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1.  First Dutch experience with the endoscopic laser balloon ablation system for the treatment of atrial fibrillation 
Netherlands Heart Journal  2014;23(2):96-99.
The endoscopic laser balloon ablation system (EAS) is a relatively novel technique to perform pulmonary vein isolation (PVI) in the treatment of atrial fibrillation (AF). The present study aimed to report the results of the first 50 patients treated in the Netherlands with the EAS in terms of procedural characteristics and AF-free survival.
Fifty patients successfully underwent EAS PVI. Median follow-up was 17 months. Mean age was 56 years, 82 % had paroxysmal AF.
99 % of the pulmonary veins were successfully isolated with the EAS. Mean procedure time was 171 min and mean fluoroscopy time was 36 min. One procedure was complicated by a temporary phrenic nerve palsy (2 %). During follow-up, 58 % of patients remained free of AF without the use of antiarrhythmic drugs.
PVI with EAS is associated with a low risk of complications and a medium-term AF-free survival comparable with other PVI techniques.
Electronic supplementary material
The online version of this article (doi:10.1007/s12471-014-0624-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4315796  PMID: 25388798
Atrial fibrillation; Ablation; Pulmonary vein isolation; Laser balloon ablation
2.  Chemotherapy for testicular cancer induces acute alterations in diastolic heart function 
British Journal of Cancer  2013;109(4):891-896.
After treatment with cisplatin-based chemotherapy for testicular cancer (TC), patients have higher prevalence of cardiovascular complications after long-term follow up. Little is known about acute cardiovascular effects of cisplatin-based chemotherapy. The aim of this study was to explore acute effects of chemotherapy on cardiac function in patients treated for TC.
Fourteen TC patients (age 34.6±12.3 years) were studied before and 3 months after start with cisplatin-based chemotherapy. Cardiac function was assessed with magnetic resonance imaging. Fasting glucose and insulin levels were measured and insulin sensitivity, reflected by the quantitative insulin sensitivity index (Quicki index), was calculated.
Left ventricular (LV) end-diastolic volume and LV stroke volume (SV) significantly decreased from 192±27 to 175±26 ml (P<0.05) and 109±18 to 95±16 ml (P<0.05), respectively. The ratio of early and atrial filling velocities across the mitral valve, a parameter of diastolic heart function, decreased after chemotherapy from 1.87±0.43 to 1.64±0.45 (P<0.01). Metabolic parameters were unfavourably changed, reflected by a decreased Quicki index, which reduced from 0.39±0.05 to 0.36±0.05 (P<0.05).
Chemotherapy for TC induces acute alterations in diastolic heart function, paralleled by unfavourable metabolic changes. Therefore, early after chemotherapy, metabolic treatment may be indicated to possibly reduce long-term cardiovascular complications.
PMCID: PMC3749589  PMID: 23922115
chemotherapy; cisplatin; testicular cancer; cancer survivors; cardiovascular damage; diastolic heart function
3.  Incidence of lead dislodgement, malfunction and perforation during the first year following device implantation 
Netherlands Heart Journal  2014;22(6):286-291.
The number of cardiac rhythm device implantations has been growing fast due to expanding indications and ageing of the population. Complications of implantation were rare in the trials. However, these involved small numbers and selected patients. Prospective real-life data are necessary to assess cardiac device implantation procedure-related risks.
To determine the incidence and predictors of lead-related re-intervention in a Dutch high-volume teaching hospital.
Data from all patients who underwent cardiac rhythm device implantation between January 2010 and December 2011 were collected in a prospective registry. At least 1 year of follow-up regarding re-intervention was available for all patients. Lead-related reasons for re-intervention were categorised into lead dislodgement, malfunctioning or perforation.
