Comparative study of the effects of osteoprotegerin and testosterone on bone quality in male orchidectomised rats.

Aim: The aim of this work is to compare the effects of osteoprotegerin (OPG) and testosterone on bone quality in a model of orchidectomised (ORX) rats.Methods: Three-month-old ORX or SHAM operated groups (n = 15 each group) were used. The SHAM and ORX groups received saline. There were two ORX groups, receiving OPG-Fc (10 mg/kg twice weekly) (ORX + OPG-Fc) or testosterone cypionate (1.7 mg/kg/weekly) for 8 weeks. After sacrifice, bone analysis by femoral and lumbar dual-energy X-ray absorptiometry and micro-computed tomography in femora were performed. Histological sections of vertebrae were dyed with hematoxylin-eosin or safranin. Serum osteocalcin (BGP), total alkaline phosphatase (ALP), and C-terminal telopeptide of type I collagen (CTX) were analyzed.Results: ORX resulted in femoral and vertebral bone loss and in microarchitectural deterioration. Treatment with OPG-Fc and testosterone recovered lumbar (L) and femoral (F) bone mineral densitometry bone mineral density (BMD) to SHAM levels. Femoral BMD was significantly higher after treatment with OPG-Fc than after testosterone treatment due to the presence of osteopetrotic changes in the metaphyseal region of long bones. Serum levels of ALP and CTX increased, while OPG levels were unchanged in ORX rats. Treatment with OPG-Fc decreased the levels of BGP, ALP, and CTX. Treatment with testosterone maintained biochemical markers of bone turnover at levels similar to or higher than those of ORX rats.

Can childhood trauma influence facial emotion recognition independently from a diagnosis of severe mental disorder? / ¿Influye el trauma infantil en el reconocimiento de las emociones faciales independientemente del diagnóstico de trastorno mental grave?

INTRODUCTION: Facial emotion recognition (FER) is a fundamental component in social interaction. We know that FER is disturbed in patients with severe mental disorder (SMD), as well as those with a history of childhood trauma. MATERIAL AND METHODS: We intend to analyze the possible relationship between the existence of trauma in childhood irrespective of a SMD, measured by the CTQ scale and facial expression recognition, in a sample of three types of subjects (n=321): healthy controls (n=179), patients with BPD (n=69) and patients with a first psychotic episode (n=73). Likewise, clinical and socio-demographic data were collected. The relationship was analyzed by a technique of multivariate regression adjusting for sex, age, IQ, current consumption of drugs and group to which the subject belonged. RESULTS: Sexual and/or physical trauma in childhood related independently to the existence of SMD with a worse total FER ratio, as well as to a worse rate of recognition in expressions of happiness. Furthermore, the subjects with a history of childhood trauma attributed expressions of anger and fear more frequently to neutral and happy faces, irrespective of other variables. CONCLUSIONS: The existence of trauma in childhood seems to influence the ability of subjects to recognize facial expressions, irrespective of SMD. Trauma is a preventable factor with specific treatment; therefore, attention should be paid to the existence of this background in clinical populations.

Differential Modulation of Cancellous and Cortical Distal Femur by Fructose and Natural Mineral-Rich Water Consumption in Ovariectomized Female Sprague Dawley Rats.

Bone mineral density (BMD) and microstructure depend on estrogens and diet. We assessed the impact of natural mineral-rich water ingestion on distal femur of fructose-fed estrogen-deficient female Sprague Dawley rats. Ovariectomized rats drank tap or mineral-rich waters, with or without 10%-fructose, for 10 weeks. A sham-operated group drinking tap water was included (n = 6/group). Cancellous and cortical bone compartments were analyzed by microcomputed tomography. Circulating bone metabolism markers were measured by enzyme immunoassay/enzyme-linked immunosorbent assay or multiplex bead assay. Ovariectomy significantly worsened cancellous but not cortical bone, significantly increased circulating degradation products from C-terminal telopeptides of type I collagen and receptor activator of nuclear factor-kappaB ligand (RANKL), and significantly decreased circulating osteoprotegerin and osteoprotegerin/RANKL ratio. In ovariectomized rats, in cancellous bone, significant water effect was observed for all microstructural properties, except for the degree of anisotropy, and BMD (neither a significant fructose effect nor a significant interaction between water and fructose ingestion effects were observed). In cortical bone, it was observed a significant (a) water effect for medullary volume and cortical endosteal perimeter; (b) fructose effect for cortical thickness, medullary volume, cross-sectional thickness and cortical endosteal and periosteal perimeters; and (c) interaction effect for mean eccentricity. In blood, significant fructose and interaction effects were found for osteoprotegerin (no significant water effect was seen). For the first time in ovariectomized rats, the positive modulation of cortical but not of cancellous bone by fructose ingestion and of both bone locations by natural mineral-rich water ingestion is described.

