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Introduction: We examined data from a large, high acuity, pediatric psychiatric emergency department (ED) to assess both the immediate and longer-term impact of the pandemic on ED visits for suicidal thoughts and behaviors (STBs) among youth., Methods: Youth ages 5-17 years presenting at a pediatric psychiatric ED in New York, NY from March 2019-November 2021 were included in this study. Visits were categorized as pre-pandemic, pandemic year 1, or pandemic year 2. We examined changes in demographic and clinical characteristics among patients presenting across the three time periods, as well as multivariable associations between these characteristics and STBs., Results: Over 32 months, 2728 patients presented at 4161 visits. The prevalence of a discharge diagnosis of STBs increased from 21.2% pre-pandemic to 26.3% (p < 0.001) during pandemic year 1, and further increased to 30.1% (p = 0.049) during pandemic year 2. Youth were 21% more likely to receive a discharge diagnosis of STBs in pandemic year 1 (RR 1.21, 95% CI 1.07, 1.36) and 35% more likely in pandemic year 2 (RR 1.35, 95% CI 1.19, 1.52) compared to pre-pandemic baseline., Conclusions: In a large, high-acuity ED, STBs continued to increase 20 months after the initial COVID-19 lockdown. These findings highlight the persistent detrimental impact of the pandemic on youth mental health., (© 2023 The American Association of Suicidology.)

Mesothelioma is an aggressive cancer of the mesothelial layer associated with an extensive fibrotic response. The latter is in large part mediated by cancer-associated fibroblasts which mediate tumour progression and poor prognosis. However, understanding of the crosstalk between cancer cells and fibroblasts in this disease is mostly lacking. Here, using co-cultures of patient-derived mesothelioma cell lines and lung fibroblasts, we demonstrate that fibroblast activation is a self-propagated process producing a fibrotic extracellular matrix (ECM) and triggering drug resistance in mesothelioma cells. Following characterisation of mesothelioma cells/fibroblasts signalling crosstalk, we identify several FDA-approved targeted therapies as far more potent than standard-of-care Cisplatin/Pemetrexed in ECM-embedded co-culture spheroid models. In particular, the SRC family kinase inhibitor, Saracatinib, extends overall survival well beyond standard-of-care in a mesothelioma genetically-engineered mouse model. In short, we lay the foundation for the rational design of novel therapeutic strategies targeting mesothelioma/fibroblast communication for the treatment of mesothelioma patients., (© 2023. The Author(s).)

BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of Braf V600E in the intestinal tissue of an inducible mouse model. We show that Braf V600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, Braf V600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in Braf V600E -mutant mice. Overall, our work unveils the long-term impact of Braf V600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins., (© 2023. Springer Nature Limited.)

Hypothesis: Asbestos-driven inflammation contributes to malignant pleural mesothelioma beyond the acquisition of rate-limiting mutations. Methods: Genetically modified conditional allelic mice that were previously shown to develop mesothelioma in the absence of exposure to asbestos were induced with lentiviral vector expressing Cre recombinase with and without intrapleural injection of amosite asbestos and monitored until symptoms required euthanasia. Resulting tumours were examined histologically and by immunohistochemistry for expression of lineage markers and immune cell infiltration. Results: Injection of asbestos dramatically accelerated disease onset and end-stage tumour burden. Tumours developed in the presence of asbestos showed increased macrophage infiltration. Pharmacological suppression of macrophages in mice with established tumours failed to extend survival or to enhance response to chemotherapy. Conclusion: Asbestos-driven inflammation contributes to the severity of mesothelioma beyond the acquisition of rate-limiting mutations, however, targeted suppression of macrophages in established epithelioid mesothelioma showed no therapeutic benefit., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Farahmand, Gyuraszova, Rooney, Raffo-Iraolagoitia, Jayasekera, Hedley, Johnson, Chernova, Malviya, Hall, Monteverde, Blyth, Duffin, Carlin, Lewis, Le Quesne, MacFarlane and Murphy.)

The e-cigarette (EC) epidemic began in the United States (US) in 2007; since 2014 EC is the most commonly used form of tobacco. However, the mental health implications of vaping are grossly unknown. The aim of this umbrella review is to provide astate-of-the-art summary of existing research concerning vaping and mental health conditions in children. Following the PRISMA Statement 2020 guidelines, a systematic search was conducted across PubMed, Cochrane Library, and Google Scholar up to April 15th, 2022 to locate relevant studies. The Joana Briggs Institute (JBI) methodology for umbrella reviews and quality appraisal tool was utilized. Six studies, pooling a total of 846,510 adolescents aged 21 years or below, were included by collating 85 primary clinical studies. Of these, 58.8% of the primary clinical studies originated in the US, with 4.7% from Canada, South Korea, and the United Kingdom each; 3.5% each from England and Taiwan; 2.4% each from Australia, France, Hawaii, Mexico, and Russia; and 1.2% each from Denmark, Greece, Hong Kong, Iceland, New Zealand, Poland, and Switzerland. Overall, significant associations were found between mental health outcomes, including depression and suicidality, among current EC users and those who had ever used EC. Compared to adolescents who had never used EC, both depression and anxiety were reportedly higher among EC users. Impulsive behaviors, reported as impulsivity, were also found to be correlated with the adoption of EC use. However, there is a lack of evidence regarding the impact of EC use on mental health outcomes in children. This umbrella review highlights the urgent need to further explore the effects of current EC use from a psychiatric and public health perspective., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background and Objectives: Here we aimed to characterize clinical outcomes in those receiving treatment at a Veterans Health Administration (VHA) methadone maintenance treatment program (MMT) during the COVID 19 pandemic in which SAMSHA regulations for MMTs were changed to provide a greater number of methadone allotments and decreased clinic-visit frequency., Methods: We report results of a single-site, pre-post cohort study of urine drug screen data 3 months before and after an increase in allotments of take-home medication from the methadone clinic. One hundred twenty-nine patients met inclusion criteria for this study. The study was reviewed by the NYHHS IRB committee and granted final approval by the Research and Development Committee., Results: The sample was predominately male, average age 66years and average years in most recent treatment is 4.1 years. No statistical significance was found between period 1 and period 2 in the positive test detection for nonprescribed opiates, methadone and illicit substances ( P  > .05), number of new medical illnesses or overdoses. We controlled for participant age, substance use disorder diagnosis, psychiatric disorder diagnosis, and number of years in treatment., Discussion/conclusions: The results of the study illustrate the relative safety of the changes made at this particular MMT during the pandemic. Additionally, there was continued adherence to methadone treatment with minimal change in illicit substance use during period 1 and period 2., Scientific Significance: To these authors' knowledge this paper is one of the first to examine clinical outcomes in those with opioid addiction prescribed methadone from MMTs during the COVID 19 pandemic., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Objective: The increasingly widespread use of kratom in the United States has raised concerns about its safety as well as spurring research into potential applications of its active ingredients in medical treatments., Methods: We reviewed the literature published over the past 20 years, including peer-reviewed publications and data released by United States government health agencies to provide an overview of this topic., Results: A variety of potentially beneficial and adverse effects of kratom use related to its opioid and stimulant properties have been documented, including addiction and withdrawal. Preliminary research in animals and case reports in humans have suggested medical utility for kratom in treating alcohol and opioid use disorders, pain, depression, and anxiety. However, the lack of controlled, standardized studies limits the clinical utility of this agent and is a barrier to safe consumption., Conclusions: Historically, kratom has been used for medical purposes and for the treatment of alcohol and substance use disorders. The currently available literature suggests a potential for similar clinical applications. However, without controlled research studies or regulation, kratom poses numerous health risks to consumers., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Malignant mesothelioma (MpM) is an aggressive, invariably fatal tumour that is causally linked with asbestos exposure. The disease primarily results from loss of tumour suppressor gene function and there are no 'druggable' driver oncogenes associated with MpM. To identify opportunities for management of this disease we have carried out polysome profiling to define the MpM translatome. We show that in MpM there is a selective increase in the translation of mRNAs encoding proteins required for ribosome assembly and mitochondrial biogenesis. This results in an enhanced rate of mRNA translation, abnormal mitochondrial morphology and oxygen consumption, and a reprogramming of metabolic outputs. These alterations delimit the cellular capacity for protein biosynthesis, accelerate growth and drive disease progression. Importantly, we show that inhibition of mRNA translation, particularly through combined pharmacological targeting of mTORC1 and 2, reverses these changes and inhibits malignant cell growth in vitro and in ex-vivo tumour tissue from patients with end-stage disease. Critically, we show that these pharmacological interventions prolong survival in animal models of asbestos-induced mesothelioma, providing the basis for a targeted, viable therapeutic option for patients with this incurable disease., (© 2021. The Author(s).)

