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1.  Non-infectious osteomyelitis of the mandible in a young woman: a case report 
We present the case of a patient with non-infectious osteomyelitis of the mandible, which is a recognized but unusual condition of unknown cause.
Case presentation
A 14-year-old Caucasian girl presented with pain and edema in the left side of her jaw. A clinical examination led to a diagnosis of osteomyelitis and she was treated with antibiotics. Our patient continued antibiotic treatment for osteomyelitis and underwent decortication. Histology based on a biopsy showed new bone formation and chronic inflammation, and a diagnosis of sclerotic osteomyelitis was made. Over the next few years, she experienced pain on the left side of her jaw and increasing edema, and the size of the left side of her jaw bone increased. She was then sent to our Department of Medicine at the age of 16 years. Her symptoms included pain in the left side of her jaw that scored 4 on a visual analogue scale of 1 to 10. A diagnosis of bone disease was made based on bone scintigraphy and single photon emission computed tomography that showed hot spots in the affected left side of the jaw. Our patient was treated with a single dose of intravenous zoledronic acid (5mg) at age 17 years, which was repeated after 12 months. The bone pain was significantly reduced six months after treatment and had disappeared 24 months after treatment.
We report an unusual localization of non-infectious osteomyelitis of the jaw in a young woman. Even though the presentation was in the jaw, her condition improved after intravenous bisphosphonate treatment, as evaluated by reduced clinical symptoms, bone turnover evaluation as assessed by biochemical bone markers, and reduced activity on bone scintigraphy.
PMCID: PMC3942813  PMID: 24521360
Bisphosphonate; Bone; Non-infectious osteomyelitis; Zoledronic acid
2.  Gastrointestinal Events with Clopidogrel: A Nationwide Population-Based Cohort Study 
Clopidogrel prevents cardiovascular events, but has been linked with adverse gastrointestinal (GI) complications, particularly bleeding events.
We aimed to investigate the risk of adverse GI events in patients treated with clopidogrel.
A nationwide population-based cohort study based on linkage of three administrative registries in Denmark.
All individuals who redeemed at least one prescription of clopidogrel from 1996 to 2008 were included as exposed subjects (n = 77,503). For each exposed subject, three matched controls were randomly selected from the background population (n = 232,510).
Follow-up began on January 1, 1996, and was censored on December 31, 2007, or if patients emigrated or died. The study endpoint was the occurrence of any gastritis, GI ulcer or bleeding. Analyses were adjusted for comorbidity and medication.
Regardless of dose, adjusted odds ratios associating clopidogrel use with the study endpoint were statistically significant and followed a dose–response pattern. The crude absolute risk of GI events were: never users: 2.2 %; <0.1 defined daily dose (DDD) of clopidogrel per day: 7.1 %; 0.1–0.39 DDD: 6.0 %; 0.4–0.79 DDD: 5.7 %; ≥0.80 DDD: 4.4 %. Adjusted odds ratios were: <0.1 DDD: 1.34, 95 % CI: 1.26–1.42; 0.1–0.39 DDD: 1.58, 95 % CI: 1.48–1.68; 0.4–0.79 DDD: 1.91, 95 % CI: 1.77–2.06; ≥0.80 DDD: 1.77, 95 % CI: 1.66–1.89, all p-values < 0.01. Depending on the dose, numbers needed to harm ranged from 58 to 33 patients receiving 12 months of clopidogrel treatment.
The well-known cardioprotective effect of clopidogrel must be carefully weighed against an increased risk of GI events.
PMCID: PMC3614150  PMID: 22948933
clopidogrel; coronary artery disease; gastritis; gastrointestinal hemorrhage; stomach ulcer
3.  The P2X7 Receptor: A Key Player in Immune-Mediated Bone Loss? 
The Scientific World Journal  2014;2014:954530.