The relationship between theory of mind deficits and neurocognition in first episode-psychosis.

Research suggests that theory of mind (ToM) deficits are related to chronic psychosis and to first-episode psychosis (FEP) independently of other neurocognition domains. The aim of this study was to measure the differences in ToM area in a Spanish population of FEP sample (N = 32) and in a healthy control group (N = 32). A further aim was to describe the relationship between different domains of neurocognition, psychotic symptoms and social functioning with ToM in this sample. ToM was assessed with the MASC task. Estimated IQ with a short version of the WAIS III, Rey-Osterrieth Complex figure, Trail Making Test, Stroop test and Wisconsin Carting Sorting test were used to assess neurocognition. Psychotic symptoms were assessed with Community Assessment of Psychic Experiences (CAPE) in both groups and with PANSS scale in FEP group. GAF and Cannon-Spoor scales were used to measure social functioning before and after onset of psychosis. FEP showed important deficits in ToM domain compared to controls. A worse executive functioning was associated with worse scores in ToM task. However, no relation was found between positive or negative psychotic symptoms and ToM or social functioning and ToM. In our sample neurocognition tests were strongly related to ToM domain independently of other variables.

Atlases with Arcuate Foramen Present Cortical Bone Thickening That May Contribute to Lower Fracture Risk.

BACKGROUND: To date, no information about the cortical bone microstructural properties in atlas vertebrae with arcuate foramen has been reported. As a result, we aimed to test in an experimental model if there is a cortical bone thickening in an atlas vertebra which has an arcuate foramen that may play a protective role against bone fracture. METHODS: We analyzed by means of micro-computed tomography the cortical bone thickness, the cortical volume, and the medullary volume (SkyScan 1172 Bruker micro-CT NV, Kontich, Belgium) in cadaveric dry atlas vertebrae with arcuate foramen and without arcuate foramen. We also reviewed a case series of 31 posterior atlas arch fractures to correlate the possible presence in the same atlas of both fracture and arcuate foramen. RESULTS: The micro-computed tomography study revealed significant differences in cortical bone thickness (P < 0.001), cortical volume (P < 0.004), and medullary volume (P = 0.013) values between the arcuate foramen vertebrae and the nonarcuate foramen vertebrae. The clinical series found no coexistence in the same vertebra of a posterior atlas arch fractures and the arcuate foramen. CONCLUSIONS: An atlas with arcuate foramen presents cortical bone thickening. This advantage in bone microarchitecture seems to contribute to a lower fracture risk compared to subjects without arcuate foramen as no coexistence in the same vertebra of a posterior atlas arch fractures and arcuate foramen was found.

Cortical bone thickening in Type A posterior atlas arch defects: experimental report.

BACKGROUND CONTEXT: To date, no information about the cortical bone microstructural properties in atlas vertebrae with posterior arch defects has been reported. PURPOSE: To test if there is an increased cortical bone thickening in atlases with Type A posterior atlas arch defects in an experimental model. STUDY DESIGN: Micro-computed tomography (CT) study on cadaveric atlas vertebrae. METHODS: We analyzed the cortical bone thickness, the cortical volume, and the medullary volume (SkyScan 1172 Bruker micro-CT NV, Kontich, Belgium) in cadaveric dry vertebrae with a Type A atlas arch defect and normal control vertebrae. RESULTS: The micro-CT study revealed significant differences in cortical bone thickness (p=.005), cortical volume (p=.003), and medullary volume (p=.009) values between the normal and the Type A vertebrae. CONCLUSIONS: Type A congenital atlas arch defects present a cortical bone thickening that may play a protective role against atlas fractures.

Effects of diacerein on cartilage and subchondral bone in early stages of osteoarthritis in a rabbit model.