One thousand nine hundred twenty-nine devices including 3909 leads were implanted. In 595 patients (30.8 %) a CRT-D/P was implanted. Lead-related re-intervention was necessary in 86 (4.4 %) patients; it was more common in younger and male patients, and due to either lead dislodgement (66 %), malfunctioning (20 %) or perforation (18 %). Coronary sinus lead dislodgement or malfunctioning was 1.4 %. Right atrial dislodgement (1.9 %, p < 0.001) or ICD lead dislodgement (1.8 %, p = 0.002) was more common than right ventricular dislodgement (0.3 %). The incidence of lead malfunctioning was higher (0.8 %) in ICD leads. An apical position of the right ventricular lead and lateral wall position of the right atrial lead were related to cardiac perforation.
The incidence of lead-related re-intervention was comparable with the literature. The majority of re-interventions were due to lead dislodgements, particularly with right atrial and ICD leads. Re-intervention due to coronary sinus lead dislodgement was rare.
PMCID: PMC4031363  PMID: 24807834
Lead complication; Dislodgement; Malfunction; Perforation; Re-intervention
4.  Lyophilized Platelet-Rich Fibrin (PRF) Promotes Craniofacial Bone Regeneration through Runx2 
Freeze-drying is an effective means to control scaffold pore size and preserve its composition. The purpose of the present study was to determine the applicability of lyophilized Platelet-rich fibrin (LPRF) as a scaffold for craniofacial tissue regeneration and to compare its biological effects with commonly used fresh Platelet-rich fibrin (PRF). LPRF caused a 4.8-fold ± 0.4-fold elevation in Runt-related transcription factor 2 (Runx2) expression in alveolar bone cells, compared to a 3.6-fold ± 0.2-fold increase when using fresh PRF, and a more than 10-fold rise of alkaline phosphatase levels and mineralization markers. LPRF-induced Runx2 expression only occurred in alveolar bone and not in periodontal or dental follicle cells. LPRF also caused a 1.6-fold increase in osteoblast proliferation (p < 0.001) when compared to fresh PRF. When applied in a rat craniofacial defect model for six weeks, LPRF resulted in 97% bony coverage of the defect, compared to 84% for fresh PRF, 64% for fibrin, and 16% without scaffold. Moreover, LPRF thickened the trabecular diameter by 25% when compared to fresh PRF and fibrin, and only LPRF and fresh PRF resulted in the formation of interconnected trabeculae across the defect. Together, these studies support the application of lyophilized PRF as a biomimetic scaffold for craniofacial bone regeneration and mineralized tissue engineering.
PMCID: PMC4057745  PMID: 24830554
Platelet-rich fibrin; lyophilization; calvaria; alveolar bone; Runx2
5.  Combinatorial Design of Hydrolytically Degradable, Bone–like Biocomposites Based on PHEMA and Hydroxyapatite 
Polymer  2012;54(2):909-919.
With advantages such as design flexibility in modifying degradation, surface chemistry, and topography, synthetic bone–graft substitutes are increasingly demanded in orthopedic tissue engineering to meet various requirements in the growing numbers of cases of skeletal impairment worldwide. Using a combinatorial approach, we developed a series of biocompatible, hydrolytically degradable, elastomeric, bone–like biocomposites, comprising 60 wt% poly(2–hydroxyethyl methacrylate–co–methacrylic acid), poly(HEMA–co–MA), and 40 wt% bioceramic hydroxyapatite (HA). Hydrolytic degradation of the biocomposites is rendered by a degradable macromer/crosslinker, dimethacrylated poly(lactide–b–ethylene glycol–b–lactide), which first degrades to break up 3–D hydrogel networks, followed by dissolution of linear pHEMA macromolecules and bioceramic particles. Swelling and degradation were examined at Hank’s balanced salt solution at 37 °C in a 12–week period of time. The degradation is strongly modulated by altering the concentration of the co–monomer of methacrylic acid and of the macromer, and chain length/molecular weight of the macromer. 95% weight loss in mass is achieved after degradation for 12 weeks in a composition consisting of HEMA/MA/Macromer = 0/60/40, while 90% weight loss is seen after degradation only for 4 weeks in a composition composed of HEMA/MA/Macromer = 27/13/60 using a longer chain macromer. For compositions without a co–monomer, only about 14% is achieved in weight loss after 12–week degradation. These novel biomaterials offer numerous possibilities as drug delivery carriers and bone grafts particularly for low and medium load–bearing applications.