Inflammatory diseases are often multiorganic diseases with manifestations not related directly to the primary affected organ. They are often complicated by a generalized bone loss that subsequently leads to osteoporosis and bone fractures. The exact mechanism for the accompanying bone loss is not understood in full detail, but factors such as glucocorticoid treatment, immobilization, malnutrition, and insufficient intake of vitamin D play a role. However, it has become evident that the inflammatory process itself is involved and the resulting bone loss is termed immune-mediated bone loss. It stems from an increase in bone resorption and the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin 1 beta and has been shown to not only mediate the inflammatory response but also to strongly stimulate bone degradation. The purinergic P2X7 receptor is central in the processing of these two cytokines and in the initiation of the inflammatory response, and it is a key molecule in the regulation of both bone formation and bone resorption. The aim of this review is therefore to provide evidence-based novel hypotheses of the role of ATP-mediated purinergic signalling via the P2X7 receptor in immune-mediated bone loss and -osteoporosis.
PMCID: PMC3915485  PMID: 24574936
4.  A Standardized Vascular Disease Health Check in Europe: A Cost-Effectiveness Analysis 
PLoS ONE  2013;8(7):e66454.
No clinical trials have assessed the effects or cost-effectiveness of health check strategies to detect and manage vascular disease. We used a mathematical model to estimate the cost-effectiveness of several health check strategies in six European countries.
We used country-specific data from Denmark, France, Germany, Italy, Poland, and the United Kingdom to generate simulated populations of individuals aged 40–75 eligible for health checks in those countries (e.g. individuals without a previous diagnosis of diabetes, myocardial infarction, stroke, or serious chronic kidney disease). For each country, we used the Archimedes model to compare seven health check strategies consisting of assessments for diabetes, hypertension, lipids, and smoking. For patients diagnosed with vascular disease, treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, major adverse cardiovascular events (MACE), and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY).
Compared with current care, health checks reduced the incidence of MACE (6–17 events prevented per 1000 people screened) and diabetes related microvasular complications (5–11 events prevented per 1000 people screened), and increased QALYs (31–59 discounted QALYs) over 30 years, in all countries. The cost per QALY of offering a health check to all individuals in the study cohort ranged from €14903 (France) to cost saving (Poland). Pre-screening the population and offering health checks only to higher risk individuals lowered the cost per QALY. Pre-screening on the basis of obesity had a cost per QALY of €10200 (France) or less, and pre-screening with a non-invasive risk score was similar.
A vascular disease health check would likely be cost effective at 30 years in Denmark, France, Germany, Italy, Poland, and the United Kingdom.
PMCID: PMC3712021  PMID: 23869204
5.  Single-nucleotide polymorphisms in the P2X7 receptor gene are associated with post-menopausal bone loss and vertebral fractures 
The purinergic P2X7 receptor has a major role in the regulation of osteoblast and osteoclast activity and changes in receptor function may therefore affect bone mass in vivo. The aim of this study was to determine the association of non-synonymous single-nucleotide polymorphisms in the P2RX7 gene to bone mass and fracture incidence in post-menopausal women. A total of 1694 women (aged 45–58) participating in the Danish Osteoporosis Prevention Study were genotyped for 12 functional P2X7 receptor variants. Bone mineral density was determined at baseline and after 10 years. In addition, vertebral fracture incidence was documented at 10 years. We found that the rate of bone loss was clearly associated with the Arg307Gln amino acid substitution such that individuals heterozygous for this polymorphism had a 40% increased rate of bone loss. Furthermore, individuals carrying the Ile568Asn variant allele had increased bone loss. In contrast, the Gln460Arg polymorphism was associated with protection against bone loss. The Ala348Thr polymorphism was associated with a lower vertebral fracture incidence 10 years after menopause. Finally, we developed a risk model, which integrated P2RX7 genotypes. Using this model, we found a clear association between the low-risk (high-P2X7 function) alleles and low rate of bone loss. Conversely, high-risk (reduced P2X7 function) alleles were associated with a high rate of bone loss. In conclusion, an association was demonstrated between variants that reduce P2X7 receptor function and increased rate of bone loss. These data support that the P2X7 receptor is important in regulation of bone mass.
PMCID: PMC3355253  PMID: 22274585
osteoporosis; vertebral fracture; P2X7; polymorphism; purinergic
6.  Purinergic Signaling in Bone 
Journal of Osteoporosis  2013;2013:673684.