BACKGROUND: Osteoarthritis is thought to be the most prevalent chronic and disabling joint disease in animals and humans. At present, there is no ideal treatment option. The aim of this study was to assess the effects of the treatment with oral diacerein on articular cartilage, synovial membrane and subchondral bone in an experimental rabbit model of osteoarthritis by micro-CT evaluation and histological analysis. To this purpose, osteoarthritis was surgically induced on one knee of 16 rabbits using the contralateral knee as healthy controls. Treatment was started three weeks later and lasted eight weeks. Animals were divided into two groups for treatment: Placebo (treated daily with oral saline) and diacerein (treated orally with 1.5 mg/kg/day of diacerein). RESULTS: Sample analysis revealed that this model induced osteoarthritis in the operated knee joint. Osteoarthritis placebo group showed a significant increase in non-calcified cartilage thickness and volume with respect to the control placebo group and important changes in the synovial membrane; whereas the parameters measured in subchondral bone remained unchanged. In the osteoarthritis diacerein-treated group the results showed an improvement with respect to the OA placebo group in all parameters, although the results were not statistically significant. CONCLUSION: The results of this animal study suggested that the diacerein treatment for OA may be able to ameliorate the swelling and surface alterations of the cartilage and exert an anti-inflammatory effect on the synovial membrane, which might contribute to OA improvement, as well as an anabolic effect on subchondral trabecular bone.

Comparison of various SYSADOA for the osteoarthritis treatment: an experimental study in rabbits.

BACKGROUND: Osteoarthritis is thought to be the most prevalent chronic and disabling joint disease in animals and humans and its treatment is a major orthopaedic challenge because there is no ideal drug treatment to preserve joint structure and function, as well as to ameliorate the symptomatology of the disease. The aim of the present study was to assess, using histology, histomorphometry and micro-CT, the effects of the treatment with several drugs of the SYSADOA group and a bisphosphonate in a model of early osteoarthritis, comparing all the results obtained. METHODS: Osteoarthritis was surgically induced by anterior cruciate ligament transection and partial meniscectomy on one knee of 56 rabbits; treatment was started three weeks after surgery and lasted 8 weeks; at the end of this period, the animals were sacrificed. Animals were divided into seven groups (8 animals each), one for each regimen of treatment (glucosamine sulfate, chondroitin sulfate, hyaluronic acid, diacerein, risedronate and a combination of risedronate and glucosamine) and one for the control (placebo-treated) group. Following sacrifice, femoral osteochondral cylinders and synovial membrane samples were obtained for their evaluation by qualitative and quantitative histology and micro-CT. RESULTS: The model induced osteoarthritic changes in the knee joints and none of the treatments showed a significantly better efficacy over the others. Regarding cartilage thickness and volume, all the treatments achieved scores halfway between control groups, without statistical differences. Regarding the synovial membrane, diacerein and risedronate showed the best anti-inflammatory profile, whereas glucosamine and chondroitin did not present any effect standing the hyaluronic acid results between the others. Regarding the subchondral bone, there were no differences in thickness or volume, but risedronate, diacerein and hyaluronic acid seemed to have considerably modified the orientation of the trabecular lattice. CONCLUSIONS: Out of the different drugs evaluated in the study for OA treatment, diacerein and risedronate showed, in all the parameters measured, a better profile of effectiveness; hyaluronic acid ameliorated cartilage swelling and promoted bone formation, but with a poor synovial effect; and finally, chondroitin and glucosamine sulfate prevented cartilage swelling in a similar way to the others, but had no effect on cartilage surface, synovial membrane or subchondral bone.

Impact of estrogens on atherosclerosis and bone in the apolipoprotein E-deficient mouse model.

