Differential effects of teriparatide, denosumab and zoledronate on hip structural and mechanical parameters in osteoporosis; a real-life study.

PURPOSE: The aim of this study was to evaluate changes in hip geometry parameters following treatment with teriparatide (TPD), denosumab (Dmab) and zoledronate (ZOL) in real-life setting. METHODS: We studied 249 patients with osteoporosis (OP) with mean [SD] age of 71.5 [11.1] years divided into 3 treatment groups; Group A received TPD; n = 55, Group B (Dmab); n = 116 and Group C (ZOL); n = 78 attending a routine metabolic bone clinic. Bone mineral density (BMD) was measured by DXA at the lumbar spine (LS), total hip (TH) and femoral neck (FN) prior to treatment and after 2 years (Group A), after a mean treatment duration of 3.3 [1.3] years (Group B) and after 1, 2 and 3 doses of ZOL (Group C) to assess treatment response. Hip structural analysis (HSA) was carried out retrospectively from DXA-acquired femur images at the narrow neck (NN), the intertrochanter (IT) and femoral shaft (FS). RESULTS: Changes in parameters of hip geometry and mechanical strength were seen in the following treatment. Percentage change in cross-sectional area (CSA): 3.56[1.6] % p = 0.01 and cross-sectional moment of inertia (CSMI): 4.1[1.8] % p = 0.029 increased at the NN only in Group A. Improvement in HSA parameters at the IT were seen in group B: CSA: 3.3[0.67]% p < 0.001, cortical thickness (Co Th): 2.8[0.78]% p = 0.001, CSMI: 5.9[1.3]% p < 0.001, section modulus (Z):6.2[1.1]% p < 0.001 and buckling ratio (BR): - 3.0[0.86]% p = 0.001 with small changes at the FS: CSA: 1.2[0.4]% p = 0.005, Z:1.6 [0.76]%, p = 0.04. Changes at the IT were also seen in Group C (after 2 doses): CSA: 2.5[0.77]% p = 0.017, Co Th: 2.4[0.84]% p = 0.012, CSMI: 3.9[1.3]% p = 0.017, Z:5.2[1.16]% p < 0.001 and BR: - 3.1[0.88]% p = 0.001 and at the NN (following 3 doses): outer diameter (OD): 4.0[1.4]% p = 0.0005, endocortical diameter(ED): 4.3[1.67% p = 0.009, CSA:5.2[1.8]% p = 0.003, CSMI: 9.3[3.8]% p = 0.019. CONCLUSIONS: Analysis of the effect of OP therapies on hip geometry is useful in understanding the mechanisms of their anti-fracture effect and may provide additional information on their efficacy.

The effect of previous treatment with bisphosphonate and renal impairment on the response to denosumab in osteoporosis: a 'real-life' study.

PURPOSE: To investigate changes in bone mineral density (BMD) following denosumab after previous bisphosphonate therapy and the impact of chronic kidney disease (CKD) on response. METHODS: A retrospective study of 134 patients (11 M, 123 F) aged [mean (SD)] 72 [11] years on denosumab was undertaken. Ninety-five patients had previously been on oral and 28 on iv bisphosphonate. Lumbar spine (LS), total hip (TH) and femoral neck (FN) BMD were measured before treatment and at 2.7 [1.2] years. GFR was < 35 ml/min in 24 patients (18%). Ninety-four (18 M, 76 F) patients aged 71 [11] years transitioning to zoledronate were also studied. RESULTS: BMD improved following denosumab [mean (SEM) % change LS: 6.0 (0.62) p < 0.001, TH: 2.28 (0.64) p < 0.001, FN: 1.9 (0.77) p = 0.045]. Changes at the TH and FN were lower in patients with GFR < 35 ml/min (Group B) compared to those with GFR > 35 ml/min (Group A) [% change TH; Group A: 2.9 (0.72), Group B: - 0.84 (1.28), p = 0.015, FN; Group A: 2.76 (0.86), Group B: - 1.47 (1.53), p = 0.025]. % change in BMD at the FN and PTH were negatively associated (r = - 0.25, p = 0.013). BMD changes were not different at 12-18 months between patients on denosumab compared to zoledronate [% change at LS: denosumab: 3.97% (0.85), zoledronate: 2.6% (0.5), p = 0.19 TH: denosumab: 0.97% (0.58), zoledronate: 0.92% (0.6), p = 0.95). CONCLUSION: Denosumab increases BMD following previous bisphosphonate treatment and is comparable to zoledronate. Lower response seen at the hip in CKD is related to PTH concentrations.