PMCID: PMC3671543  PMID: 23762774
8.  Genetic Background Strongly Influences the Bone Phenotype of P2X7 Receptor Knockout Mice 
Journal of Osteoporosis  2012;2012:391097.
The purinergic P2X7 receptor is expressed by bone cells and has been shown to be important in both bone formation and bone resorption. In this study we investigated the importance of the genetic background of the mouse strains on which the P2X7 knock-out models were based by comparing bone status of a new BALB/cJ P2X7−/− strain with a previous one based on the C57BL/6 strain. Female four-month-old mice from both strains were DXA scanned on a PIXImus densitometer; femurs were collected for bone strength measurements and serum for bone marker analysis. Bone-related parameters that were altered only slightly in the B6 P2X7−/− became significantly altered in the BALB/cJ P2X7−/− when compared to their wild type littermates. The BALB/cJ P2X7−/− showed reduced levels of serum C-telopeptide fragment (s-CTX), higher bone mineral density, and increased bone strength compared to the wild type littermates. In conclusion, we have shown that the genetic background of P2X7−/− mice strongly influences the bone phenotype of the P2X7−/− mice and that P2X7 has a more significant regulatory role in bone remodeling than found in previous studies.
PMCID: PMC3425798  PMID: 22934234
9.  Association between P2X7 Receptor Polymorphisms and Bone Status in Mice 
Journal of Osteoporosis  2012;2012:637986.
Macrophages from mouse strains with the naturally occurring mutation P451L in the purinergic receptor P2X7 have impaired responses to agonists (1). Because P2X7 receptors are expressed in bone cells and are implicated in bone physiology, we asked whether strains with the P451L mutation have a different bone phenotype. By sequencing the most common strains of inbred mice, we found that only a few strains (BALB, NOD, NZW, and 129) were harboring the wild allelic version of the mutation (P451) in the gene for the purinergic receptor P2X7. The strains were compared by means of dual energy X-ray absorptiometry (DXA), bone markers, and three-point bending. Cultured osteoclasts were used in the ATP-induced pore formation assay. We found that strains with the P451 allele (BALB/cJ and 129X1/SvJ) had stronger femurs and higher levels of the bone resorption marker C-telopeptide collagen (CTX) compared to C57Bl/6 (B6) and DBA/2J mice. In strains with the 451L allele, pore-formation activity in osteoclasts in vitro was lower after application of ATP. In conclusion, two strains with the 451L allele of the naturally occurring mutation P451L, have weaker bones and lower levels of CTX, suggesting lower resorption levels in these animals, which could be related to the decreased ATP-induced pore formation observed in vitro. The importance of these findings for the interpretation of the earlier reported effects of P2X7 in mice is discussed, along with strategies in developing a murine model for testing the therapeutic effects of P2X7 agonists and antagonists upon postmenopausal osteoporosis.
PMCID: PMC3420134  PMID: 22919543
10.  Association of P2Y2 receptor SNPs with bone mineral density and osteoporosis risk in a cohort of Dutch fracture patients 
Purinergic Signalling  2012;9(1):41-49.
The P2Y2 receptor is a G-protein-coupled receptor with adenosine 5′-triphosphate (and UTP) as natural ligands. It is thought to be involved in bone physiology in an anti-osteogenic manner. As several non-synonymous single nucleotide polymorphisms (SNPs) have been identified within the P2Y2 receptor gene in humans, we examined associations between genetic variations in the P2Y2 receptor gene and bone mineral density (BMD) (i.e., osteoporosis risk), in a cohort of fracture patients. Six hundred and ninety women and 231 men aged ≥50 years, visiting an osteoporosis outpatient clinic at Maastricht University Medical Centre for standard medical follow-up after a recent fracture, were genotyped for three non-synonymous P2Y2 receptor gene SNPs. BMD was measured at three locations (total hip, lumbar spine, and femoral neck) using dual-energy X-ray absorptiometry. Differences in BMD between different genotypes were tested using analysis of covariance. In women, BMD values at all sites were significantly different between the genotypes for the Leu46Pro polymorphism, with women homozygous for the variant allele showing the highest BMD values (0.05 > p > 0.01). The Arg312Ser and Arg334Cys polymorphisms showed no differences in BMD values between the different genotypes. This is the first report that describes the association between the Leu46Pro polymorphism of the human P2Y2 receptor and the risk of osteoporosis.