OBJECTIVE: The common inflammatory pathophysiology has nourished the hypothesis of a relationship between osteoporosis and cardiovascular disease. Estrogens are key agents in the modulation of both processes. We investigated whether induction of atherosclerosis affects bone and whether estrogens modulate both processes. METHODS: Female apolipoprotein E-deficient mice (a well-established model of atherogenesis) were ovariectomized or falsely operated and fed either standard diet or high-fat diet (HFD). Six animals were included in each of the four groups. To clarify mechanisms, we treated preosteoblastic MC3T3-E1 cells with mouse serum. RESULTS: Physiological levels of estrogens in falsely operated mice limited atherosclerotic burden in the thoracic aorta, but not in the aortic arch. Bone resorption, as assessed by C-telopeptides, was increased by ovariectomy in animals fed standard diet, but not in animals fed HFD. Bone microstructural properties at the distal femur showed deteriorated trabecular architecture in bone volumetric fraction and trabecular number after ovariectomy, but trabecular pattern factor, trabecular thickness, trabecular spacing, or the structural model index remained unchanged. Changes in cortical parameters were not significant. Volumetric bone mineral density was reduced in trabecular bone, but not in cortical bone, in ovariectomized mice fed standard diet. Preosteoblastic MC3T3-E1 cells exhibited increased cellular proliferation and viability and alkaline phosphatase activity after treatment with sera from animals fed HFD. CONCLUSIONS: Endogenous estrogens partially reduce atherogenic burden in female apolipoprotein E-deficient mice. Ovariectomy increases bone resorption, but not under exacerbated proatherogenic conditions induced by HFD. The absence of apolipoprotein E might have an influence on the asymmetric responses of atherogenesis and bone resorption.

Sirolimus and tacrolimus rather than cyclosporine A cause bone loss in healthy adult male rats.

The aim of this work was to study the effects of cyclosporine (CsA), tacrolimus (FK-506), and rapamycin (RAPA) on bone mass, femoral microstructure, femoral biomechanical properties, and bone remodeling in healthy adult male rats. Forty-eight 5-month-old male Wistar rats were used. CsA (2 mg/kg/day), FK-506 (3 mg/kg/day), RAPA (1.25 mg/kg/day), or water (0.5 ml/rat/day, control group) were administered orally for 3 months. After sacrifice, mean values of immunosuppressants in blood were: CsA (670.4 ng/ml), FK-506 (19.2 ng/ml), and RAPA (4.8 ng/ml). Levels of biochemical parameters were normal in all groups. Femoral BMD was decreased in FK-506 and RAPA groups and lumbar BMD in FK-506 group. Trabecular volume fraction (BV/TV) decreased only in FK-506 group. RAPA and CsA affected femoral cortical structure, but FK-506 did not. FK-506 produced an increase in bone remodeling, and CsA a decrease. FK-506 group showed a decrease in biomechanical parameters relative to all groups. RAPA group showed a decrease in ultimate stress vs control group, and CsA group presented an increase in biomechanical parameters versus control group. We found that administration of both RAPA and FK-506 as monotherapy for healthy rats produced osteopenia. CsA treatment only produces slight damages in the cortical zone of the femur.

Effect of lysophosphatidic acid receptor inhibition on bone changes in ovariectomized mice.

Pharmacological inhibition of signaling through lysophosphatidic acid (LPA) receptors reduces bone erosions in an experimental model of arthritis by mechanisms involving reduced osteoclast differentiation and bone resorption and increased differentiation of osteoblasts and bone mineralization. These results led us to hypothesize that LPA receptor inhibition would be beneficial in osteoporosis. Our aim was to test this hypothesis with the LPA receptor antagonist, Ki16425, in ovariectomized mice, a model of postmenopausal osteoporosis. Ovariectomized mice treated with Ki16425 showed bone loss similar to that observed in the controls. Osteoblast markers, Alpl, Bglap and Col1a1, were increased at the mRNA level but no changes were detected in serum. No additional difference was observed in the Ki16425-treated mice relative to the ovariectomized controls with regard to osteoclast function markers or assays of matrix mineralization or osteoclast differentiation. Thus, pharmacological inhibition of LPA receptor was not beneficial for preventing bone loss in ovariectomized mice, indicating that its favorable effect on bone remodeling is less general than hypothesized.

Effects of Nrf2 deficiency on bone microarchitecture in an experimental model of osteoporosis.