Changes in epidermal morphology associated with dandruff.

OBJECTIVE: Dandruff is a very common scalp condition characterized by flaking and pruritus usually with no visible signs of inflammation, such as redness and erythema. Dandruff is considered a multifactorial condition with both microbial colonization and host factors such as sebum production thought to play a role. There is evidence of changes in epidermal morphology in the scalp skin of dandruff sufferers, with reports of an increase in mean thickness and more nucleated cell layers. The underlying mechanisms driving these morphological changes are currently unclear. The objective of this study was to fully characterize epidermal morphology in dandruff compared to healthy scalp skin and to evaluate potential mechanisms underlying any changes observed. METHODS: Scalp skin biopsies were taken from 22 healthy female subjects and 21 dandruff sufferers, from both lesional and non-lesional sites. Samples were processed, sectioned and stained using haematoxylin and eosin (H&E). To fully characterize epidermal morphology, measurements were taken of epidermal thickness, the convolution of the dermal-epidermal junction and the depth of epidermal rete ridges. To analyse changes in epidermal proliferation immunohistochemical staining was performed using Ki67, a well-established marker of cell proliferation, and quantified using image analysis. RESULTS: Histochemical analysis of skin sections revealed that in dandruff lesional samples, the epidermis was thicker, had a more convoluted dermal epidermal junction and the rete ridges were elongated, compared to healthy scalp skin. Similar directional changes in epidermal morphology, were observed in non-lesional dandruff samples, albeit to a lesser extent. Image analysis of Ki67 expression in the epidermis revealed dandruff lesional skin contained significantly more Ki67-positive proliferating keratinocytes than healthy controls samples. This suggests dandruff scalp skin epidermal keratinocytes are in a hyper-proliferative state. CONCLUSION: There were significant changes in epidermal morphology in dandruff lesional skin compared to healthy scalp skin including increased epidermal thickness, a more convoluted dermal-epidermal junction and elongation of rete ridges. Interestingly, we found there was evidence of an increase in the percentage of epidermal Ki67-positive cells, which has not been reported previously, and demonstrates dandruff is a condition displaying epidermal hyper-proliferation.

OBJECTIF: Les pellicules constituent une affection du cuir chevelu très fréquente caractérisée par une desquamation et un prurit ne présentant pas, en général, des signes visibles d'inflammation, comme une rougeur et un érythème. Les pellicules sont considérées être une affection multifactorielle présentant une colonisation microbienne ainsi que des facteurs-hôtes, tels que la production de sébum, qui pourraient avoir un rôle à jouer. Il existe des preuves qu'il se produit des changements dans la morphologie épidermique de la peau du cuir chevelu des personnes qui ont des pellicules, et des rapports font cas d'une augmentation de l'épaisseur moyenne et d'un plus grand nombre de couches de cellules nucléées. Les mécanismes sous-jacents à ces changements morphologiques sont jusqu'ici peu élucidés. L'objectif de cette étude était de caractériser pleinement la morphologie épidermique en la présence de pellicules par comparaison à la peau du cuir chevelu sain, et d'évaluer les mécanismes potentiels sous-jacents à tout changement observé. MÉTHODES: Des biopsies de la peau du cuir chevelu ont été pratiquées chez 22 femmes en bonne santé et 21 femmes présentant des pellicules, dans des sites lésionnés et non lésionnés. Les échantillons ont été traités, coupés en lamelles et colorés en utilisant de l'hématoxyline et de l'éosine (H&E). Pour caractériser pleinement la morphologie épidermique, des mesures de l'épaisseur épidermique, de la convolution de la jonction dermo-épidermique et de la profondeur des crêtes du réseau épidermique ont été effectuées. Pour analyser les changements dans la prolifération épidermique, une coloration immunohistochimique a été réalisée en utilisant du Ki67, un marqueur bien établi de la prolifération cellulaire, et quantifiée à l'aide de l'analyse d'images. RÉSULTATS: L'analyse histochimique des sections de peau a révélé que, dans les échantillons de lésions avec pellicules, l'épiderme était plus épais, présentait une jonction dermo-épidermique plus compliquée et des crêtes du réseau plus allongées, par comparaison à la peau du cuir chevelu en bonne santé. Des changements directionnels analogues de la morphologie épidermique ont été observés dans les échantillons sans lésions et avec pellicules, toutefois en une moindre mesure. L'analyse des images de l'expression de Ki67 dans l'épiderme a révélé que la peau avec lésions et pellicules contenait des kératinocytes prolifératifs bien plus Ki67-positifs que les échantillons de témoins en bonne santé. Cela suggère que les kératinocytes épidermiques de la peau du cuir chevelu présentant des pellicules sont dans un état hyper-prolifératif. CONCLUSION: Il s'est produit des changements significatifs dans la morphologie épidermique de la peau avec lésions et pellicules, par comparaison à la peau du cuir chevelu en bonne santé, y compris un épaississement de l'épiderme, une jonction dermo-épidermique plus compliquée et un allongement des crêtes du réseau. Fait intéressant, nous avons découvert des signes d'augmentation du pourcentage de cellules épidermiques Ki67-positives, ce qui n'avait encore jamais été rapporté, et qui démontre que la présence de pellicules est une affection affichant une hyper-prolifération épidermique.

