Baseline observations from the POSSIBLE EU® study: characteristics of postmenopausal women receiving bone loss medications

Summary

Prospective Observational Scientific Study Investigating Bone Loss Experience in Europe (POSSIBLE EU®) is an ongoing longitudinal cohort study that utilises physician- and patient-reported measures to describe the characteristics and management of postmenopausal women on bone loss therapies. We report the study design and baseline characteristics of 3,402 women recruited from general practice across five European countries.

Purpose

The POSSIBLE EU® is a study describing the characteristics and management of postmenopausal women receiving bone loss medications.

Methods

Between 2005 and 2008, general practitioners enrolled postmenopausal women initiating, switching or continuing treatment with bone loss treatment in France, Germany, Italy, Spain and the UK. Patients and physicians completed questionnaires at study entry and at 3-month intervals, for 1 year.

Results

Of 3,402 women enrolled (mean age 68.2 years [SD] 9.83), 96% were diagnosed with low bone mass; 55% of these using dual energy X-ray absorptiometry. Most women (92%) had comorbidities. Mean minimum T score (hip or spine) at diagnosis was ?2.7 (SD 0.89; median ?2.7 [interquartile range, ?3.2, ?2.2]) indicating low bone mineral density. Almost 40% of the women had prior fractures in adulthood, mostly non-vertebral, non-hip in nature, 30% of whom had at least two fractures and more than half experienced moderate/severe pain or fatigue. Bisphosphonates were the most common type of bone loss treatment prescribed in the 12 months preceding the study.

Conclusions

POSSIBLE EU® characterises postmenopausal women with low bone mass, exhibiting a high rate of prevalent fracture, substantial bone fragility and overall comorbidity burden. Clinical strategies for managing osteoporosis in this population varied across the five participating European countries, reflecting their different guidelines, regulations and standards of care.     

Psychobiological modulation in anxious and depressed patients after a mindfulness meditation programme: a pilot study

Mindfulness meditation is an ancient and simple form of meditation that has been said to induce several important physical and psychological benefits. The present study was designed with the aim of investigating the psychobiological effects of mindfulness meditation practice in a clinical population. Sixteen patients with depression and anxiety symptoms were submitted to a mindfulness meditation programme for the period of 2 months. Psychological well‐being [5‐item Mental Health (MH‐5)] and several endocrine parameters [adrenocorticotropic hormone (ACTH), cortisol, dehydroepiandrosterone‐sulphate (DHEAS), thyroid‐stimulating hormone, triiodothyronine, thyroxine and parathyroid hormone (PTH)] were assessed before and after the meditation programme. At post‐test, the MH‐5 score improved, while the levels of DHEAS and ACTH were raised, and those of PTH decreased. Our results suggest that mindfulness meditation can exert a significant psychobiological modulation by enhancing psychological well‐being, as well as by regulating the levels of several hormonal parameters on different axes. Copyright © 2010 John Wiley & Sons, Ltd.     

Predicting fractures in an international cohort using risk factor algorithms without BMD

Clinical risk factors are associated with increased probability of fracture in postmenopausal women. We sought to compare prediction models using self‐reported clinical risk factors, excluding BMD, to predict incident fracture among postmenopausal women. The GLOW study enrolled women aged 55 years or older from 723 primary‐care practices in 10 countries. The population comprised 19,586 women aged 60 years or older who were not receiving antiosteoporosis medication and were followed annually for 2 years. Self‐administered questionnaires were used to collect data on characteristics, fracture risk factors, previous fractures, and health status. The main outcome measure compares the C index for models using the WHO Fracture Risk (FRAX), the Garvan Fracture Risk Calculator (FRC), and a simple model using age and prior fracture. Over 2 years, 880 women reported incident fractures including 69 hip fractures, 468 “major fractures” (as defined by FRAX), and 583 “osteoporotic fractures” (as defined by FRC). Using baseline clinical risk factors, both FRAX and FRC showed a moderate ability to correctly order hip fracture times (C index for hip fracture 0.78 and 0.76, respectively). C indices for “major” and “osteoporotic” fractures showed lower values, at 0.61 and 0.64. Neither algorithm was better than the model based on age + fracture history alone (C index for hip fracture 0.78). In conclusion, estimation of fracture risk in an international primary‐care population of postmenopausal women can be made using clinical risk factors alone without BMD. However, more sophisticated models incorporating multiple clinical risk factors including falls were not superior to more parsimonious models in predicting future fracture in this population. © 2011 American Society for Bone and Mineral Research     

Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes

OBJECTIVE

To determine the role of hepatocyte growth factor (HGF)/c-Met on β-cell survival in diabetogenic conditions in vivo and in response to cytokines in vitro.

RESEARCH DESIGN AND METHODS

We generated pancreas-specific c-Met-null (PancMet KO) mice and characterized their response to diabetes induced by multiple low-dose streptozotocin (MLDS) administration. We also analyzed the effect of HGF/c-Met signaling in vitro on cytokine-induced β-cell death in mouse and human islets, specifically examining the role of nuclear factor (NF)-κB.