PMCID: PMC3568433  PMID: 22773251
P2Y2 receptor; Osteoporosis; Bone mineral density; Polymorphisms
11.  Long-Term Benefits From Lifestyle Interventions for Type 2 Diabetes Prevention 
Diabetes Care  2011;34(Suppl 2):S210-S214.
PMCID: PMC3632163  PMID: 21525457
12.  Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles 
AAPS PharmSciTech  2012;13(1):218-230.
In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems.
PMCID: PMC3279638  PMID: 22215291
CMC; ICH; quality by design (QbD); residual drug; TDS
13.  Passive Transdermal Systems Whitepaper Incorporating Current Chemistry, Manufacturing and Controls (CMC) Development Principles 
AAPS PharmSciTech  2012;13(1):218-230.
In this whitepaper, the Manufacturing Technical Committee (MTC) of the Product Quality Research Institute has updated the 1997 Transdermal Drug Delivery Systems Scale-Up and Post Approval Change workshop report findings to add important new product development and control principles. Important topics reviewed include ICH harmonization, quality by design, process analytical technologies, product and process validation, improvements to control of critical excipients, and discussion of Food and Drug Administration’s Guidance on Residual Drug in Transdermal and Related Drug Delivery Systems as well as current thinking and trends on in vitro–in vivo correlation considerations for transdermal systems.
PMCID: PMC3279638  PMID: 22215291
CMC; ICH; quality by design (QbD); residual drug; TDS
14.  Clinical and biochemical outcomes of cinacalcet treatment of familial hypocalciuric hypercalcemia: a case series 
Familial hypocalciuric hypercalcemia is a rare benign autosomal-dominant genetic disease with high penetrance. In most cases, patients with familial hypocalciuric hypercalcemia experience unspecific physical discomfort or asymptomatic disease. These patients are typically characterized by mild to moderately increased blood ionized calcium and a normal to slightly elevated serum parathyroid hormone.
Case presentation
Four female patients with familial hypocalciuric hypercalcemia with inactivating mutations in the CaSR gene were included in the treatment study. Three patients were related: two were siblings and one was the daughter of one of these. The ages of the related patients were 51 years, 57 years and 35 years. All three patients were carriers of the same mutation. The fourth patient, unrelated to the others, was 53 years old, and a carrier of a novel and previously unknown mutation leading to familial hypocalciuric hypercalcemia. All four patients were Caucasians of Danish nationality. Biochemically, all patients had elevated blood ionized calcium, serum parathyroid hormone, serum magnesium and total serum calcium, except one, whose serum parathyroid hormone was within the normal range prior to treatment. All patients were treated with cinacalcet in a dosage of 30 mg to 60 mg per day.
Three months after the initiation of cinacalcet treatment, all our patients experiencing clinical signs of hypercalcemia had improved in self -reported well-being and in biochemical parameters. None of our patients suffered adverse events to cinacalcet treatment. Biochemical markers of calcium homeostasis were improved and remained stable during the observation period of 12 months (two patients), 24 and 36 months, in both the symptomatic and the asymptomatic patients.
PMCID: PMC3287106  PMID: 22142470
15.  Estimating the cost-effectiveness of lifestyle intervention programmes to prevent diabetes based on an example from Germany: Markov modelling 
Type 2 diabetes mellitus (T2D) poses a large worldwide burden for health care systems. One possible tool to decrease this burden is primary prevention. As it is unethical to wait until perfect data are available to conclude whether T2D primary prevention intervention programmes are cost-effective, we need a model that simulates the effect of prevention initiatives. Thus, the aim of this study is to investigate the long-term cost-effectiveness of lifestyle intervention programmes for the prevention of T2D using a Markov model. As decision makers often face difficulties in applying health economic results, we visualise our results with health economic tools.