Skeletal response to treatment with teriparatide (TPD) after bisphosphonate in post-menopausal women with osteoporosis and a high prevalence of secondary risk factors in real-life setting of a metabolic bone clinic; effect of age and vitamin D status.

PURPOSE: Teriparatide (TPD) is a skeletal anabolic agent used in patients with severe post-menopausal osteoporosis (PMO) and steroid-induced osteoporosis who are at hish risk of fracture. Predictors of therapeutic response to teriparatide in real-life setting are not well characterised. We investigated potential factors associated with teriparatide response in post-menopausal women with established osteoporosis. METHODS: We carried out a retrospective survey of 48 women, aged 73.2 [7.5] years with severe osteoporosis and prevalent fractures treated with TPD according to the NICE criteria. BMD was measured at baseline, 6-12 and 18-24 months at the lumbar spine (LS), total hip (TH) and femoral neck (FN). Bone turnover markers, serum 25 (OH)vitamin D were determined at 3-12 and 12-24 months. RESULTS: BMD increased at 6-12 months (% change mean [SEM] 6.5 [1.1] p = 0.004) and 18-24 months (8.45 % [1.2] p<0.001) at the LS. A significant increase in BMD was observed at FN (3.1 [1.3] % p = 0.02). Changes in BMD at the TH was higher in patients younger than 73 years compared to older women (% change in BMD 4.13 [1.64] % v/s -1.7 [1.1] p = 0.007). Baseline 25 (OH) vitamin D correlated with change in P1NP at 3-12 months (r = 0.45 p = 0.049). CONCLUSIONS: TPD-induced changes in BMD at the TH appears may be dependent on age. Vitamin D status may influence the early anabolic effect to TPD. Our data suggest that these factors may be important considerations when initiating and optimising treatment with TPD, although further larger studies are needed to confirm these findings.

CaSiO3 perovskite in diamond indicates the recycling of oceanic crust into the lower mantle.

Laboratory experiments and seismology data have created a clear theoretical picture of the most abundant minerals that comprise the deeper parts of the Earth's mantle. Discoveries of some of these minerals in 'super-deep' diamonds-formed between two hundred and about one thousand kilometres into the lower mantle-have confirmed part of this picture. A notable exception is the high-pressure perovskite-structured polymorph of calcium silicate (CaSiO3). This mineral-expected to be the fourth most abundant in the Earth-has not previously been found in nature. Being the dominant host for calcium and, owing to its accommodating crystal structure, the major sink for heat-producing elements (potassium, uranium and thorium) in the transition zone and lower mantle, it is critical to establish its presence. Here we report the discovery of the perovskite-structured polymorph of CaSiO3 in a diamond from South African Cullinan kimberlite. The mineral is intergrown with about six per cent calcium titanate (CaTiO3). The titanium-rich composition of this inclusion indicates a bulk composition consistent with derivation from basaltic oceanic crust subducted to pressures equivalent to those present at the depths of the uppermost lower mantle. The relatively 'heavy' carbon isotopic composition of the surrounding diamond, together with the pristine high-pressure CaSiO3 structure, provides evidence for the recycling of oceanic crust and surficial carbon to lower-mantle depths.

The relationship between circulating adiponectin, leptin and vaspin with bone mineral density (BMD), arterial calcification and stiffness: a cross-sectional study in post-menopausal women.

