Role of the community pharmacist in detecting frailty and spatio-temporal disorientation among community-dwelling older people in France.

BACKGROUND: Many older community-dwelling subjects may be frail and/or disoriented, putting them at risk of adverse outcomes. We investigated the prevalence of frailty and spatiotemporal disorientation among patients aged > 65 years collecting regular medication at a community pharmacy. METHODS: Prospective, cross-sectional study of geriatric evaluation in 218 community pharmacies in France. Regular customers aged > 65 years attending the pharmacy to receive ≥ 1 prescription drug were eligible. Spatio-temporal disorientation was assessed using a 4-item screening test; subjects were considered disoriented if they had ≥ 1 incorrect answers. Frailty was evaluated using the Short Emergency Geriatric Assessment (SEGA) grid. Subjects were considered as not frail (score < 8), or frail/very frail (score of 8 or more). RESULTS: 4090 subjects were included, average age 77.5 ± 7.6 years, 60.1% females. Overall, 1025 (25%) were frail/very frail, and 384 (9.4%) were disoriented in space or time. On average, subjects were taking 5.4 ± 3.5 medications per day. Among non-frail patients, 116/3065 (3.8%) were disoriented, of whom 87 (87/116, 75%) managed their medication alone. Among frail/very frail patients, 268/1025 (26.1%) were disoriented, of whom 46 (46/268, 16.8%) managed their medication alone. The majority of patients (77.9%) collected their medication alone at the pharmacy, but significantly fewer frail patients came to collect their drugs alone (p < 0.001). CONCLUSION: It is feasible for community pharmacists to detect disorientation and frailty among older patients. A quarter of subjects were frail/very frail, and 3.2% were disoriented yet managing their drugs alone. Additional social support should be envisaged for these subjects.

The relationships between serum sclerostin, bone mineral density, and vascular calcification in rheumatoid arthritis.

CONTEXT: Recent data indicate that the secreted glycoprotein sclerostin may be involved in vascular calcification (VC). OBJECTIVE: The objective of the study was to establish whether serum sclerostin levels are associated with VC in patients with rheumatoid arthritis (RA). DESIGN: This was a cross-sectional study. SETTING: The study was conducted with ambulatory care. PATIENTS: We compared 75 RA patients with 75 age- and gender-matched control participants. INTERVENTION: Coronary artery calcification (CAC) and abdominal aortic calcification (AAC) scores were evaluated by computed tomography. MAIN OUTCOME MEASURE: Serum sclerostin levels (determined with an ELISA) were assessed. A statistical analysis was performed to identify the determinants of serum sclerostin and VC. RESULTS: AAC and CAC were more prevalent and more severe in patients with RA than in controls. Higher levels of AAC (P = .02) and a higher lumbar bone mineral density (BMD; P = .03) were identified as independent determinants of higher serum sclerostin levels in RA patients, whereas male gender (P = .03), higher lumbar BMD (P < .0001), and low estimated glomerular rate (P < .001) were identified as determinants in controls. In RA patients, a multivariate logistic regression analysis indicated that older age [P < .01, with an odds ratio (OR) per year 1.10] and male gender (P = .02, OR 6.79) were independent determinants of CAC and that older age (P < .001, OR 1.16) were independent determinants of AAC. In controls, the independent determinants were older age (P < .01, OR 1.19), hypertension (P < .01, OR 7.31), and lumbar BMD (P = .03, OR per 30 mg/cm(2) increment of 1.14) for CAC and older age (P = .01, OR 1.11) for AAC. CONCLUSIONS: Serum sclerostin levels were significantly and independently associated with AAC in RA patients.

Vascular calcification in rheumatoid arthritis: prevalence, pathophysiological aspects and potential targets.

Individuals with rheumatoid arthritis (RA) are at increased risk for morbidity and mortality from cardiovascular disease. Excess cardiovascular mortality in RA patients cannot be fully explained by conventional cardiovascular risk factors. The purpose of this review is to discuss recent progress concerning the prevalence and pathophysiological aspects of vascular calcification in RA. RA patients have early-onset diffuse calcification involving multiple vascular beds compared to age and sex-matched controls. Pathogenesis of vascular calcification in RA patients is not fully understood, but specific mediators such as proinflammatory cytokines and not global inflammation could be involved. The possible link between osteoporosis and vascular calcification in RA will not be discussed. Finally, potential targets to reduce vascular calcification in RA will be discussed.

The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension.

