BMP-2 gene polymorphisms and osteoporosis: the Rotterdam Study.

After reported associations of variations in the BMP-2 gene with osteoporosis in small populations, we studied the association of the BMP-2 gene polymorphisms Ser37Ala and Arg190Ser with osteoporosis in 6353 men and women from the Rotterdam Study. We did not observe an association of these variants with BMD, bone loss, hip structural analysis parameters, and fracture risk. INTRODUCTION: Bone morphogenetic protein 2 (BMP-2) plays a role in osteoblast differentiation. BMP-2 gene variation has previously been associated with osteoporosis in various small populations, but current evidence remains inconclusive about the exact association with osteoporosis. Therefore, we studied the association of two polymorphisms located in the BMP-2 gene (Ser37Ala and Arg190Ser) and haplotypes defined by these polymorphisms with BMD, rates of bone loss, parameters of hip structural analysis (HSA), and fractures in the Rotterdam Study, a large prospective cohort study of diseases in the elderly. MATERIALS AND METHODS: Databases were searched for polymorphisms and haplotype blocks in the BMP-2 gene region. Allele frequencies for Ser37Ala and Arg190Ser were determined in 60 blacks and 110 Chinese from Coriell panels. Genotype data on Ser37Ala and Arg190Ser were available for 6353 individuals from the Rotterdam Study population. Haplotype alleles defined by Ser37Ala and Arg190Ser were inferred using PHASE software. Genotype and haplotype analyses for BMD (measured at the lumbar spine and femoral neck), bone loss per year (measured at the femoral neck), and HSA were performed using AN(C)OVA. Fractures were analyzed using a Cox proportional-hazards model and logistic regression. All outcomes were adjusted for age, height, and weight. RESULTS: Allele frequencies were 2.5% for Ala37 and 40.2% for Ser190, whereas haplotype allele frequencies were 57.28% (Ser37Arg190), 40.19% (Ser37Ser190), 2.50% (Ala37Arg190), and 0.02% (Ala37Ser190). For BMD, bone loss, HSA outcomes, and (incident) fractures, no differences could be seen between genotype and haplotype groups. Conclusions: In this large population-based cohort of Dutch whites, we conclude that the BMP-2 Ser37Ala and Arg190Ser polymorphisms or haplotypes thereof are not associated with parameters of osteoporosis.     

Cross-calibration of dual-energy X-ray densitometers for a large, multi-center genetic study of osteoporosis

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and an increased risk of fragility fractures. Bone mineral density (BMD) is the most important determinant of osteoporotic fracture risk, but the genes responsible for BMD regulation and fracture are incompletely defined. To enable multi-center studies to examine the genetic influences on BMD there is a requirement to standardize measurements across different manufacturers of bone densitometers, different versions of machines and different normative ranges. This paper describes a method developed to allow near-identical subjects with low age-adjusted BMD (based on Z-scores) to be recruited in 17 centers using 27 different densitometers. Cross-calibration was based on measurements using a European spine phantom circulated to all centers and measured ten times on each individual machine. From theses values an individual exponential curve, based on nominal versus observed BMD, was derived for each machine. As expected, there were large and significant variations in nominal BMD values, not only between scanners from different manufacturers but also between different versions of scanners from the same manufacturer. Hologic scanners tended to underestimate the nominal BMD, while Lunar scanners overestimated the value. Norland scanners gave mixed values over estimating BMD at the lower nominal value (0.5 g/cm²) while underestimating the value at the higher value (1.5 g/cm²). The validity of the exponential equations was tested using hip and spine measurements on 991 non-proband women from a familial osteoporosis study (FAMOS). After cross-calibration there was a considerable reduction in variation between machines. This observation, coupled with the absence of a similar reduction in variation attributable to a linear regression on age, demonstrated the validity of the cross-calibration approach. Use of the cross-calibration curves along with a standard normative range (in the case of this study, the Hologic normative range) allowed age-specific Z-scores to be used as an inclusion criterion in this genetic study, a method that will be useful for other trials where age-specific BMD inclusion criteria are required.     

Synopsis of the workshop report and open forum

This session was chaired by Prof. R.S. Kalucy. The workshops on curriculum content and clinical training had a discussion paper available to them prepared by Dr L. Goldman.     

Paget's disease of bone in The Netherlands: a population-based radiological and biochemical survey--the Rotterdam Study.