We use four-state Markov modelling with a probabilistic cohort analysis to calculate the cost per quality-adjusted life year (QALY) gained. A one-year cycle length and a lifetime time horizon are applied. Best available evidence supplies the model with data on transition probabilities between glycaemic states, mortality risks, utility weights, and disease costs. The costs are calculated from a societal perspective. A 3% discount rate is used for costs and QALYs. Cost-effectiveness acceptability curves are presented to assist decision makers.
The model indicates that diabetes prevention interventions have the potential to be cost-effective, but the outcome reveals a high level of uncertainty. Incremental cost-effectiveness ratios (ICERs) were negative for the intervention, ie, the intervention leads to a cost reduction for men and women aged 30 or 50 years at initiation of the intervention. For men and women aged 70 at initiation of the intervention, the ICER was EUR27,546/QALY gained and EUR19,433/QALY gained, respectively. In all cases, the QALYs gained were low. Cost-effectiveness acceptability curves show that the higher the willingness-to-pay threshold value, the higher the probability that the intervention is cost-effective. Nonetheless, all curves are flat. The threshold value of EUR50,000/QALY gained has a 30-55% probability that the intervention is cost-effective.
Lifestyle interventions for primary prevention of type 2 diabetes are cost-saving for men and women aged 30 or 50 years at the start of the intervention, and cost-effective for men and women aged 70 years. However, there is a high degree of uncertainty around the ICERs. With the conservative approach adopted for this model, the long-term effectiveness of the intervention could be underestimated.
PMCID: PMC3256095  PMID: 22099547
Diabetes mellitus; health care costs; health care economics and organisations; primary prevention; life style; early intervention; decision making
16.  Diabetes prevention: A call to action 
PMCID: PMC3249952  PMID: 22199093
17.  The Evidence for Efficacy of Osteoporosis Treatment in Men with Primary Osteoporosis: A Systematic Review and Meta-Analysis of Antiresorptive and Anabolic Treatment in Men 
Journal of Osteoporosis  2011;2011:259818.
Purpose. Fragility fractures in men constitute a major worldwide public health problem with a life-time risk of 13%. It cannot be directly inferred that antiosteoporotic drugs effective in women have the same effect in men. Our aim was to appraise the existing evidence for efficacy of osteoporosis treatment in men. Methods. This study was a systematic review of the published literature on the clinical efficacy of medical osteoporosis therapy in the reduction of fracture risk in men (age > 50 years). Studies included were randomised, placebo-controlled trials of men. Results. Five BMD studies of antiresorptive treatment were included. All studies showed an increase in BMD, but there was only a nonsignificant trend in the reduction of clinical fractures. Three BMD studies of anabolic treatment with teriparatide were also included. These showed a significant mean increase in spine BMD and for vertebral fractures a non-significant trend towards a reduction was seen. Conclusion. The evidence of medical osteoporosis treatment in men is scant and inconclusive due to the lack of prospective RCT studies with fracture prevention as primary end point. So far, all evidence is based on BMD increases in small RCT studies showing BMD increases comparable to those reported in postmenopausal women.
PMCID: PMC3138068  PMID: 21776371
18.  Systematic review of reviews of intervention components associated with increased effectiveness in dietary and physical activity interventions 
BMC Public Health  2011;11:119.
To develop more efficient programmes for promoting dietary and/or physical activity change (in order to prevent type 2 diabetes) it is critical to ensure that the intervention components and characteristics most strongly associated with effectiveness are included. The aim of this systematic review of reviews was to identify intervention components that are associated with increased change in diet and/or physical activity in individuals at risk of type 2 diabetes.
MEDLINE, EMBASE, CINAHL, PsycInfo, and the Cochrane Library were searched for systematic reviews of interventions targeting diet and/or physical activity in adults at risk of developing type 2 diabetes from 1998 to 2008. Two reviewers independently selected reviews and rated methodological quality. Individual analyses from reviews relating effectiveness to intervention components were extracted, graded for evidence quality and summarised.