Left ventricular (LV) diastolic dysfunction, particularly relaxation abnormalities, are known to be associated with the development of LV hypertrophy (LVH). Preliminary human and animal studies suggested that early LV diastolic dysfunction may be revealed independently of LVH. However, whether LV diastolic dysfunction is compromised before the onset of hypertension and LVH remains unknown. We therefore evaluated LV diastolic function in spontaneously hypertensive rats (SHR) at different ages and tested whether LV diastolic dysfunction is associated with abnormal intracellular calcium homeostasis. LV systolic and diastolic functions were evaluated by invasive and echocardiographic methods in 3-week-old (without hypertension) and 5-week-old (with hypertension) SHR and Wistar-Kyoto control rats. Basal intracytoplasmic calcium and sarcoplasmic reticulum (SR) Ca(2+) contents were measured in cardiomyocytes using fura-2 AM. Sarco(endo)plasmic Ca(2+)-ATPase isoform 2a (SERCA 2a) and phospholamban (PLB) expressions were quantified by Western blot and quantitative RT-PCR techniques. LV relaxation dysfunction was observed in 3-week-old SHR rats before onset of hypertension and LVH. An increase in basal intracytoplasmic Ca(2+) and a decrease in SR Ca(2+) release were demonstrated in SHR. Decreased expression of SERCA 2a and Ser16 PLB (p16-PLB) protein levels was also observed in SHR rats, whereas mRNA expression was not decreased. For the first time, we have shown that LV myocardial dysfunction precedes hypertension in 3-week-old SHR rats. This LV myocardial dysfunction was associated with high diastolic [Ca(2+)](i) possibly due to decreased SERCA 2a and p16-PLB protein levels. Diastolic dysfunction may be a potential predictive marker of arterial hypertension in genetic hypertension syndromes.

Is vascular calcification associated with bone mineral density and osteoporotic fractures in ambulatory, elderly women?

UNLABELLED: We analyzed the relationship between aortic calcification and two osteoporotic parameters (bone mineral density (BMD) and incident osteoporotic fractures) in 667 ambulatory, elderly women from the Epidemiology of Osteoporosis (EPIDOS) cohort (mean age, 80 years; range, 72-94 years). We did not find any correlation between the aortic calcification score and BMD or osteoporotic fractures. INTRODUCTION: The aging process is associated with osteoporosis and aortic calcification; conditions which may have similar disease mechanisms. However, the relationship between these two settings remains to be elucidated. We analyzed the relationship between aortic calcification and osteoporotic parameters (BMD and incident osteoporotic fractures) in a cohort of ambulatory, elderly women. METHODS: The study included 667 ambulatory women from the EPIDOS cohort (mean age, 80 years; age range, 72-94 years). The baseline examination included bone investigations, a clinical and functional examination, and a comprehensive questionnaire on health status and lifestyle. Semiquantitative methods were used to determine the abdominal aortic calcification score on baseline radiographs. Incident fractures were recorded via postal questionnaires issued every 4 months for about 4 years. RESULTS: Five hundred three women (75%) had aortic calcification. The mean aortic calcification score was 5.5 (median, 4). During the follow-up period, 186 (28%) women reported one or more incident osteoporotic fractures. We did not find any correlation between the aortic calcification score on one hand and the BMD or the occurrence of incident osteoporotic fractures on the other. Only age and systolic blood pressure were found to be independently associated with the aortic calcification score. Osteoporotic fractures were independently associated with age and BMD. CONCLUSIONS: Osteoporosis and aortic calcification appear to be independent processes in a cohort of ambulatory, elderly women. However, potential confounding factors may be present and prospective studies are needed to investigate this situation further.

Pathophysiological mechanisms and consequences of cardiovascular calcifications: role of uremic toxicity.

SUMMARY: Chronic kidney disease (CKD) represents an accelerated model of the active cardiovascular calcification process. Recent data from our laboratory indicate the presence of a possible vascular remodeling leading to vascular calcification similar to that observed in bone tissue, and emphasize the role of uremic toxicity. Uremic serum not only induces differentiation of smooth muscle cells into an osteoblast-like phenotype but also inhibits the differentiation of monocyte-macrophages cells into osteoclasts. The imbalance between the two processes in vascular walls in favor of osteoblast-like formation could lead to calcification. Cardiovascular calcification may contribute to the high rate of cardiovascular disease in patients with CKD. However, uremic toxicity, which participates in the pathogenesis of cardiovascular calcification, seems to have independent effects on vascular walls, at least in the early stages of CKD. We recently reported that functional (i.e. endothelial dysfunction) rather than structural changes, including vascular calcification, may contribute to the aortic hemodynamic changes observed during early CKD. Uremic toxicity also appears to be associated with calcification of intracranial arteries. Knowledge concerning the pathogenesis and consequences of cardiovascular calcification derived from the uremic model therefore opens up new perspectives for pharmacologic treatments that may also help to prevent and/or treat cardiovascular calcification, and consequently cardiovascular mortality and morbidity, not only in CKD patients but also in the general population.