Background and Objectives: Prescription Drug Monitoring Programs (PDMP) detect high-risk prescribing and patient behaviors. This study describes the characteristics associated with documented PDMP access when prescribing opioids., Methods: Retrospective chart review of 695 opioid prescriptions written from inpatient and outpatient medical and psychiatric settings. Data were abstracted and analyzed to identify characteristics associated with documented PDMP access., Results: One-third of the charts had PDMP access documented within the week of opioid prescription; 12% showed PDMP consultation on the same day. Services varied greatly from 10.5% (inpatient medicine) to 57% (inpatient psychiatry) with regard to same-day PDMP access (P < .0001). Patient characteristics associated with PDMP access include having acute pain, current mental health treatment, and current and past substance use disorders (all P < .05). Logistic regression modeling identified three variables associated with the odds of PDMP access (c-statistic = 0.66): if the prescription originated from the inpatient medicine unit (odds ratio [OR] = 0.47, 95% confidence interval [CI] = 0.32, 0.68), or if the patient received a prescription for an opioid in the past 30 days (OR = 0.30, 95% CI = 0.10, 0.90) or had a urine toxicology screen in the past year (OR = 2.00, 95% CI = 1.40, 2.90)., Discussion and Conclusions: Utilization of the PDMP varied by specialty and setting., Scientific Significance: This study is among the first to compare rates of PDMP access in a large sample by specialty and practice setting in a healthcare system with a policy requiring its access and appropriate documentation. With less than one-third adherence to the policy, additional steps to increase consistent PDMP access are warranted. (Am J Addict 2021;00:00-00)., (© 2021 American Academy of Addiction Psychiatry.)

The occurrence of multiple vertebral fractures after discontinuation of denosumab in the treatment of osteoporosis has reopened the debate on the optimal treatment duration and drug holidays.In principle, there is a difference in this regard between the discontinuation of medications such as bisphosphonates and substances without bone retention such as selective estrogen receptor modulators (SERMs), denosumab or teriparatide. Even after the end of application bisphosphonates have a very long half-life in the bones. After cessation of drug intake there is a slow, slight increase of bone turnover markers. Even after cessation of the SERM raloxifene, a decline in bone density can be observed, as with the termination of teriparatide. In contrast to these osteoporosis medications, after cessation of denosumab, a steep and rapid increase in markers of bone resorption above baseline levels ("rebound") and a reduction in bone mineral density to initial values can be observed.Osteoporosis is a disease that carries an increased risk of fracture, which is reduced for the duration of osteoporosis treatment. In certain situations, the fracture risk is only temporarily raised. In these situations, cessation of the osteoporosis treatment is possible. Beyond these special clinical situations, however, osteoporosis needs to be addressed as a chronic disease with a permanently increased fracture risk and the indication for therapy should be evaluated according to the extent of the risk of fracture.What happens after discontinuation of anti-osteoporosis drugs? The various effects on bone turnover markers, bone mineral density and fracture incidence of the individual drug groups are presented in detail, as are the resulting recommendations of the task forces of the American Society of Bone and Mineral Research (ASBMR) and the European Calcified Tissue Society (ECTS).

Background: Data on the long-term outcome of heart transplantation in patients with a ventricular assist device (VAD) are scarce., Aim: To evaluate long-term outcome after heart transplantation in patients with a VAD compared with no mechanical circulatory support., Methods: Consecutive all-comers who underwent heart transplantation were included at a single high-volume centre from January 2005 until December 2012, with 5 years of follow-up. Clinical and biological characteristics, operative results, outcomes and survival were recorded. Regression analyses were performed to determine predictors of 1-year and 5-year mortality., Results: Fifty-two patients with bridge to transplantation by VAD (VAD group) and 289 patients transplanted without a VAD (standard group) were enrolled. The mean age was 46±11 years in the VAD group compared with 51±13 years in the standard group (P=0.01); 17% of the VAD group and 25% of the standard group were women (P=0.21). Ischaemic time was longer in the VAD group (207±54 vs 169±60minutes; P<0.01). There was no difference in primary graft failure (33% vs 25%; P=0.22) or 1-year mortality (17% vs 28%; P=0.12). In the multivariable analysis, preoperative VAD was an independent protective factor for 1-year mortality (odds ratio 0.40, 95% confidence interval 0.17-0.97; P=0.04). Independent risk factors for 1-year mortality were recipient age>60 years, recipient creatinine, body surface area mismatch and ischaemic time. The VAD and standard groups had similar long-term survival, with 5-year mortality rates of 35% and 40%, respectively (P=0.72)., Conclusions: Bridge to transplantation by VAD was associated with a reduction in 1-year mortality, leading critically ill patients to similar long-term survival compared with patients who underwent standard heart transplantation. This alternative strategy may benefit carefully selected patients., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)

Opioid addiction is a chronic, relapsing disorder associated with criminality, unemployment, infectious diseases, and legal problems. Such addictions are typically over-represented in correctional populations. Inmates with untreated opioid addiction often relapse shortly after release into the community, thereby increasing the risk of overdose, serious illnesses (HIV, hepatitis C) and psychosocial problems (e.g., crimes, recidivism, and reincarceration). There are three U.S. Food and Drug Administration-approved medications for the treatment of opioid use disorder: methadone, buprenorphine, and naltrexone. Opioid replacement therapies (ORTs) are associated with significant benefits, including reducing the incidences of HIV, criminality, and opioid-related mortality. However, most opioid-dependent Americans who are incarcerated are forced to discontinue ORT upon prison entry. This article offers a rationale for providing ORT to addicted prisoners while incarcerated and providing appointments with outpatient providers for continued treatment., (© 2017 American Academy of Psychiatry and the Law.)