OBJECTIVE: Redox imbalance contributes to bone fragility. We have evaluated the in vivo role of nuclear factor erythroid derived 2-related factor-2 (Nrf2), an important regulator of cellular responses to oxidative stress, in bone metabolism using a model of postmenopausal osteoporosis. METHODS: Ovariectomy was performed in both wild-type and mice deficient in Nrf2 (Nrf2(-/-)). Bone microarchitecture was analyzed by µCT. Serum markers of bone metabolism were also measured. Reactive oxygen species production was determined using dihydrorhodamine 123. RESULTS: Sham-operated or ovariectomized Nrf2(-/-) mice exhibit a loss in trabecular bone mineral density in femur, accompanied by a reduction in cortical area in vertebrae. Nrf2 deficiency tended to increase osteoblastic markers and significantly enhanced osteoclastic markers in sham-operated animals indicating an increased bone turnover with a main effect on bone resorption. We have also shown an increased production of oxidative stress in bone marrow-derived cells from sham-operated or ovariectomized Nrf2(-/-) mice and a higher responsiveness of bone marrow-derived cells to osteoclastogenic stimuli in vitro. CONCLUSION: We have demonstrated in vivo a key role of Nrf2 in the maintenance of bone microarchitecture.

Microstructural trabecular bone from patients with osteoporotic hip fracture or osteoarthritis: its relationship with bone mineral density and bone remodelling markers.

Osteoporosis (OP) and osteoarthritis (OA) are the most prevalent musculoskeletal disorders in the elderly but the relationship between them is unclear. The purposes of this study are to analyze the bone turnover markers (BTM), bone mineral density (BMD) and the structural and mechanical properties of trabecular bone in patients with OP and OA, and to explore the relationship between these two diseases. We studied 12 OP patients and 13 OA patients. We analyzed BTM (ß-CrossLaps and PINP), BMD and microstructural and biomechanical parameters (micro-CT). Our results were: OP group has higher levels of ß-CrossLaps and lower BMD at the femoral neck. Also, OP patients have a decreased volume of trabecular bone and less trabecular number, with architecture showing prevalence of rod-like trabeculae and worse connectivity than OA patients. The biomechanical parameters were worse in OP patients. BMD was correlated with almost all the structural and biomechanical parameters. Moreover, ß-CrossLaps was negatively correlated with hip BMD and with bone surface density and positively with trabecular separation. BTM, BMD and bone microstructural changes in osteoporosis are opposite to those of OA. These findings justify a less resistant bone with higher risk of fragility fractures in OP patients. These histomorphometric and biomechanical changes may be suspected by measuring of BMD and ß-CrossLaps levels.

Effects of glucosamine and risedronate alone or in combination in an experimental rabbit model of osteoarthritis.

BACKGROUND: The osteoarthritis (OA) treatment in humans and in animals is a major orthopaedic challenge because there is not an ideal drug for preserving the joint structure and function. The aim of this study was to assess the effects of the treatment with oral glucosamine and risedronate alone or in combination on articular cartilage, synovial membrane and subchondral bone in an experimental rabbit model of OA. Osteoarthritis was surgically induced on one knee of 32 New Zealand White rabbits using the contralateral as healthy controls. Three weeks later treatments were started and lasted 8 weeks. Animal were divided in four groups of oral treatment: the first group received only saline, the second 21.5 mg/kg/day of glucosamine sulfate, the third 0.07 mg/kg/day of risedronate; and the fourth group both drugs simultaneously at the same dosages. Following sacrifice femurs were removed and osteochondral cylinders and synovial membrane were obtained for its histological and micro-CT evaluation. RESULTS: Sample analysis revealed that the model induced osteoarthritic changes in operated knees. OA placebo group showed a significant increase in cartilage thickness respect to the control and inflammatory changes in synovial membrane; whereas subchondral bone structure and volumetric bone mineral density remained unchanged. All the treated animals showed an improvement of the cartilage swelling independent of the drug used. Treatment with glucosamine alone seemed to have no effect in the progression of cartilage pathology while risedronate treatment had better results in superficial fibrillation and in resolving the inflammatory changes of the tissues, as well as modifying the orientation of trabecular lattice. The combination of both compounds seemed to have additive effects showing better results than those treated with only one drug. CONCLUSIONS: The results of this animal study suggested that glucosamine sulfate and risedronate treatment alone or in combination may be able to stop cartilage swelling. The risedronate treatment could partially stop the fibrillation and the inflammation of synovial membrane as well as modify the orientation of trabeculae in healthy and in osteoarthritic knees.

Bayesian adaptive designs in single ascending dose trials in healthy volunteers.