Is it possible to identify early predictors of the future cost of chronic arthritis? The VErA project.

This study was conducted to identify early predictors of the total cost of inflammatory arthritis (IA). One hundred and eighty patients affected by undifferentiated arthritis (UA) or rheumatoid arthritis (RA) were included in the French Very Early rheumatoid Arthritis (VErA) cohort between 1998 and 2001. Health economic data for 2003 were collected using a patient self-questionnaire. Results were analysed in terms of direct, indirect and total costs in 2003 euros (2003euro) for the population as a whole and in diagnostic subgroups. A payor perspective (the French National Health Insurance, in this case) was adopted. Multiple linear regression models were used to identify predictors of total cost from among the criteria assessed on recruitment. Results of the study showed that for the study population as a whole, the mean total cost was euro4700 per patient. The costs attributable to the RA and UA sub-groups were euro5928 and euro2424 per patient, respectively. In a univariate analysis, certain parameters were significantly correlated with a higher cost of illness. In the multivariate analysis, some of these parameters were further identified as being predictive of higher cost. Two strong significant, early predictors of total cost were identified: higher pain (P = 0.002) and the presence of rheumatoid factor (P = 0.004). In the RA sub-group, lower grip strength of the dominant hand (P = 0.039) was another predictor of the illness's subsequent economic impact. In conclusion, our data show that simple clinical and laboratory parameters can be used early in the course of IA to predict the condition's impact on healthcare budgets.

The pathophysiology of vascular calcification: are osteoclast-like cells the missing link?

There is increasing evidence to suggest that the initiation of vascular calcification is an active process involving vascular smooth muscle cell (VSMC) apoptosis and trans-differentiation into calcifying cells. This active process results in the deposition of an osteogenic extracellular matrix and may be exacerbated by a reduction in the levels of one or more native calcification inhibitors (such as fetuin A and pyrophosphate). Here, we present data which strongly suggest that the regression of vascular calcification might also be an active cellular process involving osteoclast-like cells. However, the presence of osteoclast like cells in the vascular wall is rather limited. To explain this rarity of osteoclast-like cells, we recently observed that the same factors, which promote the trans-differentiation of VSMCs into osteoblast-like cells are also capable of inhibiting the in vitro differentiation of monocytes/macrophages into osteoclast-like cells. An imbalance between osteoblast-like and osteoclast-like cell activities would therefore favour the occurrence of a pathological calcification process in vessel walls. Our new data are strongly evocative of a vascular remodelling process similar to that observed in bone tissue. To confirm this hypothesis, strategies for activating osteoclasts in the vascular wall (with a view to preventing or reversing vascular calcifications) are required.

Exploitation and enrichment: the paradox of medical experimentation.

Modern medicine is built on a long history of medical experimentation. Experiments in the past often exploited more vulnerable patients. Questionable ethics litter the history of medicine. Without such experiments, however, millions of lives would be forfeited. This paper asks whether all the "unethical" experiments of the past were unjustifiable, and do we still exploit the poorer members of the community today? It concludes by wondering if Harris is right in his advocacy of a moral duty to participate in medical research.

The in vitro osteoclastic degradation of nacre.

Osteoclast activity was studied on nacre, the mother of pearl (MOP) in order to assess the plasticity of bone resorbing cells and their capacity to adapt to a biomineralized material with a different organic and mineral composition from that of its natural substrate, bone. Pure MOP, a natural biomineralized CaCO(3) material, was obtained from Pinctada oyster shell. When implanted in the living system, nacre has proven to be a sustainable bone grafting material although a limited surface degradation process. Osteoclast stem cells and mature osteoclasts were cultured on MOP substrate and osteoclast precursor cells were shown to differentiate into osteoclasts capable of resorbing nacre substrate. However, analysis of the organization of the cytoskeleton showed that both a sealing zone and a podosome structure were observed on the nacre substrate. Moreover, MOP resorption efficiency was consistently found to be lower than that of bone and appeared to be a limited process.

Autoantibodies, metalloproteinases and bone markers in rheumatoid arthritis patients are unable to predict their responses to infliximab.