PMCID: PMC3601847  PMID: 23525786
pHEMA; hydrolytic degradation; macromer
9.  Platelet-Rich Fibrin Promotes Periodontal Regeneration and Enhances Alveolar Bone Augmentation 
BioMed Research International  2013;2013:638043.
In the present study we have determined the suitability of platelet-rich fibrin (PRF) as a complex scaffold for periodontal tissue regeneration. Replacing PRF with its major component fibrin increased mineralization in alveolar bone progenitors when compared to periodontal progenitors, suggesting that fibrin played a substantial role in PRF-induced osteogenic lineage differentiation. Moreover, there was a 3.6-fold increase in the early osteoblast transcription factor RUNX2 and a 3.1-fold reduction of the mineralization inhibitor MGP as a result of PRF application in alveolar bone progenitors, a trend not observed in periodontal progenitors. Subcutaneous implantation studies revealed that PRF readily integrated with surrounding tissues and was partially replaced with collagen fibers 2 weeks after implantation. Finally, clinical pilot studies in human patients documented an approximately 5 mm elevation of alveolar bone height in tandem with oral mucosal wound healing. Together, these studies suggest that PRF enhances osteogenic lineage differentiation of alveolar bone progenitors more than of periodontal progenitors by augmenting osteoblast differentiation, RUNX2 expression, and mineralized nodule formation via its principal component fibrin. They also document that PRF functions as a complex regenerative scaffold promoting both tissue-specific alveolar bone augmentation and surrounding periodontal soft tissue regeneration via progenitor-specific mechanisms.
PMCID: PMC3622372  PMID: 23586051
10.  Reproductive Counseling by Clinic Healthcare Workers in Durban, South Africa: Perspectives from HIV-Infected Men and Women Reporting Serodiscordant Partners 
Background. Understanding HIV-infected patient experiences and perceptions of reproductive counseling in the health care context is critical to inform design of effective pharmaco-behavioral interventions that minimize periconception HIV risk and support HIV-affected couples to realize their fertility goals. Methods. We conducted semistructured, in-depth interviews with 30 HIV-infected women (with pregnancy in prior year) and 20 HIV-infected men, all reporting serodiscordant partners and accessing care in Durban, South Africa. We investigated patient-reported experiences with safer conception counseling from health care workers (HCWs). Interview transcripts were reviewed and coded using content analysis for conceptual categories and emergent themes. Results. The study findings indicate that HIV-infected patients recognize HCWs as a resource for periconception-related information and are receptive to speaking to a HCW prior to becoming pregnant, but seldom seek or receive conception advice in the clinic setting. HIV nondisclosure and unplanned pregnancy are important intervening factors. When advice is shared, patients reported receiving a range of information. Male participants showed particular interest in accessing safer conception information. Conclusions. HIV-infected men and women with serodiscordant partners are receptive to the idea of safer conception counseling. HCWs need to be supported to routinely initiate accurate safer conception counseling with HIV-infected patients of reproductive age.
PMCID: PMC3426202  PMID: 22927713
11.  Ectopic Fat and Insulin Resistance: Pathophysiology and Effect of Diet and Lifestyle Interventions 
The storage of triglyceride (TG) droplets in nonadipose tissues is called ectopic fat storage. Ectopic fat is associated with insulin resistance and type 2 diabetes mellitus (T2DM). Not the triglycerides per se but the accumulation of intermediates of lipid metabolism in organs, such as the liver, skeletal muscle, and heart seem to disrupt metabolic processes and impair organ function. We describe the mechanisms of ectopic fat depositions in the liver, skeletal muscle, and in and around the heart and the consequences for each organs function. In addition, we systematically reviewed the literature for the effects of diet-induced weight loss and exercise on ectopic fat depositions.
PMCID: PMC3366269  PMID: 22675355
12.  2012 European Thyroid Association Guidelines for Metastatic Medullary Thyroid Cancer 
European Thyroid Journal  2012;1(1):5-14.