AIM: Recent publications indicate a strong interest in applying Bayesian adaptive designs in first time in humans (FTIH) studies outside of oncology. The objective of the present work was to assess the performance of a new approach that includes Bayesian adaptive design in single ascending dose (SAD) trials conducted in healthy volunteers, in comparison with a more traditional approach. METHODS: A trial simulation approach was used and seven different scenarios of dose-response were tested. RESULTS: The new approach provided less biased estimates of maximum tolerated dose (MTD). In all scenarios, the number of subjects needed to define a MTD was lower with the new approach than with the traditional approach. With respect to duration of the trials, the two approaches were comparable. In all scenarios, the number of subjects exposed to a dose greater than the actual MTD was lower with the new approach than with the traditional approach. CONCLUSIONS: The new approach with Bayesian adaptive design shows a very good performance in the estimation of MTD and in reducing the total number of healthy subjects. It also reduces the number of subjects exposed to doses greater than the actual MTD.

Effects of PTH (1-84) on bone quality in a validated model of osteoporosis due to androgenic deprivation.

AIM: The purpose of this study was to evaluate the effect of parathyroid hormone (PTH) (1-84) in a model of male osteoporosis induced by orchidectomy in rats. METHODS: Six-month-old Wistar rats were used as follows: SHAM (simulated orchidectomy), orchidectomized (ORX), ORX + PTH1 (ORX and treated with 10 µg/Kg/d of PTH 1-84) and ORX + PTH2 (ORX and treated with 50 µg/Kg/d of PTH 1-84) over 3 months, with treatment beginning three months after orchidectomy. RESULTS: Orchidectomy resulted in a decreased of femoral and lumbar bone mineral density (BMD), a worsening of trabecular and cortical microarchitecture and a decrease in biomechanical properties. Both doses of PTH (1-84) partially (low dose) or totally (high dose) restored the ORX-induced changes. Serum C-telopeptide of type I collagen/5b isoenzyme of tartrate-resistant acid phosphatase (CTX/TRAP) resorption index increased after orchidectomy. Osteocalcin (bone Gla protein; BGP) levels were not affected by orchidectomy. PTH (1-84) treatment did not produce any changes in the levels of CTX/TRAP with respect to the ORX group. BGP levels increased with PTH treatment. CONCLUSION: PTH (1-84) is able to restore the adverse effects of orchidectomy on bone as measured by BMD, microstructural and biomechanical properties and bone remodeling markers.

Effects of kalsis, a dietary supplement, on bone metabolism in the ovariectomized rats.

We studied the ability of Kalsis, a food supplement that contains selenium, citric acid, and vitamin E, to prevent the effects of ovariectomy on bone loss. Six-month-old, Wistar female rats were studied. Groups (n = 12): SHAM: sham-operated rats; OVX: ovariectomized rats, treated with vehicle; OVX + Kalsis: ovariectomized rats treated with Kalsis (25 mg/kg/day) for 3 months. Bone mineral density (BMD) was determined by DXA in lumbar spine and femur. Computerized microtomography (µCT) in femur and serum osteocalcin (BGP), aminoterminal propeptide of procollagen I (PINP), ß-isomer of carboxyterminal telopeptide of collagen I (CTX), and 5b isoenzyme of tartrate-resistant acid phosphatase (TRAP) were performed. Treatment with Kalsis prevented BMD loss in OVX group. µCT showed a decrease in BV/TV, and trabecular number, and an increase in trabecular separation in OVX rats. Kalsis administration attenuated partially bone loss observed by µCT due to ovariectomy. BGP, PINP, and the resorption index (CTX/TRAP) were increased in OVX group. Treatment with Kalsis maintained this increase. The mechanism of action of this supplement is not through a decrease in bone remodelling rate. The antioxidant action of this food supplement, due to the synergism of all its components, as a cause of its beneficial effect is suggested.

The deleterious effect of bariatric surgery on cortical and trabecular bone density in the femurs of non-obese, type 2 diabetic Goto-Kakizaki rats.