Of 3856 identified articles, 30 met the inclusion criteria and 129 analyses related intervention components to effectiveness. These included causal analyses (based on randomisation of participants to different intervention conditions) and associative analyses (e.g. meta-regression). Overall, interventions produced clinically meaningful weight loss (3-5 kg at 12 months; 2-3 kg at 36 months) and increased physical activity (30-60 mins/week of moderate activity at 12-18 months). Based on causal analyses, intervention effectiveness was increased by engaging social support, targeting both diet and physical activity, and using well-defined/established behaviour change techniques. Increased effectiveness was also associated with increased contact frequency and using a specific cluster of "self-regulatory" behaviour change techniques (e.g. goal-setting, self-monitoring). No clear relationships were found between effectiveness and intervention setting, delivery mode, study population or delivery provider. Evidence on long-term effectiveness suggested the need for greater consideration of behaviour maintenance strategies.
This comprehensive review of reviews identifies specific components which are associated with increased effectiveness in interventions to promote change in diet and/or physical activity. To maximise the efficiency of programmes for diabetes prevention, practitioners and commissioning organisations should consider including these components.
PMCID: PMC3048531  PMID: 21333011
19.  Prevention of Diabetes Self-Management Program (PREDIAS): Effects on Weight, Metabolic Risk Factors, and Behavioral Outcomes 
Diabetes Care  2009;32(7):1143-1146.
To evaluate the efficacy of the group program PREDIAS for diabetes prevention.
PREDIAS consists of 12 lessons and aims at lifestyle modification. The control group received written information about diabetes prevention. In this study, a total of 182 persons with an elevated diabetes risk participated (aged 56.3 ± 10.1 years, 43% female, and BMI 31.5 ± 5.3 kg/m2).
After 12 months, weight loss was significantly higher (P = 0.001) in PREDIAS than in the control group (−3.8 ± 5.2 vs. −1.4 ± 4.09 kg). There were also significant effects (P = 0.001) on fasting glucose (control group 1.8 ± 13.1 mg/dl vs. PREDIAS −4.3 ± 11.3 mg/dl), duration of physical activity per week (control group 17.9 ± 63.8 min vs. PREDIAS 46.6 ± 95.5 min; P = 0.03), and eating behavior.
PREDIAS significantly modified lifestyle factors associated with an elevated diabetes risk.
PMCID: PMC2699739  PMID: 19509014
20.  Top-Down Lipidomics Reveals Ether Lipid Deficiency in Blood Plasma of Hypertensive Patients 
PLoS ONE  2009;4(7):e6261.
Dyslipoproteinemia, obesity and insulin resistance are integrative constituents of the metabolic syndrome and are major risk factors for hypertension. The objective of this study was to determine whether hypertension specifically affects the plasma lipidome independently and differently from the effects induced by obesity and insulin resistance.
Methodology/Principal Findings
We screened the plasma lipidome of 19 men with hypertension and 51 normotensive male controls by top-down shotgun profiling on a LTQ Orbitrap hybrid mass spectrometer. The analysis encompassed 95 lipid species of 10 major lipid classes. Obesity resulted in generally higher lipid load in blood plasma, while the content of tri- and diacylglycerols increased dramatically. Insulin resistance, defined by HOMA-IR >3.5 and controlled for BMI, had little effect on the plasma lipidome. Importantly, we observed that in blood plasma of hypertensive individuals the overall content of ether lipids decreased. Ether phosphatidylcholines and ether phosphatidylethanolamines, that comprise arachidonic (20∶4) and docosapentaenoic (22∶5) fatty acid moieties, were specifically diminished. The content of free cholesterol also decreased, although conventional clinical lipid homeostasis indices remained unaffected.
Top-down shotgun lipidomics demonstrated that hypertension is accompanied by specific reduction of the content of ether lipids and free cholesterol that occurred independently of lipidomic alterations induced by obesity and insulin resistance. These results may form the basis for novel preventive and dietary strategies alleviating the severity of hypertension.
PMCID: PMC2705678  PMID: 19603071

Results 1-21 (21)