OBJECTIVE: To explore the relationship between circulating adiponectin, leptin and vaspin with bone mineral density (BMD), arterial stiffness and vascular calcification in post-menopausal women. We hypothesised that adipokines produced by adipose tissue may be mediators of bone and cardiovascular disease (CVD) and explain, in part, the observed association between osteoporosis and CVD. DESIGN: We studied 386 ambulant community dwelling postmenopausal women aged (mean [SD] 61 [6.4] years). BMD at the lumbar spine, femoral neck (FN), and total hip (TH), body composition; fat mass (FM) and lean mass (LM) as well as abdominal aortic calcification (AAC) were determined by dual energy X-ray absorptiometry. Pulse wave velocity (PWV) and augmentation index, markers of arterial stiffness were measured. Fasting adiponectin, leptin and vaspin were quantified in serum. RESULTS: A positive independent association was observed between vaspin and BMD at the FN (p = 0.009), TH (p = 0.037) in the whole study population adjusted for confounders including age, FM, LM and lifestyle variables. Using the same model, a negative association was seen between adiponectin and BMD at the FN in women with osteoporosis (p = 0.043). Serum adiponectin was significantly higher in women with fractures (20.8 [9.3] µg/ml compared to those without (18.5 [8.6] µg/ml, p = 0.018) and associated with a significant increased risk of fracture (HR 1.032, 95% CI 1.003-1.063, p = 0.032). Leptin was not associated with BMD or fracture risk after adjustment. Adiponectin was independently associated with AAC (p = 0.007) and significantly higher in women with AAC scores > 1; (19.2[9.2]) compared to those with no or low AAC scores (<1); 16.8 [8.0], p = 0.018). In adjusted analyses, PWV velocity was positively associated with circulating vaspin (p = 0.039) and AI was negatively associated with serum leptin (p = 0.002). CONCLUSION: Adiponectin, leptin, vaspin are related to markers of bone and vascular health and may contribute to the observed association between osteoporosis and CVD.

Bone Mineral Density and Body Composition are Associated with Circulating Angiogenic Factors in Post-menopausal Women.

Lean mass (LM) and fat mass (FM) are closely related to bone mass (BM) in post-menopausal women, although their relative importance is unclear. Angiogenic factors which control angiogenesis may influence BM, LM and FM. The aim of the study was to compare the contribution of LM and FM to bone mineral density (BMD) and the association between these tissues and circulating angiogenic factors. The study population comprised of 392 post-menopausal women aged mean [SD] 61.8 [6.4] years. BMD was measured at the lumbar spine (LS), neck of femur and total hip (TH) by dual-energy X-ray absorptiometry (DXA). DXA scan was also used to determine LM and FM. Angiopoietin-1 and 2 (ANG-1, ANG-2) were measured by sandwich enzyme-linked immunosorbent assay. Following adjustment for confounders, significant positive independent associations were seen between LM with BMD at all skeletal sites (TH: p < 0.0001) and FM with BMD at the hip sites (TH: p = 0.004). When BMD and LM were regressed against the angiogenic factors, positive associations were seen between ANG-2 with LM (p = 0.002) and LS BMD (p = 0.05). Negative associations were observed between the ratio of ANG-1/ANG-2 with LS BMD (p = 0.014), TH BMD (p = 0.049) and LM (p = 0.029). FM and fat distribution (android/gynoid fat ratio) were negatively associated with ANG-1 (p = 0.006) and ANG-2 (p = 0.004), respectively. ANG-1 and ANG-2 may be involved in the maintenance of bone, muscle and fat mass.

Changes in bone mineral density and bone turnover in patients on 'drug holiday' following bisphosphonate therapy: real-life clinic setting.