Distant metastases are the main cause of death in patients with medullary thyroid cancer (MTC). These 21 recommendations focus on MTC patients with distant metastases and a detailed follow-up protocol of patients with biochemical or imaging evidence of disease, selection criteria for treatment, and treatment modalities, including local and systemic treatments based on the results of recent trials. Asymptomatic patients with low tumor burden and stable disease may benefit from local treatment modalities and can be followed up at regular intervals of time. Imaging is usually performed every 6–12 months, or at longer intervals of time depending on the doubling times of serum calcitonin and carcinoembryonic antigen levels. Patients with symptoms, large tumor burden and progression on imaging should receive systemic treatment. Indeed, major progress has recently been achieved with novel targeted therapies using kinase inhibitors directed against RET and VEGFR, but further research is needed to improve the outcome of these patients.
PMCID: PMC3821456  PMID: 24782992
Medullary thyroid cancer; Metastases; Tyrosine kinase inhibitors; Rearranged during transfection mutation
13.  Apatite Microtopographies Instruct Signaling Tapestries for Progenitor-Driven New Attachment of Teeth 
Tissue Engineering. Part A  2010;17(3-4):279-290.
Dimension and structure of extracellular matrix surfaces have powerful influences on cell shape, adhesion, and gene expression. Here we show that natural tooth root topographies induce integrin-mediated extracellular matrix signaling cascades in tandem with cell elongation and polarization to generate physiological periodontium-like tissues. In this study we replanted surface topography instructed periodontal progenitors into rat alveolar bone sockets for 8 and 16 weeks, resulting in complete reattachment of tooth roots to the surrounding alveolar bone with a periodontal fiber apparatus closely matching physiological controls along the entire root surface. Displacement studies and biochemical analyses confirmed that progenitor-based engineered periodontal tissues were similar to control teeth and uniquely derived from preimplantation green fluorescent protein (GFP)-labeled progenitors. Together, these studies illustrate the capacity of natural extracellular surface topographies to instruct progenitor cell populations to fully regenerate complex cellular and structural morphologies of tissues once lost to disease. We suggest that our strategy could be used for the replantation of teeth lost due to trauma or as a novel approach for tooth replacement using tooth-shaped replicas.
PMCID: PMC3029000  PMID: 20795795
14.  Association of depressive disorders, depression characteristics and antidepressant medication with inflammation 
Translational Psychiatry  2012;2(2):e79-.
Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18–65 years) with a current (N=1132) or remitted (N=789) depressive disorder according to DSM-IV criteria and healthy controls (N=494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l−1, P<0.001, Cohen's d=0.32) and IL-6 (0.88 versus 0.72 pg ml−1, P=0.01, Cohen's d=0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators — especially body mass index — but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-α). Furthermore, inflammation was increased in men using serotonin–norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation.
PMCID: PMC3309556  PMID: 22832816
antidepressants; cohort study; depression characteristics; depressive disorder; inflammation
15.  Skin Autofluorescence, as Marker of Accumulation of Advanced Glycation Endproducts and of Cumulative Metabolic Stress, Is Not Increased in Patients with Systemic Sclerosis 
Objective. To investigate whether advanced glycation endproducts (AGEs) in the skin are increased in patients with systemic sclerosis (SSc) and are related to the presence of disease-related and traditional cardiovascular risk factors. Methods. Skin autofluorescence, as a measure for the accumulation of AGEs, was assessed by measuring UV-A light excitation-emission matrices (AF-EEMS) in 41 SSc patients and 41 age- and sex-matched controls. Traditional cardiovascular risk factors and disease-related risk factors were recorded. Results. Skin AF-EEMS did not differ between SSc patients and controls (1.68 ± 0.58 a.u. versus 1.63 ± 0.41 a.u., P = 0.684). Skin AF-EEMS in SSc patients was associated with levels of CRP (r = 0.44, P = 0.004), Medsger's severity scale (r = 0.45, P = 0.006), and use of agents intervening in the renin-angiotensin system (r = 0.33, P = 0.027). When analysing SSc patients and controls together, in multivariate analysis, only age and use of agents intervening in the renin-angiotensin system were independently associated with AF-EEMS. Conclusion. These data demonstrate that skin AGEs are not increased in SSc patients.
