OBJECTIVE: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess... Show moreOBJECTIVE: Quality of life is decreased in patients with long-term control of acromegaly. In addition, these patients suffer from irreversible osteoarthritis. The aim of this study was to assess the impact of joint-specific complaints, clinical and radiological signs of arthropathy on different aspects of quality of life (QoL) in patients with acromegaly after long-term disease control. DESIGN: Cross-sectional study. METHODS: We studied 58 patients (31 males), mean age 60years (range 32-81years), with strict biochemical control of acromegaly for a mean duration of 15years. QoL was assessed by four health-related QoL questionnaires (HADS, MFI-20, NHP, SF-36) and one disease specific QoL questionnaire (AcroQoL). The outcomes of these questionnaires were compared with joint-specific self-reported complaints of pain/stiffness, clinical osteoarthritis based on American College of Rheumatology (ACR) and radiological osteoarthritis based on the Kellgren-Lawrence (KL) scoring method. RESULTS: Long-term cured acromegaly patients had high pain scores of the spine, knee, and hip which limited physical functioning (mean difference -27.0, 95%-CI -9.5, -41.0) and psychological well-being (mean difference -44.4, 95%-CI -26.1, -60.9) (SF-36). Clinical osteoarthritis of the spine was associated mostly with impaired QoL scores, on physical, social, and emotional functioning, and on anxiety and depression. Remarkably, radiological osteoarthritis was not associated with impaired QoL. CONCLUSION: These findings accentuate the importance of recognition of the clinical manifestations of arthropathy in patients with acromegaly despite long-term disease control. Show less
Vreeburg, S.A.; Zitman, F.G.; Pelt, J. van; DeRijk, R.H.; Verhagen, J.C.M.; Dyck, R. van; ... ; Penninx, B.W.J.H. 2010
Objective: To examine the association between several subtypes of anxiety disorders and various cortisol indicators in a large cohort study. Anxiety disorders have been suggested to be linked to... Show moreObjective: To examine the association between several subtypes of anxiety disorders and various cortisol indicators in a large cohort study. Anxiety disorders have been suggested to be linked to hypothalamic-pituitary-adrenal (HPA) axis activity, although results are scarce and inconsistent. No earlier studies have examined consistency of HPA axis findings across several anxiety subtypes and whether associations are state or trait dependent. Methods: Data are derived from 1427 participants of the Netherlands Study of Depression and Anxiety. Three groups were compared: 342 control participants without psychiatric disorders; 311 persons with a remitted (no current) anxiety disorder (social phobia, generalized anxiety disorder, panic disorder); and 774 persons with a current anxiety disorder, as diagnosed using the Composite International Diagnostic Interview psychiatric interview. Cortisol levels were measured in seven saliva samples, determining the 1-hour cortisol awakening response, evening cortisol, and cortisol response after 0.5 mg of dexamethasone ingestion. Results: Current anxiety disorder was associated with higher awakening cortisol levels (p = .002). These findings were mainly present for patients with panic disorder with agoraphobia and anxious patients with comorbid depressive disorder. Remitted anxiety only showed a trend toward higher morning cortisol (p = .08). No associations were observed for anxiety status and evening cortisol level or cortisol suppression after dexamethasone. Conclusions: This study showed a modest but significantly higher 1-hour cortisol awakening response among anxiety patients, which was driven by those with panic disorder with agoraphobia and those with comorbid depression. Show less
Snel, M.; Sleddering, M.A.; Pijl, H.; Nieuwenhuizen, W.F.; Frolich, M.; Havekes, L.M.; ... ; Jazet, I.M. 2010