RESULTS

Islets exposed in vitro to cytokines or from MLDS-treated mice displayed significantly increased HGF and c-Met levels, suggesting a potential role for HGF/c-Met in β-cell survival against diabetogenic agents. Adult PancMet KO mice displayed normal glucose and β-cell homeostasis, indicating that pancreatic c-Met loss is not detrimental for β-cell growth and function under basal conditions. However, PancMet KO mice were more susceptible to MLDS-induced diabetes. They displayed higher blood glucose levels, marked hypoinsulinemia, and reduced β-cell mass compared with wild-type littermates. PancMet KO mice showed enhanced intraislet infiltration, islet nitric oxide (NO) and chemokine production, and β-cell apoptosis. c-Met-null β-cells were more sensitive to cytokine-induced cell death in vitro, an effect mediated by NF-κB activation and NO production. Conversely, HGF treatment decreased p65/NF-κB activation and fully protected mouse and, more important, human β-cells against cytokines.

CONCLUSIONS

These results show that HGF/c-Met is critical for β-cell survival by attenuating NF-κB signaling and suggest that activation of the HGF/c-Met signaling pathway represents a novel strategy for enhancing β-cell protection.Type I diabetes is an autoimmune disease that results from cellular cytotoxicity leading to selective and progressive destruction of insulin-secreting cells (1–3). Many growth factors known to control cell growth and survival in physiologic and pathologic conditions are expressed in the pancreas and could potentially participate in an autocrine/paracrine fashion in the final fate of β-cells in an autoimmune environment. Overexpression of IGF-1, transforming growth factor-β, or granulocyte macrophage-colony stimulating factor ameliorates islet infiltration and β-cell death in mouse models of increased islet inflammation and diabetes (4–6). However, the role of endogenous pancreatic growth factors in type I diabetes has not been examined. Because growth factors can locally affect β-cell survival, neogenesis, and regeneration, and modulate chemokine production and immune responses, alterations in the level/activation of growth factor signaling pathways might contribute to the delay/acceleration of the onset of diabetes.Hepatocyte growth factor (HGF)/c-Met signaling pathway participates in the control of multiple biological functions, including development, proliferation, survival, regeneration, and branching morphogenesis (7). HGF binds with high affinity to, and induces the dimerization of, c-Met, its transmembrane tyrosine kinase receptor (8). Deletion of exon 16 of the c-Met gene, which encodes Lys¹¹⁰⁸ (ATP binding site), essential for the kinase activity of this receptor, in knockout mice results in embryonic lethality (9). These mice display a phenotype identical to HGF knockout mice (10). Both HGF and c-Met are expressed in the pancreas; HGF localizes to endothelial, islet, and mesenchymal cells, and c-Met is expressed in islet, ductal, and pancreatic progenitor cells (11–14). Conditional ablation of the c-Met gene in mouse β-cells using RIP-Cre and lox-c-Met mice leads to deficient insulin secretion without alteration of β-cell mass (12,13). On the other hand, HGF overexpression in the β-cell of transgenic mice increases β-cell replication, mass, and function (15,16). Furthermore, HGF improves islet graft survival in animal models of diabetes (17–19). HGF positively influences autoimmune responses, reducing the severity of autoimmune myocarditis and arthritis (20,21). HGF also downregulates airway and kidney inflammation, and inflammatory bowel disease (22–24). Whether HGF plays a role in autoimmune diabetes is unknown.To address the function of c-Met in the development, growth, and maintenance of β-cells under physiologic conditions, as well as its role in β-cell survival and response to injury in vivo, we generated pancreas-specific c-Met-null (PancMet KO) mice. We report that although c-Met is dispensable for normal β-cell growth and function under basal conditions, it is critically important for β-cell survival in diabetogenic conditions. β-Cell survival is dramatically worsened in the absence of HGF/c-Met signaling, resulting in accelerated diabetes onset. These observations also apply to human β-cells, underscoring a therapeutic opportunity for the HGF/c-Met signaling pathway in human diabetes.     

Alemtuzumab induction and triple maintenance immunotherapy in kidney transplantation from donors after cardiac death.

We have used alemtuzumab in combination with triple maintenance immunosuppression in renal transplantation from donors after cardiac death between 2002 and 2006. We compared outcomes of induction therapy with alemtuzumab with interleukin-2 (IL-2) receptor antagonists (RA) and anti-lymphocyte antibodies. We used a retrospective sequential study design to examine 170 recipients of kidneys from donor after cardiac death (DCD) for survival, graft survival, time to first rejection, glomerular filtration and complications. Patients were stratified into high-risk and low-risk groups based on the following criteria: panel of reactive antibodies >20%, retransplants, Afro-American race. Induction with alemtuzumab was compared with anti-thymocyte globulin (ATG) in the high-risk and with IL-2RA in the low-risk group. Patients received triple immunosuppression with steroids, mycophenolate mofetil and calcineurin inhibitors. Patient survival, graft survival, rejection rate and glomerular filtration rate did not significantly differ between patients treated with alemtuzumab versus IL-2RAs or ATG. There was a trend towards reduced graft- and patient survival in the alemtuzumab group. There was an increased incidence of cytomegalovirus (CMV) infections in the alemtuzumab-induced group and a trend towards increased BK virus and bacterial infections. Induction of DCD kidney transplants with alemtuzumab compared to IL-2RA and ATG has no significant impact on acute rejection. It appears however that CMV infections are increased in patients induced with alemtuzumab. We therefore conclude that induction with alemtuzumab does not confer any advantage over traditional induction agents.     