PMCID: PMC3184409  PMID: 21977038
16.  The effect of hypertension on aortic pulse wave velocity in type-1 diabetes mellitus patients: assessment with MRI 
To investigate in type-1 diabetes mellitus (DM1) patients the role of hypertension and of DM1 itself on aortic stiffness by using magnetic resonance imaging (MRI). Consecutive patients from the diabetes and hypertension outpatient clinic and healthy volunteers were included in our study. Subjects were divided into four groups: 32 healthy volunteers (mean age: 54.5 ± 6.8 years), 20 DM1 patients (mean age: 48.3 ± 5.9 years), 31 hypertensive patients (mean age: 59.9 ± 7.2 years) and 28 patients with both DM1 and hypertension (mean age: 50.1 ± 6.2 years). Aortic stiffness was measured by means of pulse wave velocity (PWV) using velocity-encoded MRI. Analysis of variance (ANOVA), uni- and multivariable regression models and the Bonferroni-test for multiple testing, were used for statistical analyses. Mean aortic PWV was 5.7 ± 1.2 m/s in healthy volunteers, 5.9 ± 1.2 m/s in DM1 patients without hypertension, 7.3 ± 1.2 m/s in hypertensive patients and 7.3 ± 1.3 m/s in patients with both DM1 and hypertension. Compared to healthy control subjects, aortic PWV was significantly higher in patients with hypertension (P < 0.001) and in patients with both DM1 and hypertension (P < 0.001), whereas aortic PWV was not increased in patients having DM1 alone. Furthermore, aortic PWV was significantly higher in DM1 patients with hypertension than in patients with DM1 alone (P = 0.002). These findings remained after adjustment for confounding factors. Hypertension has a predominant contributive effect on aortic stiffness in DM1 patients whereas the direct diabetic effect on aortic stiffness is small.
PMCID: PMC3326366  PMID: 21394612
Aortic pulse wave velocity; MRI; Type-1 diabetes mellitus; Hypertension
17.  Extracellular Matrix-Mediated Differentiation of Periodontal Progenitor Cells 
The periodontal ligament (PDL) is a specialized connective tissue that connects the surface of the tooth root with the bony tooth socket. The healthy PDL harbors stem cell niches and extracellular matrix (ECM) microenvironments that facilitate periodontal regeneration. During periodontal disease, the PDL is often compromised or destroyed, reducing the life-span of the tooth. In order to explore new approaches toward the regeneration of diseased periodontal tissues, we have tested the effect of periodontal ECM signals, fibroblast growth factor 2 (FGF2), connective tissue growth factor (CTGF), and the cell adhesion peptide Arg-Gly- Asp (RGD) on the differentiation of two types of periodontal progenitor cells, PDL progenitor cells (PDLPs) and dental follicle progenitor cells (DFCs). Our studies documented that CTGF and FGF2 significantly enhanced the expression of collagens I & III, biglycan and periostin in tissue engineered regenerates after 4 weeks compared to untreated controls. Specifically, CTGF promoted mature PDL-like tissue regeneration as demonstrated by dense periostin localization in collagen fiber bundles. CTGF and FGF2 displayed synergistic effects on collagen III and biglycan gene expression, while effects on mineralization were antagonistic to each other: CTGF promoted while FGF2 inhibited mineralization in PDL cell cultures. Incorporation of RGD peptides in hydrogel matrices significantly enhanced attachment, spreading, survival and mineralization of the encapsulated DFCs, suggesting that RGD additives might promote the use of hydrogels for periodontal mineralized tissue engineering. Together, our studies have documented the effect of three key components of the periodontal ECM on the differentiation of periodontal progenitor populations.
PMCID: PMC2744845  PMID: 19433344
growth factors; extracellular matrix; periodontal regeneration; progenitor cells
18.  Evaluation of sub-acute changes in cardiac function after cisplatin-based combination chemotherapy for testicular cancer 
British Journal of Cancer  2009;100(12):1861-1866.