Attention-deficit hyperactivity disorder (ADHD) presents with high levels of inattention, impulsiveness, and hyperactivity. ADHD starts in childhood and results in impairments that continue into adulthood. ADHD symptoms lead to decreased functionality in various life domains and result in poor academics, behavioral challenges, delayed independence, and strained relationships. Despite advances in diagnosis and treatment, persistent residual symptoms are common, highlighting the need for novel treatment strategies. This article aims to provide a review of the psychotherapeutic interventions available for teens that receive pharmacotherapy but continue to struggle with the residual symptoms of ADHD that interfere with academic function, relationship formation, and psychological development.

The abundance of epicardial adipose tissue (EAT) is associated with atrial fibrillation (AF), the most frequent cardiac arrhythmia. However, both the origin and the factors involved in EAT expansion are unknown. Here, we found that adult human atrial epicardial cells were highly adipogenic through an epithelial-mesenchymal transition both in vitro and in vivo. In a genetic lineage tracing the WT1 CreERT2+/- Rosa tdT+/- mouse model subjected to a high-fat diet, adipocytes of atrial EAT derived from a subset of epicardial progenitors. Atrial myocardium secretome induces the adipogenic differentiation of adult mesenchymal epicardium-derived cells by modulating the balance between mesenchymal Wingless-type Mouse Mammary Tumor Virus integration site family, member 10B (Wnt10b)/β-catenin and adipogenic ERK/MAPK signaling pathways. The adipogenic property of the atrial secretome was enhanced in AF patients. The atrial natriuretic peptide secreted by atrial myocytes is a major adipogenic factor operating at a low concentration by binding to its natriuretic peptide receptor A (NPRA) receptor and, in turn, by activating a cGMP-dependent pathway. Hence, our data indicate cross-talk between EAT expansion and mechanical function of the atrial myocardium., Competing Interests: The authors declare no conflict of interest.

Aims: Accumulation of atrial adipose tissue is associated with atrial fibrillation (AF). However, the underlying mechanisms remain poorly understood. We examined the relationship between the characteristics of fatty infiltrates of the atrial myocardium and the history of AF., Methods and Results: Atrial samples, collected in 92 patients during cardiac surgery and in a sheep model of persistent AF, were subjected to a detailed histological analysis. In sections of human right atrial samples, subepicardial fatty infiltrations were commonly observed in the majority of patients. A clear difference in the appearance and fibrotic content of these fatty infiltrations was observed. Fibro-fatty infiltrates predominated in patients with permanent AF (no AF: 37 ± 24% vs. paroxysmal AF: 50 ± 21% vs. permanent AF: 64 ± 23%, P < 0.001). An inverse correlation between fibrotic remodelling and the amount of subepicardial adipose tissue suggested the progressive fibrosis of fatty infiltrates with permanent AF. This hypothesis was tested in a sheep model of AF. In AF sheep, an increased accumulation of peri-atrial fat depot was observed on cardiac magnetic resonance imaging and dense fibro-fatty infiltrations predominated in the left atria of AF sheep. Cellular inflammation, mainly consisting of functional cytotoxic T lymphocytes, was observed together with adipocyte cell death in human atria., Conclusion: Atrial fibrillation is associated with the fibrosis of subepicardial fatty infiltrates, a process in which cytotoxic lymphocytes might be involved. This remodelling of the atrial subepicardium could contribute to structural remodelling forming a substrate for AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Electroconvulsive therapy (ECT) is an effective treatment for many psychiatric illnesses including refractory depression, catatonia, bipolar disorder, and schizophrenia, along with neuropsychiatric diseases such as dementia and Parkinson's disease. The emergence of a seizure disorder after the initiation of ECT is a rare but severe occurrence. It can become challenging for clinicians to determine whether ECT should be continued. We present a case of a 73-year-old female with schizoaffective disorder who received a total of 173 ECT treatments over the course of five years for breakthrough psychosis due to medication nonadherence. After five years of treatment, she experienced her first episode of tonic-clonic seizure activity. We review the current evidence and discuss factors that should be considered when treating such an individual.

Resting in an upright position during daytime decreases downbeat nystagmus (DBN). When measured in brightness only, that is, without intermitting exposure to darkness, it does not make a significant difference whether patients have previously rested in brightness or in darkness. In real-world scenarios, people are often exposed to brightness and darkness intermittently. The aim of this study was to analyze whether resting in brightness or resting in darkness was associated with a lower post-resting DBN after intermitting exposures to brightness and darkness. Eight patients were recorded with three-dimensional video-oculography in brightness and darkness conditions, each following two 2-h resting intervals under either brightness or darkness resting conditions. The dependent variable was DBN intensity, measured in mean slow phase velocity. A repeated measures ANOVA with the factors measurement condition (brightness vs. darkness), resting condition (brightness vs. darkness), and time (after first vs. second resting interval) showed a significant effect for the factor resting condition, where previous resting in darkness was associated with a significantly lower DBN relative to previous resting in brightness (P < 0.01). The clinical relevance is to advise patients with DBN to rest in darkness., (© 2016 New York Academy of Sciences.)

Background: Osteoporosis in men is an important public health problem with more than 1 million cases in Germany. Although osteoporotic fractures have a much higher mortality in men than in women, male patients are still underdiagnosed and undertreated., Objective: Epidemiology of male osteoporosis and current treatment situation, pathophysiological aspects at the hormonal level, risk factors, diagnostic work-up and therapeutic options., Material and Methods: Overview of data concerning male osteoporosis, recommendations for diagnostic work-up and presentation of the study situation on pharmaceutical therapies., Results: As risk factors for osteoporosis are present in 50-70 % of male patients, a detailed patient history is necessary for assessment of the risk factors. Radiological imaging of the spine is primarily recommended to identify individuals with prevalent vertebral fractures, as approximately 10 % of males above the age of 50 years have suffered a vertebral fracture. Laboratory testing of relevant parameters helps to rule out other metabolic bone diseases. In Germany, specific medications available for the treatment of male osteoporosis comprise the active vitamin D analogue alfacalcidol, the oral bisphosphonates alendronate and risedronate, the intravenous biphosphonate zoledronic acid, the anti- receptor activator of NF-κB ligand (RANKL) antibody denosumab, which can be given as intravenous injection and strontium ranelate, a drug with a complex mode of action. Teriparatide, a recombinant form of the 34 N-terminal amino acid sequence of parathyroid hormone is the only anabolic agent approved for male osteoporosis., Conclusion: Osteoporosis in men is increasingly being recognized as an important public health problem and affected patients need to be adequately diagnosed and treated. Nowadays, a broad spectrum of well-proven therapeutic options with different modes of action allow individual treatment strategies for male osteoporosis patients.