OBJECTIVES: Treatment discontinuation after long-term bisphosphonate (BP), termed a 'drug holiday', has been proposed to reduce the risk of BP-associated complications. The duration of treatment cessation remains unclear. Changes in bone mineral density (BMD), bone turnover markers (BTMs) and their relationship with FRAX were assessed to help determine the optimum length of a 'drug holiday'. METHODS: A retrospective analysis of 134 patients (13M, 121F) aged [mean (SD)] 68·4 (8·2) years who discontinued BPs after treatment for 5·9 (3·0) years for osteoporosis was undertaken. BMD at the lumbar spine (LS), total hip (TH), and femoral neck (FN) and biochemical parameters including serum 25 (OH) vitamin D, bone turnover markers (plasma CTX, P1NP) and FRAX scores were determined at discontinuation, 12-18 months and 24-30 months off treatment. RESULTS: BMD decreased significantly at the LS [% change mean (SD): -0·94 (3·6), P = 0·008], TH [-1·4 (2·4), P < 0·001] and FN [-1·8 (4·4), P < 0·001] after treatment discontinuation for 12-18 months. In the subgroup who remained off treatment for 24-30 months, a progressive decline in BMD was seen at the TH and FN with total % decrease of -2·52 (3·5) and -2·7 (4·76), P < 0·001, respectively. CTX and P1NP increased significantly at 12-18 months after discontinuation [% change CTX: 95 (88), P < 0·001, P1NP: 88 (73), P < 0·001]. FRAX scores were significant predictors of % change in BMD at the FN (P < 0·05), independently of bone turnover and vitamin D status. In summary, our data show that following a 'drug holiday', the use of DEXA scans, BTMs and FRAX may help guide when to resume treatment.

Climbazole increases expression of cornified envelope proteins in primary keratinocytes.

OBJECTIVE: Dandruff is a troubling consumer problem characterized by flaking and pruritus of the scalp and is considered a multifactorial condition with sebum, individual susceptibility and the fungus Malassezia all thought to play a part. The condition is commonly treated with shampoo products containing antifungal ingredients such as zinc pyrithione and climbazole. It is hypothesized that these ingredients may be delivering additional scalp skin benefits besides their antifungal activity helping to relieve dandruff effectively. The objective of this study was to evaluate the anti-dandruff ingredient climbazole for potential skin benefits using genomics and in vitro assays. METHODS: Microarray analysis was performed to profile gene expression changes in climbazole-treated primary human keratinocyte cells. Results were independently validated using qPCR and analysis of protein expression using ELISA and immunocytochemistry. RESULTS: Microarray analysis of climbazole-treated keratinocytes showed statistically significant expression changes in genes associated with the gene ontology groups encompassing epidermal differentiation, keratinization, cholesterol biosynthesis and immune response. Upregulated genes included a number encoding cornified envelope proteins such as group 3 late-cornified envelope proteins, LCE3 and group 2 small-proline-rich proteins, SPRR2. Protein analysis studies of climbazole-treated primary keratinocytes using ELISA and immunocytochemistry were able to demonstrate that the increase in gene transcripts translated into increased protein expression of these cornified envelope markers. CONCLUSION: Climbazole treatment of primary keratinocytes results in an upregulation in expression of a number of genes including those encoding proteins involved in cornified envelope formation with further studies demonstrating this did translate into increased protein expression. A climbazole-driven increase in cornified envelope proteins may improve the scalp skin barrier, which is known to be weaker in dandruff. These studies suggest climbazole, besides its antifungal activity, is delivering positive skin benefits helping to relive dandruff symptoms effectively.

The effect of upper limb position on ultrasonographic arterial flow to the ulnar nerve.

We measured the pulsatility indices in the inferior collateral and posterior recurrent ulnar arteries, which supply the ulnar nerve at the elbow, in 38 conscious adults. Compared with a straight 30° abducted arm, elbow flexion to 120° reduced the mean (SD) pulsatility index in the inferior artery and increased the pulsatility index in the posterior artery: from 3.36 (0.86) to 3.04 (0.94), p = 0.001, and from 3.14 (0.81) to 3.64 (1.05), p < 0.0005, respectively. The mean (95% CI) pulsatility index in the inferior artery was unaffected by shoulder abduction to 120°, but it was decreased in the posterior artery in men, from 3.06 (2.76-3.36) to 2.64 (2.34-2.95), but not women, from 3.22 (2.94-3.50) to 3.25 (2.97-3.53), p = 0.01 for men vs women. Researchers should measure arterial pulsatility indices under general anaesthesia and associate them with measures of nerve function.

Differences in regional bone metabolism at the spine and hip: a quantitative study using (18)F-fluoride positron emission tomography.