Long-term cardiovascular morbidity is increasingly observed in chemotherapy-treated testicular cancer survivors, but little is known of early sub-clinical changes in cardiac function. We prospectively evaluated cardiac function in testicular cancer patients by echocardiography. Systolic (Wall Motion Score Index) and diastolic (E/A-ratio and Tissue Velocity Imaging (TVI)) parameters, and serum levels of N-Terminal pro-Brain Natriuretic Peptide (NT-proBNP) were assessed before the start of chemotherapy and 1 year later. Echocardiography data were compared with an age-matched group of healthy controls. Forty-two patients treated with bleomycin, etoposide and cisplatin were evaluated (median age 27 years, range 18–50). Systolic function and E/A-ratio did not change, whereas the median TVI decreased (12.0 vs 10.0 cms−1; P=0.002). Median levels of NT-proBNP increased (5 vs 18 pmoll−1, P=0.034). Compared with controls, TVI before the start of chemotherapy was not significantly different. In conclusion, we found that at a median of 10 months after cisplatin-based treatment for testicular cancer, TVI decreased significantly, indicating a deterioration of diastolic cardiac function. Serum levels of NT-proBNP increased. The prognostic significance of these changes for future cardiovascular morbidity is not clear.
PMCID: PMC2714243  PMID: 19455138
testicular cancer; cardiovascular toxicity; echocardiography; prospective
19.  Characteristics of Sprint Fidelis lead failure 
Netherlands Heart Journal  2010;18(1):12-17.
Background. The Medtronic Sprint Fidelis ICD lead is prone to failure and the rate of failure seems to be increasing. The aim of this study was to investigate the rate of Sprint Fidelis lead failure, the characteristics, the mode of presentation and possible predictors of lead failure.
Methods and Results. The rate, characteristics and presentation of Sprint Fidelis lead failure was assessed in this single-centre survey. 619 Sprint Fidelis ICD leads were implanted at our centre between December 2004 and August 2007. The mean follow-up was 32±10 (range 22–60) months; 35 patients (5.7%) required a lead re-implantation because of failure of the pace-sense conductor. Mean duration of lead survival was 23±12 (2–46) months and the rate of failure did not stabilise during follow-up. The mode of presentation was inappropriate shocks in 16 patients (45.7%), alarm alert in 12 patients (34.3%), and detection at routine follow-up in seven patients (20%). In 31 patients (89%), interrogation data revealed a sudden rise in impedance and/or frequent short VV intervals prior to lead failure and in five patients an isolated decrease of R wave (<2.5 mV). The interrogation data were not different from patients with shocks compared with patients without shocks. The interrogation data at routine follow-up in the first three months after implant were normal and stable.
Conclusion. The rate of Sprint Fidelis lead failure reaches 5.7% at a mean follow-up duration of 32 months. The rate of failure does not seem to stabilise. Routine follow-up can not predict lead failure or prevent inappropriate shocks. (Neth Heart J 2010;18:12-7.)
PMCID: PMC2810030  PMID: 20111638
ICD lead failure; inappropriate shock; Sprint Fidelis
20.  Advanced glycation end products and the absence of premature atherosclerosis in glycogen storage disease Ia 
Despite their unfavourable cardiovascular risk profile, patients with glycogen storage disease type Ia (GSD Ia) do not develop premature atherosclerosis. We hypothesized that this paradox might be related to a decreased formation of advanced glycation end products (AGEs) resulting from lifetime low plasma glucose levels and decreased oxidative stress.
In 8 GSD Ia patients (age 20–24 years) and 30 matched controls we measured carotid intima-media thickness (IMT), skin autofluorescence (AF; a non-invasive index for AGEs), and specific AGEs (pentosidine, N-(carboxymethyl)lysine (CML), N-(carboxyethyl)lysine (CEL)) and collagen linked fluorescence (CLF, measured at excitation/emission wavelength combinations of 328/378 and 370/440 nm) in skin samples.