OBJECTIVES: To identify biochemical, immunological and bone markers as predictors of rheumatoid arthritis (RA) patients' responses to infliximab. METHODS: A total of 76 patients with active RA (American College of Rheumatology criteria), refractory to disease-modifying anti-rheumatic drugs, including methotrexate, received infliximab (3 mg/kg) infusions at weeks 0, 2, 6, and then every 8 weeks in combination with methotrexate or leflunomide. At week 14, infliximab efficacy was evaluated using disease activity score (DAS)28. A serum sample, collected just before starting infliximab, was tested by ELISA (unless stated otherwise) for the following immunological markers: rheumatoid factor by agglutination and ELISA (IgA, IgG and IgM isotypes); anti-cyclic citrullinated protein; autoantibodies recognizing calpastatin domain I and its 27 C-terminal fragment, glucose-6-phosphate isomerase, alpha-enolase; anti-keratin and anti-perinuclear factor antibodies (immunofluorescence); biochemical markers: C-reactive protein (nephelometry), metalloproteinase-1 and -3, tissue inhibitors of metalloproteinases-1 and -2, antioxidants (vitamins A and E; selenium); bone resorption markers: pyridinoline, deoxypyridinoline, osteoprotegerin, soluble receptor activator of nuclear factor-kappaB ligand, cartilage oligomeric matrix protein. Each parameter's predictive value of the response to infliximab was analysed using Fisher's exact, Mann-Whitney and chi-square tests. Hierarchical clustering was performed with The Institute for Genomic Research (TIGR) multiple experiment viewer software. RESULTS: Good, moderate and non-responder rates were 6.5, 61.8 and 31.5%, respectively. No significant difference was observed between responders and non-responders, regardless of the serum parameters considered. Analysis of dichotomous or continuous variables failed to identify markers predictive of a good or poor response to infliximab. CONCLUSION: The search for soluble markers in RA patients' sera likely to predict response to infliximab because of their involvement in RA pathogenesis seems disappointing. However, because of the limited power to detect smaller differences in biomarkers, the present study is a preliminary exploratory analysis.

The calcium sensing receptor is directly involved in both osteoclast differentiation and apoptosis.

Intracellular transduction pathways that are dependent on activation of the CaR by Ca(o)2+ have been studied extensively in parathyroid and other cell types, and include cytosolic calcium, phospholipases C, A2, and D, protein kinase C isoforms and the cAMP/protein kinase A system. In this study, using bone marrow cells isolated from CaR-/- mice as well as DN-CaR-transfected RAW 264.7 cells, we provide evidence that expression of the CaR plays an important role in osteoclast differentiation. We also establish that activation of the CaR and resultant stimulation of PLC are involved in high Ca(o)2+-induced apoptosis of mature rabbit osteoclasts. Similar to RANKL, Ca(o)2+ (20 mM) appeared to trigger rapid and significant nuclear translocation of NF-kappaB in a CaR- and PLC-dependent manner. In summary, our data suggest that stimulation of the CaR may play a pivotal role in the control of both osteoclast differentiation and apoptosis in the systems studied here through a signaling pathway involving activation of the CaR, phospholipase C, and NF-kappaB.

Impact of inflammation and oxidative stress on vascular calcifications in chronic kidney disease.

Vascular and/or valvular calcifications in patients with chronic kidney disease (CKD) appear to indicate a poor prognosis in terms of overall survival and cardiovascular morbidity and mortality. Inflammation and oxidative stress represent new features of the arterial and/or valvular calcification process. However, only limited observational and epidemiological data are available in these areas. Therefore, the link between inflammation, oxidation and vascular and/or valvular calcifications deserves careful consideration in CKD patients, since they may become targets for the development of new therapeutic strategies.

Biological effects of drinking-water mineral composition on calcium balance and bone remodeling markers.

OBJECTIVE: To compare the effects of 2 drinking waters containing similar calcium (Ca) concentration in order to analyze the role of ions other than Ca on bone metabolism. These mineral drinking-waters differed by their mineral composition primarily concerning the concentration of bicarbonate (HCO3-), high in the HB, and sulfate, high in HS water. DESIGN: Of 60 included women, 39 completed the study. Patients were randomly assigned to an intake of 1 liter per day of mineral water HB or HS for 28 d, followed by cross-over to the alternative drinking-water for a further 28 d. At baseline and after each period of one month, Ca metabolism parameters, acid-base status, and bone remodeling markers were measured. RESULTS: Changes in Ca metabolism were significant in the HB group where the ionized Ca increased and the PTH decreased. Serum pH showed a similar increase whatever the used drinking water compared to baseline. In the HB group, significant increase in urine pH, and significant decrease in AT-HCO3- and NH4+ were observed. Bone resorption markers, urinary CTx/Cr, Pyr/Cr, and D-Pyr/Cr, significantly decreased in the HB group compared to baseline, and were not significantly modified in the HS group. CONCLUSIONS: These results showed a beneficial effect of the bicarbonaterich HB water on bone metabolism. This may account for a better bioavailability of the Ca, a greater alkalinization, and a larger decrease in PTH level secondary to a higher ionized Ca level. The higher content of silica in HB water may have also participated to the positive action on bone balance that was observed. In this short term study, these data underlined the potential role of the mineral drinking water composition on bone metabolism.