SUMMARY: This study showed that regional bone blood flow and (18)F-fluoride bone plasma clearance measured by positron emission tomography are three times lower at the hip than the lumbar spine. INTRODUCTION: Measurements of effective bone plasma flow (K (1)), bone plasma clearance (K ( i )) and standardised uptake values (SUV) using (18)F-fluoride positron emission tomography ((18)F-PET) provide a useful means of studying regional bone metabolism at different sites in the skeleton. This study compares the regional (18)F-fluoride kinetics and SUV at the hip and lumbar spine (LS). METHODS: Twelve healthy postmenopausal women with no history of metabolic bone disease apart from two with untreated osteoporosis were recruited. Each subject underwent 60-min dynamic (18)F-PET scans at the LS and proximal femur two weeks apart. K (1), K ( i ) and SUV were measured at the LS (mean of L(1)-L(4)), femoral neck (FN), total hip (TH) and femoral shaft (FS). Differences between sites were assessed using the nonparametric Kruskal-Wallis test with a Bonferroni correction for multiple comparisons. RESULTS: Values of K (1), K ( i ) and SUV at the FN, TH and FS were three times lower than at the LS (p = 0.003). Amongst the proximal femur sites, K ( i ) and SUV were lower at the FS compared with the FN and TH, and SUV was lower at the TH compared with the FN (all p < 0.05). The volume of distribution was lower at the TH and FS compared with the LS (p < 0.05). CONCLUSION: The lower values of K (1), K ( i ) and SUV at the hip suggest that lower bone blood flow in the proximal femur is an important factor explaining the principal reason for the differences in bone fluoride kinetics between the LS and hip sites.

Iatrogenic nerve injury in a national no-fault compensation scheme: an observational cohort study.

BACKGROUND: Iatrogenic nerve injury causes distress and disability, and often leads to litigation. The scale and profile of these injuries has only be estimated from published case reports/series and analyses of medicolegal claims. AIM: To determine the current spectrum of iatrogenic nerve injury in New Zealand by analysing treatment injury claims accepted by a national no-fault compensation scheme. METHODS: The Accident Compensation Corporation (ACC) provides national no-fault personal accident insurance cover, which extends to patients who have sustained a treatment injury from a registered healthcare professional. Nerve injury claims identified from 5227 treatment injury claims accepted by the ACC in 2009 were analysed. RESULTS: From 327 claims, 292 (89.3%) documenting 313 iatrogenic nerve injuries contained sufficient information for analysis. Of these, 211 (67.4%) occurred in 11 surgical specialties, particularly orthopaedics and general surgery; the remainder involved phlebotomy services, anaesthesia and various medical specialties. The commonest causes of injury were malpositioning (n = 40), venepuncture (n = 26), intravenous cannulation (n = 21) and hip arthroplasty (n = 21). Most commonly injured were the median nerve and nerve roots (n = 32 each), brachial plexus (n = 26), and the ulnar nerve (n = 25). At least 34 (11.6%) patients were referred for surgical management of their nerve injury. CONCLUSIONS: Iatrogenic nerve injuries are not rare and occur in almost all branches of medicine, with malpositioning under general anaesthesia and venepuncture as leading causes. Some of these injuries are probably unavoidable, but greater awareness of which nerves are at risk and in what context should facilitate the development and/or wider implementation of preventive strategies.

Regional bone metabolism at the lumbar spine and hip following discontinuation of alendronate and risedronate treatment in postmenopausal women.

UNLABELLED: The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using (18) F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1 year but increased in the hip in the alendronate group only. INTRODUCTION: Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation. METHODS: Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN (n = 11) or RIS (n = 9) for a minimum of 3 years at screening (range 3-9 years, mean 5 years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12 months following treatment discontinuation. (18) F-fluoride plasma clearance (K(i)) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed. RESULTS: With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12 months for both study groups. Measurements of K(i) and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% (p = 0.028) and 24.0% (p = 0.013), respectively. CONCLUSIONS: Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12 months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment.

A common single-nucleotide polymorphism in cyclooxygenase-2 disrupts microRNA-mediated regulation.