Background:Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA... Show moreBackground:Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity.Objective:To study the effect of dietary supplementation with PS on cholesterol and glucose metabolism in humans.Methods:Twelve men with the metabolic syndrome (MetS) (according to the International Diabetes Federation (IDF) criteria; age 51+/-2 years (mean+/-s.e.m.); body mass index (BMI) 32+/-1 kg/m(2)) were randomly assigned to 4 weeks of PS (500 mg twice daily) and 4 weeks of placebo (P) in a double-blind cross-over study, with a 4-week wash-out period between both interventions. At the end of each intervention anthropometric measures and serum lipids were measured and an intravenous glucose tolerance test (IVGTT) was performed.Results:Phytosphingosine did not affect body weight and fat mass compared with P. PS decreased serum total cholesterol (5.1+/-0.3 (PS) vs 5.4+/-0.3 (P) mmol/l; P<0.05) and low-density lipoprotein (LDL)-cholesterol levels (3.1+/-0.3 (PS) vs 3.4+/-0.3 (P) mmol/l; P<0.05), whereas it did not alter serum triglyceride and high-density lipoprotein (HDL)-cholesterol levels. In addition, PS lowered fasting plasma glucose levels (6.2+/-0.3 (PS) vs 6.5+/-0.3 (P) mmol/l; P<0.05). PS increased the glucose disappearance rate (K-value) by 9.9% during the IVGTT (0.91+/-0.06 (PS) vs 0.82+/-0.05 (P) %/min; P<0.05) at similar insulin levels, compared with P, thus implying enhanced insulin sensitivity. PS induced only minor gastrointestinal side effects.Conclusion:Dietary supplementation of PS decreases plasma cholesterol levels and enhances insulin sensitivity in men with the MetS.European Journal of Clinical Nutrition advance online publication, 24 February 2010; doi:10.1038/ejcn.2009.154. Show less
Recent models hypothesize that adolescents' risky behavior is the consequence of increased sensitivity to rewards in the ventral medial (VM) prefrontal cortex (PFC) and the ventral striatum (VS),... Show moreRecent models hypothesize that adolescents' risky behavior is the consequence of increased sensitivity to rewards in the ventral medial (VM) prefrontal cortex (PFC) and the ventral striatum (VS), paired with immature cognitive control abilities due to slow maturation of the dorsal anterior cingulate cortex (ACC) and lateral PFC. We tested this hypothesis with fMRI using a gambling task in which participants chose between Low-Risk gambles with a high probability of obtaining a small reward (1 Euro) and High-Risk gambles with a smaller probability of obtaining a higher reward (2, 4, 6, or 8 Euro). We examined neural responses during choice selection and outcome processing in participants from 4 age groups (pre-pubertal children, early adolescents, older adolescents and young adults). High-Risk choices increased with rewards for all ages, but risk-taking decreased with age for low reward gambles. The fMRI results confirmed that High-Risk choices were associated with activation in VMPFC, whereas Low-Risk choices were associated with activation in lateral PFC. Activation in dorsal ACC showed a linear decrease with age, whereas activation in VMPFC and VS showed an inverted-U shaped developmental pattern, with a peak in adolescence. In addition, behavioral differences in risk-taking propensity modulated brain activation in all age groups. These findings support the hypothesis that risky behavior in adolescence is associated with an imbalance caused by different developmental trajectories of reward and regulatory brain circuitry. Show less
Scherer, H.U.; Woude, D. van der; Ioan-Facsinay, A.; Bannoudi, H. el; Trouw, L.A.; Wang, J.; ... ; Toes, R.E.M. 2010
OBJECTIVE:: Anti-citrullinated protein antibodies (ACPA) exhibit unique specificity for RA. Whether and how ACPA contribute to disease pathogenesis, however, is incompletely understood. The Fc part... Show moreOBJECTIVE:: Anti-citrullinated protein antibodies (ACPA) exhibit unique specificity for RA. Whether and how ACPA contribute to disease pathogenesis, however, is incompletely understood. The Fc part of human IgG carries two N-linked glycan moieties which are crucial for the structural stability of the antibody and modulate its binding affinity to Fcgamma receptors and its ability to activate complement. We have purified ACPA from serum and synovial fluid and analyzed Fc glycosylation profiles in a specific manner. METHODS:: ACPA were isolated by affinity purification using cyclic citrullinated peptides as antigen. IgG(1) Fc glycosylation was analyzed by mass spectrometry. ACPA glycan profiles were compared to glycan profiles of total serum IgG(1) obtained from 85 well-characterised patients. Glycan profiles of paired synovial fluid and serum samples were available from 11 additional patients. RESULTS:: Compared to the pool of serum IgG(1), ACPA