Carotid IMT was significantly lower in GSD Ia patients. Skin AF did not differ between patients and controls. The skin samples showed higher CEL levels in the patient group (p=0.008), but similar levels of pentosidine, CML, and CLF. In the total group, skin AF correlated with CML (r=0.39, p=0.031), CLF 328/378 nm (r=0.53; p=0.002) and CLF 370/440 nm (r=0.60; p=0.001). In the control group, AF also correlated with the maximum carotid IMT (r=0.6; p=0.004).
Although our data confirm that GSD Ia patients present with a reduced burden of atherosclerosis, this phenomenon cannot be explained by differences in AGE accumulation as measured in the skin.
PMCID: PMC2799632  PMID: 17570077
21.  Genetic association analysis of LARS2 with type 2 diabetes 
Diabetologia  2009;53(1):103-110.
LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk.
We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent.
No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95–1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90–1.08], p = 0.78, n = 35,715 respectively).
In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-009-1557-7) contains supplementary material, which is available to authorised users.
PMCID: PMC2789927  PMID: 19847392
Genetics; LARS2; Mitochondria; SNP; Type 2 diabetes
22.  Aortic stiffness is associated with cardiac function and cerebral small vessel disease in patients with type 1 diabetes mellitus: assessment by magnetic resonance imaging 
European Radiology  2009;20(5):1132-1138.
To evaluate, with the use of magnetic resonance imaging (MRI), whether aortic pulse wave velocity (PWV) is associated with cardiac left ventricular (LV) function and mass as well as with cerebral small vessel disease in patients with type 1 diabetes mellitus (DM).
Materials and methods
We included 86 consecutive type 1 DM patients (49 male, mean age 46.9 ± 11.7 years) in a prospective, cross-sectional study. Exclusion criteria included aortic/heart disease and general MRI contra-indications. MRI of the aorta, heart and brain was performed for assessment of aortic PWV, as a marker of aortic stiffness, systolic LV function and mass, as well as for the presence of cerebral white matter hyperintensities (WMHs), microbleeds and lacunar infarcts. Multivariate linear or logistic regression was performed to analyse the association between aortic PWV and outcome parameters, with covariates defined as age, gender, mean arterial pressure, heart rate, BMI, smoking, DM duration and hypertension.
Mean aortic PWV was 7.1 ± 2.5 m/s. Aortic PWV was independently associated with LV ejection fraction (ß = -0.406, P = 0.006), LV stroke volume (ß = -0.407, P = 0.001), LV cardiac output (ß = -0.458, P = 0.001), and with cerebral WMHs (P < 0.05). There were no independent associations between aortic stiffness and LV mass, cerebral microbleeds or lacunar infarcts.
Aortic stiffness is independently associated with systolic LV function and cerebral WMHs in patients with type 1 DM.
PMCID: PMC2850521  PMID: 19915847
Aorta; Magnetic resonance imaging; Type 1 diabetes mellitus; Heart; Brain
23.  Skin autofluorescence is elevated in acute myocardial infarction and is associated with the one-year incidence of major adverse cardiac events 
Netherlands Heart Journal  2009;17(4):162-168.
ST-elevation myocardial infarction (STEMI) is associated with increased inflammation and oxidative stress, enhancing the formation of advanced glycation endproducts (AGEs). These encompass a characteristic fluorescence pattern, which can be non-invasively measured as skin autofluorescence (AF). In this study we investigate whether skin AF is elevated in STEMI, its association with inflammatory and glycaemic stress and its predictive value for future events.
Skin AF was measured in 88 STEMI patients (mean age 64±13 years) within 72 hours and around six months after discharge, in 81 stable coronary artery disease (sCAD) patients (64±10 years), and in 32 healthy controls (63±11 years). The cumulative one-year incidence of all-cause mortality and hospitalisation for myocardial infarction or heart failure was documented.