Involvement of capacitive calcium entry and calcium store refilling in osteoclastic survival and bone resorption process.

Bone resorption is closely dependent on osteoclastic survival and osteoclast apoptotic cell death could represent a key step at the end of this process. In order to precise the possible role of calcium movement in osteoclastic cell death, we investigated whether intracellular calcium store replenishment and capacitive calcium entry (CCE) are involved in osteoclastic survival and bone resorption. We demonstrate that (i). thapsigargin, a sarco-endoplasmic reticulum calcium ATPase pump (SERCA) blocker, decreases both osteoclastic survival and bone resorption process, (ii). 2-aminoethoxydiphenyl borate (2-APB) and SKF-96365, two store-operated channel (SOC) blockers, dramatically decrease osteoclastic survival and bone resorption and (iii). culture in calcium-free medium and thapsigargin exposure synergically inhibit osteoclastic survival which falls dramatically to a value close to 0% (P<0.001). Inversely, osteoclastic survival increases significantly when thapsigargin-treated cells are cultured in the presence of 20mM calcium, suggesting that increasing extracellular calcium concentration stimulates osteoclasts survival when the filling of intracellular stores is prevented. Taken together, our data strongly suggest that in osteoclasts, calcium movements between cellular compartments involved in the regulation of calcium signalling, such as calcium stores refilling and CCE, are closely associated to the regulation of osteoclast survival and bone resorption.

Regulation of bone resorption and osteoclast survival by nitric oxide: possible involvement of NMDA-receptor.

Nitric oxide has been shown to play an important role in regulation of bone resorption. However, the role of endogenous nitric oxide on osteoclast activity remains still controversial. In this work, using RT-PCR amplification, we demonstrated that rabbit mature osteoclasts express mRNA encoding for neuronal nitric oxide synthase suggesting that this enzyme could be involved in basal nitric oxide production in these cells. Then we assessed the effect of carboxy-PTIO, a nitric oxide scavenger, on in vitro bone resorption and osteoclast survival. Carboxy-PTIO (10-100 microM) inhibited osteoclastic bone resorption in a dose dependent manner and induced osteoclast apoptosis by a mechanism involving caspase 3 activation. These results suggest that basal concentration of endogenous nitric oxide may be essential for normal bone resorption by supporting osteoclast survival. Because osteoclasts express N-methyl-d-aspartate-receptor (NMDA-R), we hypothesized that in osteoclasts NMDA-R may be involved in nitric oxide production as in neuronal cells. We confirmed that blockade of NMDA-R with specific non-competitive antagonists, MK801 and DEP, strongly inhibited bone resorption. As for carboxy-PTIO, we showed that blockade of NMDA-R by both antagonists induced osteoclast apoptosis in a dose dependent manner by a mechanism dependent on caspase 3 activation. Intracellular calcium concentration in osteoclasts decreased within minutes in the presence of both antagonists. Finally, MK801-induced osteoclast apoptosis was partially reversed in the presence of small amount of SNAP (100 nM), a nitric oxide donor, suggesting that the effect of NMDA-R on osteoclast apoptotic cell death could be due to a decrease in nitric oxide production. Taken together, our results are consistent with the hypothesis that NMDA-R on osteoclasts could have a similar function as those in neuronal cells, i.e., to allow a calcium influx, which in turn activates a constitutive neuronal nitric oxide synthase. Nitric oxide generated by this pathway may be essential for osteoclast survival and hence for normal bone resorption.

Organ retention and return: problems of consent.

This paper explores difficulties around consent in the context of organ retention and return. It addresses the proposals of the Independent Review Group in Scotland on the Retention of Organs at Post Mortem to speak of authorisation rather than consent. Practical problems about whose consent determines disputes in relation to organ retention are explored. If a young child dies and his mother refuses consent but his father agrees what should ensue? Should the expressed wishes of a deceased adult override the objections of surviving relatives? The paper suggests much broader understanding of the issues embedded in organ retention is needed to provide solutions which truly meet families' and society's needs.