Serum ALP may be a good indicator of Paget's disease in epidemiologic studies. Subjects with raised and normal ALP from a population cohort were matched (1 in 6, total 548), and radiographs were taken. ALP was an excellent marker of the disease (RR, 10.9), but the majority of those affected had normal ALP. INTRODUCTION: Evidence from radiographic surveys of limited skeletal sites has shown that Paget's disease of bone (PDB) is common in the elderly and has a distinct geographic variation. There is no information, however, about the relation of serum alkaline phosphatase (ALP) activity, a marker of the disease, and its prevalence in the population. MATERIALS AND METHODS: We analyzed data from a well-defined Dutch population cohort (the Rotterdam study) with the following specific aims: (1) to assess the relationship between serum ALP activity and prevalence of radiographically diagnosed PDB, (2) to estimate the overall prevalence of the disease in the Netherlands, and (3) to assess the appearance of the disease with time. Using a nested case-control design, subjects with an increased serum ALP and normal serum liver enzymes were matched for gender and age (1 to 6) with subjects with normal serum ALP activity. Radiographs of the thoracic and lumbar spine, pelvis, proximal femurs, knees, wrists, and hands were taken. RESULTS AND CONCLUSIONS: PDB was diagnosed in 20.5% of subjects with elevated serum ALP activity and in 2.3% in those with normal serum ALP activity, increasing with age in both groups. The relative risk (RR) for PDB in the presence of raised serum ALP activity was 10.9 (95% CI, 4.8, 24.9). The estimated prevalence of PDB in the population was 3.6%, and the large majority (about 86%) had normal serum ALP activity, contrasting findings in bone clinics where the opposite is the case. Finally, in subjects with normal and raised serum ALP activity but no PDB at baseline, radiographs taken 6-9 years later showed no evidence of the disease. This study demonstrated that serum ALP activity is a sensitive marker of PDB in men and women >55 years of age, but the majority of those affected have normal serum ALP activity.     

Dopamine modulates exocytosis independent of Ca(2+) entry in melanotropic cells

Dopamine is a known inhibitor of pituitary melanotropic cells. It reduces Ca(2+) influx by hyperpolarizing the cell membrane and by modulating high- and low-voltage-activated (HVA and LVA) Ca(2+) channels. As a result, dopamine reduces the hormonal output of the cell. However, it is unknown how dopamine affects each of the four different HVA Ca(2+) channel types individually. Moreover, it is unknown whether dopamine interacts with exocytosis independent of Ca(2+) channels. Here we show that dopamine differentially modulates the HVA Ca(2+) channels and that it affects the stimulus-secretion coupling through a direct effect on the exocytotic machinery. Sustained L- and P-type Ba(2+) currents are reduced in amplitude and inactivating N- and Q-type currents acquire different activation and inactivation kinetics in the presence of dopamine. The Q-type current shows slow activation, which is a hallmark for direct G-protein modulation. We used membrane capacitance measurements to monitor exocytosis. Surprisingly, we find that the amount of exocytosis per step depolarization is not diminished by dopamine despite the reduction in Ca(2+) current. To test whether dopamine affects the release machinery downstream of Ca(2+) entry, we stimulated exocytosis by dialyzing cells with buffered high-Ca(2+) solutions. Dopamine increased the amount and the rate of exocytosis. In the first 90 s, the rate of secretion was increased two- to threefold, but it was normalized again at 180 s, suggesting that predominantly vesicles that fuse early in the exocytotic phase are modulated by dopamine. Thus while Ca(2+) channels are inhibited by dopamine, the exocytotic machinery downstream of Ca(2+) influx is sensitized. As a result, release is more effectively stimulated by Ca(2+) influx during dopamine inhibition.     

Micronutrients: highlights and research challenges from the 1994-5 National Diet and Nutrition Survey of people aged 65 years and over