Skin AF was significantly higher in STEMI compared with sCAD and controls, irrespective of confounders, and was associated with HbA1c and C-reactive protein. Skin AF decreased significantly in STEMI patients, when measured >200 days after discharge. In STEMI patients, skin AF above the median was predictive of future events (hazard ratio 11.6, 95% CI 1.5 to 90.8, p=0.019).
Skin AF is elevated in STEMI, is associated with inflammation and glycaemic stress, and predicts future major adverse cardiac events. (Neth Heart J 2009;17:162-8.19421362Neth Heart J 2009;17:162–8.)
PMCID: PMC2669246  PMID: 19421362
myocardial infarction; oxidative stress; inflammation; autofluorescence; advanced glycation endproducts
24.  Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus 
Diabetologia  2008;51(9):1581-1593.
Cardiovascular disease is the major cause of mortality in type 2 diabetes mellitus. The criteria for the selection of those asymptomatic patients with type 2 diabetes who should undergo cardiac screening and the therapeutic consequences of screening remain controversial. Non-invasive techniques as markers of atherosclerosis and myocardial ischaemia may aid risk stratification and the implementation of tailored therapy for the patient with type 2 diabetes. In the present article we review the literature on the implementation of non-invasive vascular tools and cardiac imaging techniques in this patient group. The value of these techniques as endpoints in clinical trials and as risk estimators in asymptomatic diabetic patients is discussed. Carotid intima–media thickness, arterial stiffness and flow-mediated dilation are abnormal long before the onset of type 2 diabetes. These vascular tools are therefore most likely to be useful for the identification of ‘at risk’ patients during the early stages of atherosclerotic disease. The additional value of these tools in risk stratification and tailored therapy in type 2 diabetes remains to be proven. Cardiac imaging techniques are more justified in individuals with a strong clinical suspicion of advanced coronary heart disease (CHD). Asymptomatic myocardial ischaemia can be detected by stress echocardiography and myocardial perfusion imaging. The more recently developed non-invasive multi-slice computed tomography angiography is recommended for exclusion of CHD, and can therefore be used to screen asymptomatic patients with type 2 diabetes, but has the associated disadvantages of high radiation exposure and costs. Therefore, we propose an algorithm for the screening of asymptomatic diabetic patients, the first step of which consists of coronary artery calcium score assessment and exercise ECG.
PMCID: PMC2516193  PMID: 18607561
Cardiac imaging; Cardiovascular disease; Diabetes mellitus; Review; Risk stratification; Vascular tools
25.  Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents 
Osteoporosis International  2007;19(5):663-671.
The effect of equivalent oral doses of vitamin D3 600 IU/day, 4200 IU/week and 18,000 IU/month on vitamin D status was compared in a randomized clinical trial in nursing home residents. A daily dose was more effective than a weekly dose, and a monthly dose was the least effective.
It is assumed that equivalent daily, weekly or monthly doses of vitamin D3 equally influence vitamin D status. This was investigated in a randomized clinical trial in nursing home residents.
The study was performed in ten nursing homes including 338 subjects (76 male and 262 female), with a mean age of 84 (± SD 6.3 years). They received oral vitamin D3 either 600 IU/day, or 4200 IU/week, or 18,000 IU/month or placebo. After 4 months, calcium was added during 2 weeks, 320 mg/day or 640 mg/day or placebo. Outcome: serum levels of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and bone turnover markers. Statistical approach: linear multilevel analysis.
At baseline, mean serum 25(OH)D was 25.0 nmol/L (SD 10.9), and in 98%, it was lower than 50 nmol/L. After 4 months, mean serum 25(OH)D levels increased to 62.5 nmol/L (after daily vitamin D3 69.9 nmol/L, weekly 67.2 nmol/L and monthly 53.1 nmol/L,  < 0.001 between groups). Median serum PTH levels decreased by 23% ( < 0.001). Bone turnover markers did not decrease. Calcium supplementation had no effect on serum PTH and bone turnover.
Daily vitamin D was more effective than weekly, and monthly administration was the least effective.
PMCID: PMC2277446  PMID: 17874029
Calcium supplementation; Secondary hyperparathyroidism; Vitamin D deficiency; Vitamin D supplementation

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