Attention deficit hyperactivity disorder (ADHD) manifests by high levels of inattention, impulsiveness and hyperactivity. ADHD starts in childhood and results in impairments that continue into adulthood. While hyperactivity declines over time, inattention and executive function difficulties persist, leading to functional deficits. Adolescents and adults with ADHD have pervasive impairment in interpersonal and family relationships. They may develop addiction, delinquent behavior and comorbid psychiatric disorders. Despite advances in diagnosis and treatment, persistent residual symptoms are common, highlighting the need for novel treatment strategies. Mindfulness training, derived from Eastern meditation practices, may improve self-regulation of attention. It may also be a useful strategy to augment standard ADHD treatments and may be used as a potential tool to reduce impairments in patients with residual symptoms of ADHD. Clinically, this would manifest by an increased ability to suppress task-unrelated thoughts and distractions resulting in improved attention, completion of tasks and potential improvement in occupational and social function.

Objective: To investigate construct validity of linear encoder measurement of sit-to-stand performance power in older people by showing associations with relevant functional performance and physiological parameters., Design: Cross-sectional study., Setting: Movement laboratory of a geriatric rehabilitation clinic., Participants: Eighty-eight community-dwelling, cognitively unimpaired older women (mean age 78 years)., Main Outcome Measures: Sit-to-stand performance power and leg power were assessed using a linear encoder and the Nottingham Power Rig, respectively. Gait speed was measured on an instrumented walkway. Maximum quadriceps and hand grip strength were assessed using dynamometers. Mid-thigh muscle cross-sectional area of both legs was measured using magnetic resonance imaging., Results: Associations of sit-to-stand performance power with power assessed by the Nottingham Power Rig, maximum gait speed and muscle cross-sectional area were r=0.646, r=0.536 and r=0.514, respectively. A linear regression model explained 50% of the variance in sit-to-stand performance power including muscle cross-sectional area (p=0.001), maximum gait speed (p=0.002), and power assessed by the Nottingham Power Rig (p=0.006)., Conclusions: Construct validity of linear encoder measurement of sit-to-stand power was shown at functional level and morphological level for older women. This measure could be used in routine clinical practice as well as in large-scale studies., Clinical Trial Registration Number: DRKS00003622., (Copyright © 2015 Chartered Society of Physiotherapy. Published by Elsevier Ltd. All rights reserved.)

Treating refractory late-onset bipolar disorder has not been sufficiently presented in the literature. In this case report, we present a 54-year-old male with late-onset bipolar disorder, who did notimprove despite multiple medication and dosage changes. This case outlines the challenges in treatment of these patients as well as identifies areas of further study regarding late-onset bipolar disorder management.

Objective: Eating disorders (EDs) result in the highest mortality rate of all psychiatric disorders, and in the United States, approximately one in twenty females suffers from an eating disorder. However, training provided within residency programs to address the needs of these patients is sparse. The objective of this study was to conduct a national survey that assesses the amount of EDs training for trainees across five ACGME accredited specialties: internal medicine, pediatrics, family medicine, psychiatry, and child and adolescent psychiatry. The results of the survey will be used to develop strategies to improve eating disorder education among residents., Method: Eight hundred eighty training coordinators were contacted using information available on the ACGME website and asked to complete the survey., Results: Of the 637 responding programs, 514 did not offer any scheduled or elective rotations for EDs. Of the 123 programs offering rotations, only 42 offered a formal, scheduled rotation. Child and adolescent psychiatry offered the most clinical experiences, and pediatric programs offered the greatest number of didactic hours on EDs., Discussion: Training in EDs is limited. Simulated patient encounters, massive open online courses, web-based curricula, dedicated rotations and clinical experiences, didactic curricula, and brief-training programs may help to improve eating disorder diagnostic and treatment skills among trainees., (© 2014 Wiley Periodicals, Inc.)

Almost 50 % of osteoporosis (OP) patients discontinue bisphosphonate (BP) therapy within 1-2 years after the start of their treatment. Denosumab's longer dosing interval with its administration every 6 months (Q6M) as a subcutaneous (sc) injection might result in a better real-life treatment adherence and persistence than weekly or monthly oral BP treatment regimen. The objectives of this open, investigator-initiated, prospective, observational, single-center study were to evaluate adherence with denosumab 60 mg sc every 6 months (Q6M) (Prolia(®)) injections in osteoporotic patients in a routine clinical care setting and to describe whether positive feedback to OP patients based on measured bone mineral density (BMD) increases and good safety profile have an impact on patients' real-life adherence. Results indicate that the rarity of adverse events and reduced dosage frequency together with the consistency of rapid and highly significant increases in BMD already after 6 months of denosumab therapy used as a positive reinforcement during doctor-patient interactions had a significant, positive impact on osteoporotic patient's adherence to continue with the 6-monthly sc denosumab injections.

Unlabelled: Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide., Introduction: To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO., Methods: A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n = 45) and risedronate (35 mg/week, n = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables., Results: PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group., Conclusions: Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

Data on treatment of glucocorticoid-induced osteoporosis (GIO) in men are scarce. We performed a randomized, open-label trial in men who have taken glucocorticoids (GC) for ≥3 months, and had an areal bone mineral density (aBMD) T-score ≤ -1.5 standard deviations. Subjects received 20 μg/d teriparatide (n = 45) or 35 mg/week risedronate (n = 47) for 18 months. Primary objective was to compare lumbar spine (L1 -L3 ) BMD measured by quantitative computed tomography (QCT). Secondary outcomes included BMD and microstructure measured by high-resolution QCT (HRQCT) at the 12th thoracic vertebra, biomechanical effects for axial compression, anterior bending, and axial torsion evaluated by finite element (FE) analysis from HRQCT data, aBMD by dual X-ray absorptiometry, biochemical markers, and safety. Computed tomography scans were performed at 0, 6, and 18 months. A mixed model repeated measures analysis was performed to compare changes from baseline between groups. Mean age was 56.3 years. Median GC dose and duration were 8.8 mg/d and 6.4 years, respectively; 39.1% of subjects had a prevalent fracture, and 32.6% received prior bisphosphonate treatment. At 18 months, trabecular BMD had significantly increased for both treatments, with significantly greater increases with teriparatide (16.3% versus 3.8%; p = 0.004). HRQCT trabecular and cortical variables significantly increased for both treatments with significantly larger improvements for teriparatide for integral and trabecular BMD and bone surface to volume ratio (BS/BV) as a microstructural measure. Vertebral strength increases at 18 months were significant in both groups (teriparatide: 26.0% to 34.0%; risedronate: 4.2% to 6.7%), with significantly higher increases in the teriparatide group for all loading modes (0.005 < p < 0.015). Adverse events were similar between groups. None of the patients on teriparatide but five (10.6%) on risedronate developed new clinical fractures (p = 0.056). In conclusion, in this 18-month trial in men with GIO, teriparatide showed larger improvements in spinal BMD, microstructure, and FE-derived strength than risedronate., (Copyright © 2013 American Society for Bone and Mineral Research.)