IgG(1) lack terminal sialic acid residues. In synovial fluid, ACPA are highly agalactosylated and lack sialic acid residues, a feature that was not detected for total synovial fluid IgG(1). Moreover, differential ACPA glycan profiles were detected in RF-positive versus -negative patients. CONCLUSION:: ACPA IgG(1) exhibit a specific Fc-linked glycan profile which is distinct from total serum IgG(1). Moreover, Fc glycosylation of ACPA differs markedly between synovial fluid and serum. As Fc glycosylation directly affects the recruitment of Fc-mediated effector mechanisms, these data could further our understanding of the contribution of ACPA to disease pathogenesis. Show less
Delgado, V.; Ng, A.C.T.; Veire, N.R. van de; Kley, F. van der; Schuijf, J.D.; Tops, L.F.; ... ; Bax, J.J. 2010
Aims Aortic regurgitation after transcatheter aortic valve implantation (TAVI) is one of the most frequent complications. However, the underlying mechanisms of this complication remain unclear. The... Show moreAims Aortic regurgitation after transcatheter aortic valve implantation (TAVI) is one of the most frequent complications. However, the underlying mechanisms of this complication remain unclear. The present evaluation studied the anatomic and morphological features of the aortic valve annulus that may predict aortic regurgitation after TAVI. Methods and results In 53 patients with severe aortic stenosis undergoing TAVI, multi-detector row computed tomography (MDCT) assessment of the aortic valve apparatus was performed. For aortic valve annulus sizing, two orthogonal diameters were measured (coronal and sagittal). In addition, the extent of valve calcifications was quantified. At 1-month follow-up after procedure, MDCT was repeated to evaluate and correlate the prosthesis deployment to the presence of aortic regurgitation. Successful procedure was achieved in 48 (91%) patients. At baseline, MDCT demonstrated an ellipsoid shape of the aortic valve annulus with significantly larger coronal diameter when compared with sagittal diameter (25.1 +/- 2.4 vs. 22.9 +/- 2.0 mm, P < 0.001). At follow-up, MDCT showed a non-circular deployment of the prosthesis in six (14%) patients. Moderate post-procedural aortic regurgitation was observed in five (11%) patients. These patients showed significantly larger aortic valve annulus (27.3 +/- 1.6 vs. 24.8 +/- 2.4 mm, P = 0.007) and more calcified native valves (4174 +/- 1604 vs. 2444 +/- 1237 HU, P = 0.005) at baseline and less favourable deployment of the prosthesis after TAVI. Conclusion Multi-detector row computed tomography enables an accurate sizing of the aortic valve annulus and constitutes a valuable imaging tool to evaluate prosthesis location and deployment after TAVI. In addition, MDCT helps to understand the underlying mechanisms of post-procedural aortic regurgitation. Show less
Buijs, J.T.; Petersen, M.; Horst, G. van der; Pluijm, G. van der 2010
Breast and prostate cancer are osteotropic cancers, i.e., carcinomas that have a special predilection to form bone metastases. At postmortem examination, approximately 70% of patients dying of... Show moreBreast and prostate cancer are osteotropic cancers, i.e., carcinomas that have a special predilection to form bone metastases. At postmortem examination, approximately 70% of patients dying of these cancers have evidence of metastatic bone disease. Bone Morphogenetic Proteins (BMPs) were first identified by their ability to induce ectopic bone formation in vivo. Since prostate cancer cells express several BMPs, BMPs have been implicated in the osteoblastic phenotype of bone metastases. In addition to their osteogenic function, BMPs turned out to be multifunctional proteins regulating cell growth, differentiation, migration, and apoptosis in various target cells, including breast and prostate cancer cells. Especially in the last decade, studies have focused on the role of several BMPs in osteotropic cancers. In this review, the role of BMPs, particularly that of BMP7, in breast and prostate cancer will be discussed. Show less
Jonker, J.T.; Wang, Y.N.; Haan, W. de; Diamant, M.; Rijzewijk, L.J.; Meer, R.W. van der; ... ; Smit, J.W.A. 2010