Elevated expression of the prostaglandin synthase cyclooxygenase-2 (COX-2) is commonly observed in many chronic inflammatory diseases and cancer. However, the mechanisms allowing for pathogenic COX-2 overexpression are largely unknown. The gene for COX-2 (PTGS2) carries a common single-nucleotide polymorphism (SNP) at position 8473 (T8473C), in exon 10 that is associated with diseases in which COX-2 overexpression is a contributing factor. We demonstrate that the T8473C SNP resides within a region that targets COX-2 mRNA for degradation through microRNA-mediated regulation. miR-542-3p was identified to bind transcripts derived from the 8473T allele and promote mRNA decay. By contrast, the presence of the variant 8473C allele interfered with miR-542-3p binding, allowing for mRNA stabilization, and this effect was rescued using a mutated miR-542-3p at the respective 8473 site. Colon cancer cells and tissue displayed COX-2 mRNA levels that were dependent on T8473C allele dosage, and allele-specific expression of COX-2 was observed to be a contributing factor promoting COX-2 overexpression. These findings provide a novel molecular explanation underlying disease susceptibility associated with COX-2 T8473C SNP, and identify it as a potential marker for identifying cancer patients best served through selective COX-2 inhibition.

Circulating fibroblast growth factor-23 increases following intermittent parathyroid hormone (1-34) in postmenopausal osteoporosis: association with biomarker of bone formation.

Uncertainties exist regarding whether FGF-23 production is influenced by PTH and its involvement in bone formation. We evaluated FGF-23 response and its relation to changes in biomarkers of bone formation following intermittent PTH treatment. Twenty-seven women with a mean [SD] age of 75.8 [5.4] years with postmenopausal osteoporosis were treated with PTH(1-34) for 18 months. Bone mineral density (BMD) was measured at 6 and 18 months at the lumbar spine (LS) and total hip (TH). Blood samples were obtained at baseline, 1-3, 6-9, and 12-18 months. Serum calcium, phosphate, PTH, 25(OH)vitamin D, 1,25(OH)(2)vitamin D, markers of bone turnover, FGF-23, and sclerostin were measured. BMD increased at both the LS (11.6%, P < 0.001) and TH (2.5%, P < 0.01). The bone formation marker P1NP increased early (baseline mean [SD] 39.9 [24.4] µg/l, 1-3 months 88 [37.9] µg/l; P < 0.001) and remained higher than baseline throughout 18 months. FGF-23 also increased, with a peak response at 6-9 months (increase 65%, P = 0.002). Serum phosphate remained stable. A significant increase in 1.25(OH)(2)vitamin D (P = 0.02) was seen at 1-3 months only. A small but significant reduction in sclerostin was seen at 6-9 (P = 0.02) and 12-18 months (P = 0.06). There was a positive correlation between changes in P1NP and FGF-23 (6-9 months r = 0.78, P < 0.001). FGF-23 is increased by intermittent PTH(1-34). This is related to early changes in P1NP, suggesting that the skeletal effects of PTH may involve FGF-23. Further studies are required to elucidate this.

The effects of anterior load carriage on lower limb gait parameters during obstacle clearance.

The purpose of this study was to assess the effect of anterior load carriage on obstacle-crossing behaviour, with a focus on lower limb gait parameters. Nine male participants (age 23+/-1.8 years, height 176+/-5.0cm) volunteered. Participants either walked without a load (No Load), or carried a load (2KG (empty box), 5KG, 10KG), and stepped over a 20cm obstacle. Vision of the obstacle was obscured 1.0m to 1.3m prior to the obstacle. Significant correlations were found between trail limb toe distance and lead limb toe clearance, in the 2KG, 5KG, and 10KG conditions. Toe clearance increased with load (No Load, 147.3+/-13.9mm; 2KG, 162.5+/-15.6mm; 5KG, 167.6+/-17.6mm; 10KG, 173.9+/-17.5mm; p<0.0001). Trail limb toe distance, trail limb toe distance variability, lead heel distance variability, and lead limb toe clearance variability were greater in the 2KG, 5KG, and 10KG conditions, compared with the No Load condition. Participants adopted a conservative gait pattern during obstacle crossing when carrying a load, evidenced by increasing toe clearance, which may have been influenced by availability of visual information regarding obstacle position. In contrast with previous literature, increased lead limb toe clearance may have been associated with absence of relative surface height difference pre- and post-obstacle crossing.

Spatial and temporal clustering of calcium oxalate and magnesium ammonium phosphate uroliths in dogs living in Ontario, Canada between 1998 and 2006.