Due to pleiotropic-synergistic actions on bone, muscle, gut, brain and different other non-skeletal tissues, alfacalcidol is an interesting drug for treating osteoporosis. In studies on glucocorticoid-induced osteoporosis, men have always been treated with calcitriol or this active D-hormone prodrug, but there is no study of male patients only in the literature. The AIM-Trial (Alfacalcidol In Men) is an extension of the control group (n = 158) of our former risedronate study in male osteoporosis (Ringe et al. in Rheumatol Int 29:311-315, 2009). In that study, we treated daily those controls with prevalent vertebral fractures with 1 μg alfacalcidol + 500 mg calcium (group A) and those without prevalent vertebral fractures with 1,000 IU plain vitamin D (Vit. D) + 1,000 mg calcium (group B). Subsequently, we added an additional 56 pairs of patients to these two groups: 28 with and 28 without prevalent vertebral fractures, reaching a total of 214 cases. That means with this design, we are comparing two groups with a different risk at onset. Due to the prevalent vertebral fractures and lower average bone mineral density (BMD) values, there was a higher risk of incident fractures in group A. After 2 years, we found significantly higher increases in lumbar spine BMD (+3.2 vs. +0.8 %) and total hip BMD (+1.9 vs. -0.9 %) in group A and B, respectively. Eighteen incident falls were recorded in the alfacalcidol group and 38 in the group treated with Vit. D (p = 0.041). There were significantly lower rates of patients with new vertebral and non-vertebral fractures in group A than in group B. Back pain was significantly reduced only with alfacalcidol. Concerning the incidence of new non-vertebral fractures, we found that there was a relation to renal function in the two groups. The advantage for alfacalcidol was mainly due to a higher non-vertebral fracture-reducing potency in patients with a creatinine clearance (CrCl) below 60 ml/min (p = 0.0019). There were no serious adverse events (SAE), and the numbers of mild-to-moderate adverse events (AE) were not different between groups. Despite the higher initial fracture risk in the alfacalcidol group, 2-year treatment with this active D-hormone prodrug showed a higher therapeutic efficacy in terms of BMD, falls and fractures. One important advantage of alfacalcidol may be that it is effective even in patients with mild-to-moderate renal insufficiency.

Therapeutic intracavitary stem cell infusion currently suffers from poor myocardial homing. We examined whether cardiac cell retention could be enhanced by magnetic targeting of endothelial progenitor cells (EPCs) loaded with iron oxide nanoparticles. EPCs were magnetically labeled with citrate-coated iron oxide nanoparticles. Cell proliferation, migration, and CXCR4 chemokine receptor expression were assessed in different labeling conditions and no adverse effects of the magnetic label were observed. The magnetophoretic mobility of labeled EPCs was determined in vitro, with the same magnet as that subsequently used in vivo. Coronary artery occlusion was induced for 30 min in 36 rats (31 survivors), followed by 20 min of reperfusion. The rats were randomized to receive, during brief aortic cross-clamping, direct intraventricular injection of culture medium (n = 7) or magnetically labeled EPCs (n = 24), with (n = 14) or without (n = 10) subcutaneous insertion of a magnet over the chest cavity (n = 14). The hearts were explanted 24 h later and engrafted cells were visualized by magnetic resonance imaging (MRI) of the heart at 1.5 T. Their abundance in the myocardium was also analyzed semiquantitatively by immunofluorescence, and quantitatively by real-time polymerase chain reaction (RT-PCR).Although differences in cell retention between groups failed to be statistically significant using RT-PCR quantification, due to the variability of the animal model, immunostaining showed that the average number of engrafted EPCs was significantly ten times higher with than without magnetic targeting. There was thus a consistent trend favoring the magnet-treated hearts, thereby suggesting magnetic targeting as a potentially new mean of enhancing myocardial homing of intravascularly delivered stem cells. Magnetic targeting has the potential to enhance myocardial retention of intravascularly delivered endothelial progenitor cells.

Objective: The objective of this article is to determine how to prevent road injuries in schoolchildren by reducing the prevalence of speeding., Methods: On a busy road in the neighborhood of a preschool and two secondary schools in Oberhaching (greater Munich, Germany), a board was mounted next to the road (visible to the drivers as well as the pedestrians). The board consisted of a picture of a smiling child. Underneath the picture, an LED display read "Thank you!" in green blinking letters when the speed limit was adhered to and "Slowly!" in red blinking letters when speeding was detected. The main outcome assessment was the number of drivers adhering to the speed limit in the experimental condition (i.e., facing the device) compared to the number in the control condition (on the same road within the same time period but traveling in the opposite direction; i.e., drivers not facing the device)., Results: In the control condition 27.6 percent (230) of drivers adhered to the speed limit compared to 41.1 percent (427) of drivers in the experimental condition, χ(2) = 36.1, P < .0001. Only 12 drivers exceeded the speed limit by more than 20 km per hour in the experimental condition, whereas 34 drivers did so in the control condition, χ(2) = 9.6, P < .01., Discussion: The display is associated with a significantly lower percentage of speeding drivers but does not seem to be sufficient, because the majority of drivers still did not observe the speed limit in the presence of the display. Additional factors on how speed reduction can be achieved will be discussed in the light of future applications and possible modifications of the device.

