by various types of care. In all countries, the lower-income groups are more intensive users of the health care system. But after indirect standardization for need differences, there is little or no evidence of significant inequity in the delivery of health care overall, though in half of the countries, significant pro-rich inequity emerges for physician contacts. This seems to be due mainly to a higher use of medical specialist services by higher-income groups and a higher use of GP care among lower-income groups. These findings appear to be fairly general and emerge in countries with very diverse characteristics regarding access and provider incentives.

Equity in the finance of health care: some further international comparisons.

This paper presents further international comparisons of progressivity of health care financing systems. The paper builds on the work of Wagstaff et al. [Wagstaff, A., van Doorslaer E., et al., 1992. Equity in the finance of health care: some international comparisons, Journal of Health Economics 11, pp. 361-387] but extends it in a number of directions: we modify the methodology used there and achieve a higher degree of cross-country comparability in variable definitions; we update and extend the cross-section of countries; and we present evidence on trends in financing mixes and progressivity.

The redistributive effect of health care finance in twelve OECD countries.

The OECD countries finance their health care through a mixture of taxes, social insurance contributions, private insurance premiums and out-of-pocket payments. The various payment sources have very different implications for both vertical and horizontal equity and on redistributive effect which is a function of both. This paper presents results on the income redistribution consequences of the health care financing mixes adopted in twelve OECD countries by decomposing the overall income redistributive effect into a progressivity, horizontal inequity and reranking component. The general finding of this study is that the vertical effect is much more important than horizontal inequity and reranking in determining the overall redistributive effect but that their relative importance varies by source of payment. Public finance sources tend to have small positive redistributive effects and less differential treatment while private financing sources generally have (larger) negative redistributive effects which are to a substantial degree caused by differential treatment.

Self-care within a model for demand for medical care.

Self-care is interpreted from a health economic point of view. Various approaches are presented. It is stressed that the decision-oriented approach used by other health service researchers is an integral part of the economic approach to the topic as is the idea of a continuum of care, from self-care to professional care. A new approach is taken to the modeling of self-care, in that self-care becomes part of a four-part demand for care model. This makes it possible to model the demand for care for three different groups separately: 1--persons with zero episodes; 2--persons with pure illness episodes and illness episodes with self-care; 3--persons with episodes involving professional care or professional care combined with self-care. Another contribution is due to the so-called episodic approach to the demand for care. The natural counting units are illness and treatment episodes, i.e. instead of counting for instance number of times a general practitioner is consulted we ought to count the number of episodes involving professional care, self-care or both types of care. The episodic approach seems to be well suited for work with self-care. The empirical part is based on a unique Danish panel study using health diaries returned weekly. Data from 27 of the 52 reporting weeks are used, involving more than 14,000 episodes distributed across about 2800 persons belonging to about 1000 households. The use of health diaries seems to be very well suited to the study of self-care in that less salient events and activities than professional care are picked up far better in prospective health diary studies than in retrospective questionnaire based surveys. Descriptive and regression (logistic and ordinary) results are presented.