Using the spatial scan statistic with a Bernoulli model, in a comparison of the two most common canine uroliths, calcium oxalate (CaOx) and magnesium ammonium phosphate (struvite) we determined whether there was evidence of spatial and/or temporal clustering of each urolith type based on canine submissions from Ontario to the Canadian Veterinary Urolith Centre (CVUC) between 1998 and 2006. During this period, there were 10,478 canine submissions, excluding cases that were identified as recurrent. We were able to georeference approximately 93% of these incident cases. After adjusting for spatial and temporal distributions of dogs based on the demographic risk factors of age, sex, and breed-type, statistically significant spatial and temporal clusters were present for both CaOx and struvite urolith types. A purely temporal struvite cluster occurred between February 10, 1998 and December 20, 2001, whereas, a purely temporal CaOx cluster occurred between September 2, 2005 and December 21, 2006. Hypotheses to explain the spatial clustering of uroliths include variation in the spatial distribution of water hardness, diet-type, access to veterinary care, and the use of surgical versus medical therapies to treat these uroliths. Based on the cluster locations, water hardness was unlikely to explain the spatial difference between the two cluster types whereas variables related to human population density were more consistent with our findings; the CaOx cluster occurred in the highest population density area of Ontario, and the struvite cluster occurred in the lowest population density area of southern Ontario. The temporal struvite cluster at the beginning and CaOx cluster at the end of the study period reflect a similar trend away from struvite towards CaOx urolithiasis among both canines and humans in the developed countries of North America and Europe.

Impact of shaving and anti-perspirant use on the axillary vault.

Shaving the axilla is a regular part of the personal care regime for many women in Europe, North and South America. To assess the impact of shaving on underarm skin, a series of investigations were carried out, in which the thickness of the axillary vault and fossa were measured using optical coherence tomography (OCT), and underarm shaving debris was collected for study. The response of the axilla to histamine iontophoresis was also investigated. Additionally, a study was carried out to investigate the impact of a novel anti-perspirant roll-on formulation on irritation and self-perceived sensory properties of the axilla. The results clearly demonstrate that shaving the underarm consistently removes skin (stratum corneum) as well as axillary hair (with a mean value of 36.1% of the debris being skin). OCT measurements demonstrated that in shaved areas of the axilla, epidermal thickness is higher than in unshaved areas. In response to histamine, wheal and flare were both found to be greater in the shaved axilla, when compared with an unshaved control, but flare in the fossa was greater than that in the vault. On the basis of these results, we propose that the axillary vault has adapted to frequent shaving, notably by the development of a thickened epidermis. However, this adaptation is often not sufficient to fully protect the axilla from damage and irritation resulting from hair removal (shaving). In these instances, we have demonstrated that use of a novel anti-perspirant roll-on formulation containing glycerol and sunflower seed oil was able to reduce the impact of shaving-induced irritation and improve self-assessment of axillary condition.

Histological evaluation of hyperpigmentation on female Filipino axillary skin.

Females in South East Asia (Thailand, Indonesia and the Philippines) show concern about dark areas of skin which develop in their underarms, but little is known about the features differentiating pale and hyperpigmented axillary skin in the general population. To investigate this, a histology study was undertaken in the Philippines to define the aetiology of underarm darkening, which is postulated to be a mild form of postinflammatory hyperpigmentation (PIHP). Punch biopsies were taken from dark and light axillary skin sites of 20 female subjects, of whom seven had hyperpigmented underarms, based on an instrumental (Mexameter MX-18, Courage and Khazaka Electronic GmbH, Cologne, Germany) measure, and 13 had not. Histological and immunohistochemical analyses were undertaken using a range of stains and antibodies, including haematoxylin-eosin for general histopathology, Masson-Fontana for melanin, anti-CD68 for monocytes and macrophages, Van Gieson's technique for fibrosis, anti-proliferating cell nuclear antigen for cell mitosis, and the melanocyte-specific immunostains, anti-tyrosinase and anti-tyrosinase-related protein 1. In most cases, dark skin sites from hyperpigmented panelists had increased intensity of Masson-Fontana, anti-tyrosinase and/or anti-TRP1 staining, indicative of melanocyte stimulation and increased melanin production. Furthermore, hair plucking emerged as a key stimulus to increased pigmentation. The trauma of hair plucking slightly increased the number of infiltrating mononuclear cells and macrophages that ingested melanosomes leaking from the damaged epidermis, more so in the skin of hyperpigmented panelists; this, in turn, potentially increases pigmentation. However, cell infiltration was focal, mainly near the plucked follicles, and not indicative of diffuse inflammation. The results from this study support the hypothesis that axillary darkening is mild PIHP, characterized by increased epidermal melanin, following stimulation or mild irritation of skin, with hair plucking as a key factor in this process.