Background: To report the rare diagnosis and the surgical treatment of a young patient presenting a symptomatic dissection of the abdominal aorta revealing a Takayasu's arteritis (TA)., Methods and Results: A 24-year-old woman developed a painful chronic dissection of the infrarenal aorta associated with a claudication of both lower extremities. As the patient was still symptomatic despite an optimal medical treatment, a surgical revascularization was proposed. An aortobifemoral bypass was performed allowing the removal of infrarenal aorta and the histologic diagnosis of TA., Conclusion: Isolated abdominal aortic dissection is an unusual event in TA, and this is the first surgically treated case. Only few reports of aortic dissection in TA have been published so far which are commented in this article., (Copyright © 2011 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Background: Endoleak is one of the rare complications that occur after thoracic endovascular aneurysm repair (TEVAR). The aim of this study was to assess the incidence of endoleaks and the predictive factors for their occurrence, as well as their effect on secondary interventions after TEVAR., Methods: Medical and radiological data of all TEVAR procedures performed between 2004 and 2008 were entered prospectively into our database and reviewed retrospectively. Primary endpoints included were the incidence and the type of endoleak, aneurysmal sac expansion, and secondary interventions., Results: In all, 67 patients (18 women and 49 men; mean age, 67 ± 14 years) were treated consecutively for descending thoracic aortic aneurysms (mean diameter: 69 ± 18 mm) by TEVAR during the observed period, using 83 stent-grafts (11 Cook TX2, 31 Gore TAG, and 41 Medtronic Valiant), with a median follow-up of 27 months (range: 2-64). In 13 of 67 patients, 14 (19.4%) endoleaks were diagnosed, of which 71% (10 of 14) were type I, 29% (4 of 14) were type II, and none were type III. Ten endoleaks (71%) were diagnosed on the first postoperative computed tomographic angiography at 1 month, and the other four (29%) developed later on. Predictive factors for endoleaks on univariate analysis included age (p = 0.04), length of the proximal neck immediately after the left subclavian artery (p = 0.04), the fusiform morphology of the descending thoracic aortic aneurysms (p = 0.04), and the type of stent-graft used (p = 0.02). Eight of the 10 type I endoleaks (80%) were successfully treated by endovascular means, using proximal cuffs (n = 5) or distal extensions (n = 3). None of type II endoleaks were treated by secondary intervention. The six endoleaks treated conservatively were all associated with a significant mean increase of their aneurysmal sac (+3.2 ± 2.6 mm) during follow-up. No secondary conversion to open surgery was performed to treat an endoleak., Conclusions: On the basis of the study, it seems as if endoleaks are detected in one of the five patients treated with TEVAR during follow-up period, particularly if they are old with a proximal and fusiform aneurysm. Short- and mid-term follow-up suggest that most type I endoleaks can successfully be treated by endovascular techniques and that type II endoleaks treated conservatively require a close radiological monitoring., (Copyright © 2011 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

In an open-label, prospective, controlled, 12-month study the effects of strontium ranelate (SR, CAS 135459-87-9) or alendronate (CAS 129318-43-0) on bone mineral density (BMD) were compared in 152 men with primary osteoporosis. Patients were randomized to SR 2 g/day (n = 76) or alendronate 70 mg/week (n = 76) supplemented daily with 1200 mg calcium and 800 IU vitamin D. The main outcome measure was percent change in lumbar spine and total hip BMD from baseline. Mean BMD (+/- SD) increased by 5.8 +/- 3.7% at the lumbar spine and 3.5 +/- 2.8% at the total hip with SR compared to increases of 4.5 +/- 3.4 % and 2.7 +/- 3.2%, respectively, with alendronate. Increases in BMD in the SR group are consistent with 1-year results from two pivotal fracture studies in postmenopausal women with osteoporosis. SR was associated with a 22% greater increase in BMD at the lumbar spine (p = 0.033) and 23% greater increase at the total hip (p = 0.002) than alendronate. New fractures were observed in 7 SR and 10 alendronate patients. Height loss (-0.1 +/- 0.7 cm) was less with SR compared with alendronate (-0.5 +/- 0.8 cm) (p = 0.026). SR was also associated with significantly greater reductions in back pain and analgesic use scores. Adverse events were experienced by 28 (37%) patients in the SR group and 38 (50%) patients in the alendronate group, none of which were serious. In men with osteoporosis, SR produced significantly greater mean increases in BMD over 12 months compared with alendronate, an agent already approved for male osteoporosis. Mean increases in BMD with SR in men were similar to those previously documented for this agent in postmenopausal women, suggesting that similar benefits on anti-fracture efficacy may be expected.

The aim of this study was to assess the effect of treatment with risedronate 5 mg daily relative to control in men with primary or secondary osteoporosis over 2 years. Osteoporosis is a common condition in men that can have serious clinical consequences. In an earlier interim report, we found that 1 year of risedronate therapy resulted in significant increases in bone mineral density (BMD) and a significant reduction in vertebral fractures compared to control in men with osteoporosis. We conducted an open-label, prospective, match-control trial on men with primary or secondary osteoporosis in a single center, outpatient setting. Men with primary or secondary osteoporosis, as defined by a baseline lumbar spine BMD T-score < or = -2.5 and a baseline femoral neck BMD T-score < or = 2.0, were eligible for this study. Patients who had been treated with bisphosphonates or fluoride within the last 12 months were excluded. A total of 316 men were randomized to risedronate (n = 158) or control (n = 158). Patients were stratified by the presence of prevalent vertebral fractures at baseline and case by case allocated to either daily treatment with risedronate 5 mg daily plus calcium (1,000 mg) and vitamin D (800 IU) or to a control group (daily alfacalcidol (1 microg) plus calcium (500 mg) for those with prevalent vertebral fractures; daily vitamin D (800 IU) plus calcium (1,200 mg) for those without previous vertebral fractures). Primary study end points were identified prior to study initiation as the incidence of new vertebral fractures and changes in BMD at the lumbar spine, femoral neck, and total hip. Other end points included incidence of nonvertebral fractures and change in body height and back pain. Compared to control, the incidence of new vertebral fractures was significantly reduced in the risedronate 5 mg daily group at 2 years [14/152 (9.2%) for risedronate vs. 35/148 (23.6%) for control (61% risk reduction; P = 0.0026)]. Treatment with risedronate 5 mg daily also resulted in significant improvements in BMD at 2 years at all three skeletal sites (lumbar spine, 6.5 vs. 2.2%; femoral neck, 3.2 vs. 0.6%; total hip, 4.4 vs. 0.4% (P < 0.001 for all treatment comparisons). Significant reductions in the incidence of nonvertebral fractures (11.8 vs. 22.3%; P = 0.032), average loss in height, and back pain were also observed in risedronate-treated patients relative to control. In this 2-year study, daily 5 mg risedronate significantly reduced the risk of vertebral and nonvertebral fractures, improved BMD, decreased height loss, and reduced back pain in men with osteoporosis. Efficacy was sustained over 2 years; a consistent 60-61% risk reduction in vertebral fractures was observed at 1 and 2 years, respectively. These data demonstrate that daily risedronate is effective long-term therapy for men with primary or secondary osteoporosis.