BACKGROUND: The effects of type 2 diabetes on bone mass and microstructure are not clear. The aim of this study was to evaluate bone microstructural properties and volumetric bone mineral density (vBMD) in type 2 diabetic Goto-Kakizaki non-obese rats after gastrojejunal bypass and their relationship with hormonal parameters. METHODS: We designed an experimental study in Goto-Kakizaki rats with and without gastrojejunal bypass, performing densitometric and microstructural studies of the distal femur using X-ray computed microtomography (micro-CT). Levels of insulin, glucagon, leptin, and glucagon-like peptide-1 (GLP-1) were also determined. RESULTS: We observed reduced cortical (1,488.92 ± 98.2 vs. 1,727.92 ± 133.45 mg/cm(3), p = 0.028) and trabecular (180.8 ± 9 vs. 261.23 ± 45.54 mg/cm(3), p = 0.036) vBMD in operated rats. Bone volume fraction (BV/TV) and trabecular connectivity were reduced in operated rats, while there was a reduction in cortical thickness and an increase in rod-like trabeculae at the expense of plate-like trabeculae. Leptin was reduced (1,042 ± 549 vs. 2,447 ± 1,035 pg/ml, p = 0.05) and GLP-1 increased (1.62 ± 0.32 vs. 0.96 ± 0.1 ng/ml, p = 0.008) but only leptin showed a significant association with vBMD CONCLUSIONS: In type 2 diabetic Goto-Kakizaki rats, gastrojejunal bypass produces a reduction in cortical and trabecular bone mineral density and a deterioration in bone quality that could be explained, in part, by the reduction in leptin levels.

The intramammary efficacy of first generation cephalosporins against Staphylococcus aureus mastitis in mice.

Staphylococcus aureus-induced mastitis in cattle causes important financial losses in the dairy industry due to lower yield and bad milk quality. Although S. aureus is susceptible to many antimicrobials in vitro, treatment often fails to cure the infected udder. Hence, comprehensive evaluation of antimicrobials against S. aureus mastitis is desirable to direct treatment strategies. The mouse mastitis model is an elegant tool to evaluate antimicrobials in vivo while circumventing the high costs associated with bovine experiments. An evaluation of the antimicrobial efficacy of the intramammary (imam) applied first generation cephalosporins cefalexin, cefalonium, cefapirin and cefazolin, was performed using the S. aureus mouse mastitis model. In vivo determination of the effective dose 2log(10) (ED(2log10)), ED(4log10), protective dose 50 (PD(50)) and PD(100) in mouse mastitis studies, support that in vitro MIC data of the cephalosporins did not fully concur with the in vivo clinical outcome. Cefazolin was shown to be the most efficacious first generation cephalosporin to treat S. aureus mastitis whereas the MIC data indicate that cefalonium and cefapirin were more active in vitro. Changing the excipient for imam application from mineral oil to miglyol 812 further improved the antimicrobial efficacy of cefazolin, confirming that the excipient can influence the in vivo efficacy. Additionally, statistical analysis of the variation of S. aureus-infected, excipient-treated mice from fourteen studies emphasizes the strength of the mouse mastitis model as a fast, cost-effective and highly reproducible screening tool to assess the efficacy of antimicrobial compounds against intramammary S. aureus infection.

Downregulation of the inflammatory response by CORM-3 results in protective effects in a model of postmenopausal arthritis.

CO-releasing molecules (CORMs) are a new class of drugs able to release small amounts of CO in biological systems. We have shown previously that one of these molecules, CORM-3, exerts anti-inflammatory effects in animal models. The aim of this study was to assess the effects of CORM-3 on bone metabolism in a model of postmenopausal rheumatoid arthritis osteoporosis. Ovariectomy was followed by collagen-induced arthritis in female DBA-1/J mice. Animals showing arthritis on day 22 after immunization were then randomized into control and treatment groups. CORM-3 was administered at 10 mg/kg, intraperitoneally, once a day. Alendronate was administered at 100 µg/kg, orally, once a day. On days 36 and 50 after immunization, animals were killed and tissues analyzed. The arthritic score was significantly reduced by CORM-3 but not by alendronate treatment. Histopathological analyses indicated that both compounds reduced cellular infiltration and cartilage degradation. Local bone erosion and reduction in TNFα levels were seen for CORM-3 on day 50 and for alendronate on day 36. Serum levels of COMP, IL-6, MMP-3, CTX-I, alkaline phosphatase, and osteocalcin were decreased by both treatments, whereas TNFα levels were reduced by CORM-3 and TRAP-5b by alendronate. Micro-computed tomographic analysis showed protective effects on trabecular bone, which were more prominent for CORM-3 on day 36 and for alendronate on day 50. Our results suggest that CORMs represent a novel anti-inflammatory strategy to counteract joint bone erosion with partial protective effects on systemic bone loss in postmenopausal rheumatoid arthritis.