The aims of the National Diet and Nutrition Survey series are summarized, and the new National Diet and Nutrition Survey of people aged 65 years and over is explored, with particular emphasis on micronutrient intakes and status indices. Mean nutrient intakes were generally satisfactory for most micronutrients, but intakes of vitamin D, Mg, K and Cu were low. Intakes of vitamin D were far below the reference nutrient intake for people aged 65 years and over, and there was also biochemical evidence of vitamin D deficiency, for 8% of free-living and 37% of institution participants, attributed partly to limited exposure to sunlight. A substantial proportion of people living in institutions had inadequate biochemical status indices, notably for vitamin C, Fe and folate. Relationships between intake and status were close for vitamins. Mineral intakes did not correlate well with currently used status indices. Some intakes and indices, especially those of vitamin C, carotenoids, Na and K, were strongly correlated with socio-economic status and with north-south gradients in Britain. Future research challenges should address the functional and health significance of low intakes and sub-optimal biochemical indices for certain micronutrients, especially for people living in institutions; the shortcomings of mineral status indices especially as indicators of mineral intake; the social and geographical inequalities of micronutrient intakes and status, and why micronutrient status deteriorates with increasing age. The answers to these questions will help to define the characteristics of nutritional risk for older people in Britain, and to clarify future needs for education and intervention.     

Caudal epidural injection in the management of lumbosacral nerve pain syndromes]

The effect of epidural steroid injections was assessed in 39 patients with lumbar nerve root compression syndromes in a double-blind controlled trial, the patients were allocated at random to 3 groups. In group A (n = 13) the patients received a caudal epidural injection of 1 ml (7 mg) bethametason (Diprophos) in 10 ml normal saline and 20 ml local anesthetic (Lignocaine 1%). The second group B (n = 13) received a caudal epidural injection of 20 ml local anaesthetic (Lignocaine 1%) and 10 ml normal saline. The third group C (n = 13) received a superficial injection of 1 ml (7 mg) bethametason around of the sacral hiatus. All injections were performed by the same experienced anaesthesiologist. An independent physician, who was not aware which type of injection had been given, carried out the clinical measurements and the evaluation. Taking of analgesic drug Tramadol was permitted. The symptoms were assessed by visual analogue scale (VAS 100 mm), lumbar flexion (Schober and finger-floor distance), the angle of raised leg sign (RLS degrees), and by complete neurological examination, the investigation was made 5 times (1 hour, 24 hours, 48 hours, 1 week, and 4 weeks after epidural injections). The results between 0-1 week and 0-4 week were statistically analysed by Student-, Wilcoxon-, and Mann-Whitney test and analysis of variance (ANOVA). The mean VAS values decreased in time in all patient groups. There was no difference between the three treatment groups either after one or after 4 weeks by ANOVA. The mobility of the lumbar spine improved in all patient groups, but there was no significant difference between the three treatment groups. The raised led sign--values improved in all patient groups. There was a significant difference between the three treatment groups by ANOVA after one week, due to the difference between group A and C. After four weeks there was no significant difference. No major complications or side effects were seen in our trial. The raised leg sign due to epidural steroid injection showed better results in comparison to steroid injection around of the sacral hiatus were seen.     

Mutagenic activity in waste from an aluminum products factory in Salmonella/microsome assay

The mutagenic activity of waste material originating from an aluminum products factory was determined by the Salmonella/microsome assay, using the bacterial strains TA100, TA98 and YG1024. The material was obtained by sweeping the factory floor at the end of the work shift. Organic compounds were extracted by ultrasound for 30 min in dichloromethane or 70% ethanol. After evaporation of solvent, these extracts were dissolved in dimethylsulfoxide, and tested for the mutagenic activity at varying concentrations. All the extracts from the factory had mutagenic activity, especially in the YG1024 strain, suggesting the presence of aromatic amines, later confirmed by chemical analysis. The TA98 strain also showed mutagenic activity, though it did not exhibit the highest mutagenicity index observed with the YG1024 strain. In TA100, mutagenic activity was not observed. This study should serve as an alert to management and those who are occupationally exposed, and as a warning that this type of waste should not be discarded in the environment without any control.     

Through the looking glass: good looks and dignity in care

There are roughly two meanings attached to the concept of dignity: humanitas and dignitas. Humanitas refers to ethical and juridical notions of equality, autonomy and freedom. Much less understood is the meaning of dignitas, which this paper develops as peoples’ engagement with aesthetic values and genres, and hence with differences between people. Departing from a critical reading of Georgio Agamben’s notion of ‘bare life’, I will analyze a case where aesthetics are quite literally at stake: women who lost their hair due to cancer treatment. The analysis shows a complicated interplay between varying evaluations of female baldness by the self and others, mediated by (often strongly negative) cultural imaginaries, and aesthetic genres depicting conventional ways of ‘looking good’. The paper concludes by arguing for a reconnection of the two notions of dignity, and for a rehabilitation of aesthetics in daily life and care as fundamental values for organizing our societies.