Background: The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes suggests that their beneficial effects on cardiac function after a myocardial infarction are mediated by paracrine effects. We evaluated the roles of these factors in the preservation of matrix architecture (in the infarct and remote regions) by varying the timing (postmyocardial infarction) and delivery site of the implanted cells., Methods and Results: Skeletal myoblasts (5x10(6)) or control media were injected into the infarct or noninfarcted myocardium at 5 or 30 days after coronary artery ligation in rats. Function was assessed by echocardiography before transplantation and 14 and 30 days thereafter and with a Millar catheter at 30 days after transplantation. Ventricular geometry, remote fibrillar collagen architecture, and changes in the matrix metalloproteinase-TIMP system were evaluated. Myoblast implantation in both sites and at both times preserved matrix architecture (length and width of collagen fibers) in the remote myocardium (in association with some decreases in remote myocardial matrix metalloprotease activity), improved global cardiac function, and attenuated the progressive increase in end diastolic volume (P<0.05 for all measures compared with medium controls). Cells delivered into the infarct region preserved scar thickness; cells delivered into the noninfarcted myocardium preserved wall thickness., Conclusions: Regardless of whether the cells were injected into the infarct or the noninfarcted myocardium early after an myocardial infarction or later, skeletal myoblasts improved cardiac function by preventing ventricular dilation and preserving matrix architecture in the remote region, likely mediated by paracrine effects.

Introduction: We hypothesized that the coverage of the hypogastric artery with a stent-graft causes an occlusion of the artery in its proximal segment, allowing collateral network formation in distal segments of the artery. In contrast, hypogastric embolisation may cause the formation of microthrombi that tend to disseminate leading to embolic occlusion of secondary branches and collaterals. This phenomenon worsens pelvic ischemia. To answer this question we compared two groups of patients with aortoiliac aneurysms treated with or without coil embolization to assess 1) The occurrence and evolution of buttock ischemia and 2) the effect on endoleak., Materials/methods: Between October 1995 and January 2007, 147 out of 598 EVAR patients (24.6%) required occlusion of one or both hypogastric arteries. 101 were available for over one year of follow-up. Group A included 76 patients (75%) who underwent coil embolization before EVAR and group B 25 patients (25%) who had their hypogastric artery covered by the sole limb of the stent. Patient demographics, aneurysm characteristics, operative details, immediate and long term clinical outcomes, and CT-scan evaluation were stored prospectively in a specific data base and analyzed retrospectively., Results: They were 96 males (95%). Mean age was 72.1+/-9.5 years. One month postoperatively, 51 patients (50.0%) suffered from buttock claudication. After six months, 34 patients were still disabled (34%), 32 in Group A (42%) and 2 in Group B (8%) (p=0.001). Post-operative sexual dysfunction occurred in 19 (19.6%) without statistical difference between the two groups. Type 2 endoleaks occurred in 12 patients (16.0%) in group A and 4 patients (16.0%) in group B (p=1). Endoleak from the hypogastric artery occurred in one patient in each group. Univariate analysis showed that predictive factors of long term (over six months) buttock claudication were embolization (p<0.001), younger age (p<0.03), coronary disease (p=0.06) and left ventricular dysfunction (p<0.01). The logistic regression analysis showed that buttock claudication was independently associated with embolization OR=9.1[95%CI=1.9-44] and left ventricular dysfunction OR=4.1[95%CI=1.3-12.7]., Conclusions: Coil embolization of hypogastric artery during EVAR is not an innocuous procedure and may not reduce the rate of type II endoleak.

Corticosteroids are widely used as anti-inflammatory and immunosuppressive agents to treat a variety of chronic conditions. Long-term (>1 year) corticosteroid use can lead to bone loss, and therefore, osteopenia or osteoporosis. Corticosteroid-induced osteoporosis (CIO) leads to increased bone fragility and subsequently fractures, which, in turn, lead to a loss of physical, emotional and social health for the patient and increased costs for healthcare providers. A wealth of data exists demonstrating the efficacy of the oral bisphosphonates, etidronate, alendronate and risedronate in increasing bone mineral density in patients with CIO or preventing bone loss in patients commencing corticosteroid therapy. Data regarding fracture prevention are less clear, as statistically significant reductions in the incidence of fractures have only been reported for patient subgroups or meta-analyses. However, many treatment guidelines recommend the use of oral bisphosphonates for the prevention and treatment of CIO. These guidelines are, however, not reflected in prescribing practice, and the majority of patients do not receive adequate concomitant therapy. This review summarizes the available data for bisphosphonates in CIO. Therapeutic adherence with oral bisphosphonates is an issue, with approximately 50% of patients discontinuing therapy within the first year. The primary reasons for this are poor gastrointestinal tolerability and the frequency with which complex dosing requirements must be followed. The inconvenience of taking daily or weekly bisphosphonate therapy is of particular importance in patients with CIO who may be regularly taking several other medications. Data obtained in studies with ibandronate indicate that bisphosphonate administration by rapid intravenous injection provides an effective, well-tolerated and practical alternative to current oral regimens in the management of patients with CIO.

A combined therapy with the strongly antiresorptive Alendronate and the pleiotropically acting D-hormone analogue Alfacalcidol may have additive effects on bone quality, falls and fracture risk in established osteoporosis. The aim of this study (Alfacalcidol Alendronate Combined-AAC) was to compare the efficacy and safety of a combined parallel therapy with Alendronate and Alfacalcidol to the treatment with either Alendronate in combination with plain vitamin D or Alfacalcidol alone in patients with established postmenopausal or male osteoporosis. Ninety patients were included as matched triplets to receive randomly either 1 microg Alfacalcidol daily + 500 mg calcium (group A, n = 30) or 70 mg Alendronate weekly + 1,000 mg calcium + 1,000 IU vitamin D daily (group B, n = 30) or 1 microg Alfacalcidol daily + 70 mg Alendronate weekly + 500 mg calcium daily (group C, n = 30). Patients were recruited in one centre and were followed up for 24 months. Analysis was intention-to-treat and the primary outcome was lumbar spine and total hip bone mineral density (measured observer blind). BMD was measured at the lumbar spine and at the proximal femur with dual energy X-ray absorptiometry (LUNAR Prodigy, GE, USA) at the beginning and after 12 and 24 months. During the 2-year-study we observed descriptively significant increases at the lumbar spine of 3.0% in group A compared to baseline, of 5.4% in group B and of 9.6% in group C, respectively. The superiority of the Alendronate + Alfacalcidol treatment group over Alfacalcidol alone and over Alendronate + vitamin D was of more than large rele-vance (both tests: MW > 0.71; CI-LB > 0.64; P < 0.001). We also observed median increases of the BMD at the total hip of 1.5% in group A, of 2.4% in group B and of 3.8% in group C, respectively. The superiority of group C over group A and over group B again was relevant and statistically significant in a descriptive sense. After 2 years there was a tendency towards higher rates of vertebral and non-vertebral fractures in group A and B as compared to C. Taking both fracture types together we observed 9, 10 and 2 "osteoporotic fractures" in groups A, B and C, respectively. The comparison of group C with pooled groups A and B and with each single group gave a relevantly lower fracture rate for the combination of Alendronate and Alfacalcidol. Furthermore a lower rate of falls was observed for the combination Alendronate plus Alfacalcidol versus Alendronate + vitamin D, but not versus Alfacalcidol alone. We found 80% of the patients in the Alendronate + Alfacalcidol group free from back pain at month 24, compared to 30% in the Alendronate + vitamin D and 43% in the Alfacalcidol monotherapy group. The superiority is relevant (both tests: MW > 0.64; CI-LB > 0.56; P < 0.003). Pain decrease also occurred more rapidly in the Alendronate + Alfacalcidol group than in the other groups. In general side effects in all groups were mild, and only four cases of moderate hypercalcuria in group A and one in group C were reported, but no case of hypercalcemia was documented. In conclusion, the combination therapy with Alendronate and Alfacalcidol exhibited superiority in terms of BMD, overall fractures, rate of falls and back pain over either Alendronate in combination with plain vitamin D or Alfacalcidol alone. The overall safety profiles of the three treatment regimens were found to be not different in this study.