Primary hemorrhagic intramedullary melanoma. Case report with emphasis on the difficult preoperative diagnosis

Primary melanoma of the central nervous system (CNS) is rare and primary spinal melanoma (PSM) is even more unusual. Preoperative diagnosis of melanocytic lesion as a PSM is difficult, because of the heterogeneous magnetic resonance (MR) signal intensity, due to hemorrhagic foci and melanin deposits. We describe the case of a 68 year-old male with a MR showing at Th8-Th9 level a well-defined intramedullary lesion; for the characteristics of hemorrhagic signal on MR and its association with a presumptive brain cavernoma, a preoperative diagnosis of intramedullary cavernous angioma was suspected. Pathological examination revealed a melanoma, and for the absence of other localizations outside the spinal cord, a diagnosis of primary spinal melanoma was established. The growth of PSM is slower and survival is longer than in the most common spinal metastasis from skin melanoma. Patients who undergo surgical excision, alone or associated with additional treatments, often show a long survival. We report this case to underline the importance and difficulties concerning the preoperative diagnosis of a hemorrhagic intramedullary lesion.     

Quantification of Basal and Stimulated ROS Levels as Predictors of Islet Potency and Function

We have developed a luminol-based assay using intact islets, which allows for quantification of reactive oxygen species (ROS). In addition, an index capable of characterizing metabolic and mitochondrial integrity prior to transplantation was created based on the capacity of islets to respond to high glucose and rotenone (mitochondrial respiratory chain complex I inhibitor) by production of ROS. To validate this assay, lipid peroxidation and antioxidative defense capacity were evaluated by detection of malondialdehyde (MDA) levels and glutathione peroxidase activity (GPx), respectively. Also, flow cytometric analyses of ROS (dihydroethidine), apoptosis (Annexin V, active caspases), necrosis (Topro3), and mitochondrial membrane potential (JC-1) were done in parallel to correlate with changes in luminol-measured ROS. ATP/ADP ratios were quantified by HPLC and the predictive value of ROS measurement on islet functional potency was correlated with capacity to reverse diabetes in a streptozotocin-induced diabetic NOD.scid mouse model as well as in human transplant recipients. Our data demonstrate that levels of ROS in islets correlate with the percentage of apoptotic cells and their functional potency in vivo. The ROS indices following glucose and rotenone exposure are indicative of metabolic potency and mitochondrial integrity and can be used as surrogate markers to evaluate the quality of islets prior to transplantation.     

Management of Early-stage Esophageal Neoplasia (MESEN) Consensus

Background

Treatment of esophageal adenocarcinoma often involves surgical resection. Newer technologies in interventional endoscopy have led to a substantial paradigm shift in the management of early-stage neoplasia in Barrett’s esophagus comprising high-grade dysplasia (HGD), intramucosal carcinoma, and, in some cases, submucosal carcinoma. However, there has been no consensus regarding the indications for esophageal preservation in these cases. In this work, consensus guidelines were established for the management of early-stage esophageal neoplasia considering clinically relevant aspects (age, comorbidities, and social environment) in each scenario.

Methods

Seventeen experts were invited to participate based on their background and clinical expertise at high-volume centers. A questionnaire was created that included four clinical scenarios covering a wide range of situations within HGD and/or early esophageal neoplasia, particularly where controversies are likely to exist. Each of the clinical scenarios was open to discussion subdivided by patient age (20, 50, and 80 s). For each clinical scenario an expert was chosen to defend that position. Each defense triggered a subsequent discussion during a consensus meeting. Conclusions of that discussion together with an accompanying literature analysis allowed experts to confirm or change their original choices and served as the basis for the recommendations stated in this article.

Results

There was 100 % consensus supporting esophageal preservation in patients with HGD, independent of patient age or Barrett’s length. In patients with T1a adenocarcinoma, consensus for preservation was not reached (65 %) for young and middle-aged individuals but was supported for elderly patients (100 %). For T1b adenocarcinoma, consensus was reached for surgical resection (90 %), leaving organ preservation for patients with very low risk of nodal invasion or poor surgical candidates.

Conclusion

Advances in endoscopic imaging and therapy allow for organ preservation in most settings of early-stage neoplasia of the esophagus, provided that the patient understands the implications of this decision.