Osteoporosis is prevalent in men with an estimated one in eight men older than 50 years suffering from osteoporotic fracture, and a higher mortality rate after fracture among men compared with women. There are few approved therapies for osteoporosis in men. This observational study assesses the efficacy and safety of risedronate in the treatment of men with primary and secondary osteoporosis. A single-center, open label, randomized, prospective 1-year study was conducted in men with primary or secondary osteoporosis. Patients were randomized to risedronate (risedronate 5 mg/day plus calcium 1,000 mg/day and vitamin D 800 IU/day) or control groups (alfacalcidol 1 mug/day plus calcium 500 mg/day or vitamin D 1,000 IU/day plus calcium 800 mg/day). Bone mineral density (BMD) measurements, X-rays of the spine, a medical history and physical exam, and patient self-assessments of back pain were performed at baseline and 12 months. Blinded semi-quantitative fracture assessment was conducted by a radiologist. A total of 316 men with osteoporosis were enrolled in the trial (risedronate, n=158; control, n=158). At 1 year lumbar spine BMD increased by 4.7% in the risedronate group versus an increase of 1.0% in the control group (P<0.001). Significant increases in BMD at the total hip and femoral neck were also observed with risedronate compared with the control group. The incidence of new vertebral fracture in the risedronate group was reduced by 60% versus the control group (P=0.028). Daily treatment with risedronate for 12 months significantly increased BMD at the lumbar spine, femoral neck and total hip and significantly reduced the incidence of new vertebral fractures. This is the first prospective, randomized, controlled trial to demonstrate a significant reduction in vertebral fractures in 1 year in men with primary or secondary osteoporosis.

Sternocostoclavicular hyperostosis (SCCH) is an infrequent but painful, localized disturbance of bone metabolism of unknown etiology. The diagnosis of SCCH is generally one of exclusion, and it is therefore frequently missed or delayed, leaving patients with pain that frequently fails to respond to standard analgesic therapy. Consequently, SCCH leads to significantly impaired quality of life. Characteristic increased localized bone turnover and inflammatory osteitis provide a strong rationale for using intravenous bisphosphonates to treat the condition. We report on three patients with long-standing, treatment-refractory SCCH in whom intravenous ibandronate injections (a single administration of 4 mg followed by 2 mg every 3 months for up to a year) produced prompt, dramatic, persistent pain relief and resolution of the other symptoms of the disease. We also review recent evidence suggesting that SCCH is more common than generally believed and that technetium-99 bone scanning can aid in making an accurate diagnosis.

Previous in vitro studies are in keeping with the finding that isolated and enriched megakaryocytes attach to bone marrow fibroblasts and generate an increased growth of these cells. This process was assumed to depend on a close spatial relationship between both cell types which supports the paracrine effect of platelet-derived growth factor (PDGF) and transforming growth factor (TGF)-beta1. Moreover, adhesion molecules including beta1 integrin receptors and fucosylated structures were determined to play an important role in these complex interactions. However, up to now the influence of megakaryocyte expressed glycoproteins CD41a and CD42b in these processes was not investigated. In addition, the role of megakaryocytic CD62P and also of CD62L, both adhesion molecules of the selectin group, could also be of interest. Following isolation and enrichment of bone marrow megakaryocytes and fibroblasts, both cell populations were characterized regarding their expression of these factors by applying immunocytochemical techniques. Additionally, their influence on adhesion of megakaryocytes to fibroblasts as well as fibroblast growth was evaluated by comparative megakaryocyte-fibroblast co-cultures and inhibition studies using specific monoclonal antibodies (mabs). Fibroblast monocultures served as controls. In these experiments, selectin-specific antibodies significantly reduced megakaryocyte attachment to fibroblast feeder layers and fibroblast growth in the co-cultures. The effect of CD41a and CD42b specific antibodies was limited to megakaryocyte-dependent fibroblast growth. These results elucidate the involvement of the selectins CD62P and CD62L in the basal activation of megakaryocytes inducing their attachment to bone marrow fibroblasts. In contrast, the megakaryocyte glycoproteins CD41a and CD42b exert their effect on the megakaryocyte dependent fibroblast growth. Altogether, it is tempting to speculate that the various interactions of these mediators reflect certain steps in the complex pathomechanisms causing the evolution of (reactive) myelofibrosis in hematopoietic neoplasias accompanied by megakaryocytic proliferation.

Megakaryocytes are assumed to be functionally linked with the evolution of myelofibrosis, complicating chronic myeloproliferative disorders. It has already been shown that megakaryocytes will promote fibroblast growth in vitro when in spatial proximity. Here, we demonstrate that the integrin receptors alpha3beta1 and alpha5beta1 are involved in this megakaryocyte-fibroblast interaction. Upon addition of anti-alpha3 and -alpha5 antibodies to megakaryocyte-fibroblast cocultures, fibroblast growth was significantly impaired, and megakaryocyte attachment to the fibroblast feederlayer was significantly reduced. Unilateral blocking of megakaryocytes with anti-alpha3 or -alpha5 antibodies resulted in a suppression of adhesion, probably reflecting the prominent function of fibronectin receptors on the megakaryocyte surface. Moreover, the oligopeptide RGDS (Asp-Gly-Asp-Ser) caused a significant reduction of fibroblast growth as well as megakaryocyte adhesion. This feature reinforces that fibronectin receptors are involved. In addition, fibroblast proliferation was impaired by the application of fibronectin antibodies recognizing the cell-binding domain. However, no effect was observable with respect to megakaryocyte adhesion. In conclusion, our in vitro studies demonstrate the involvement of beta1-integrins, in particular the fibronectin receptor in the megakaryocyte-dependent fibroblast proliferation and therefore suggest a pivotal role of megakaryocytes in the complex pathomechanism causing myelofibrosis.