Objective: Thiazolidinediones reduce hepatic steatosis and increase high-density lipoprotein (HDL)-cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic... Show moreObjective: Thiazolidinediones reduce hepatic steatosis and increase high-density lipoprotein (HDL)-cholesterol levels. In mice with human-like lipoprotein metabolism (APOE*3-Leiden.CETP transgenic mice), a decrease in hepatic triglyceride (TG) content is associated with a decrease in plasma cholesteryl ester transfer protein (CETP) mass and an increase in HDL levels. Therefore, the aim of the present study was to assess the effects of pioglitazone on CETP mass in patients with type 2 diabetes mellitus. Research Design and Methods: We included 78 men with type 2 diabetes mellitus (age 56.5+/-0.6 years; HbA1c 7.1+/-0.1%) who were randomized to treatment with pioglitazone (30 mg/day) or metformin (2000 mg/day) and matching placebos, in addition to glimepiride. At baseline and after 24 weeks of treatment plasma HDL-cholesterol levels and CETP mass were measured and hepatic TG content was assessed by proton magnetic resonance spectroscopy. Results: Pioglitazone decreased hepatic TG content (5.9 (2.6-17.4) vs. 4.1 (1.9-12.3)%, P<0.05), decreased plasma CETP mass (2.33+/-0.10 vs. 2.06+/-0.10 mug/mL, P<0.05) and increased plasma HDL-cholesterol levels (1.22+/-0.05 vs. 1.34+/-0.05 mM, P<0.05). Metformin did not significantly change any of these parameters. Conclusions: A decrease in hepatic TG content by pioglitazone is accompanied by a decrease in plasma CETP mass and associated with an increase in HDL-cholesterol levels. These results in patients with type 2 diabetes mellitus fully confirm recent findings in mice. Show less
HYPOTHESIS:: An objective cochlear framework, for evaluation of the cochlear anatomy and description of the position of an implanted cochlear implant electrode, would allow the direct comparison of... Show moreHYPOTHESIS:: An objective cochlear framework, for evaluation of the cochlear anatomy and description of the position of an implanted cochlear implant electrode, would allow the direct comparison of measures performed within the various subdisciplines involved in cochlear implant research. BACKGROUND:: Research on the human cochlear anatomy in relation to tonotopy and cochlear implantation is conducted by specialists from numerous disciplines such as histologists, surgeons, physicists, engineers, audiologists, and radiologists. To allow accurate comparisons between and combinations of previous and forthcoming scientific and clinical studies, cochlear structures and electrode positions must be specified in a consistent manner. METHODS:: Researchers with backgrounds in the various fields of inner ear research as well as representatives of the different manufacturers of cochlear implants (Advanced Bionics Corp., Med-El, Cochlear Corp.) were involved in consensus meetings held in Dallas, March 2005, and Asilomar, August 2005. Existing coordinate systems were evaluated, and requisites for an objective cochlear framework were discussed. RESULTS:: The consensus panel agreed upon a 3-dimensional, cylindrical coordinate system of the cochlea using the "Cochlear View" as a basis and choosing a z axis through the modiolus. The zero reference angle was chosen at the center of the round window, which has a close relationship to the basal end of the Organ of Corti. CONCLUSION:: Consensus was reached on an objective cochlear framework, allowing the outcomes of studies from different fields of research to be compared directly. Show less
Nascimento, E.B.M.; Snel, M.; Guigas, B.; Zon, G.C.M. van der; Kriek, J.; Maassen, J.A.; ... ; Ouwens, D.M. 2010
Type 2 diabetes is associated with alterations in protein kinase B (PKB/Akt) and mammalian target of rapamycin complex 1 (mTORC1) signalling. The proline-rich Akt substrate of 40-kDa (PRAS40) is a... Show moreType 2 diabetes is associated with alterations in protein kinase B (PKB/Akt) and mammalian target of rapamycin complex 1 (mTORC1) signalling. The proline-rich Akt substrate of 40-kDa (PRAS40) is a component of mTORC1, which has a regulatory function at the intersection of the PKB/Akt and mTORC1 signalling pathway. Phosphorylation of PRAS40-Thr246 by PKB/Akt, and PRAS40-Ser183 and PRAS40-Ser221 by mTORC1 results in dissociation from mTORC1, and its binding to 14-3-3 proteins. Although all phosphorylation sites within PRAS40 have been implicated in 14-3-3 binding, substitution of Thr246 by Ala alone is sufficient to abolish 14-3-3 binding under conditions of intact mTORC1 signalling. This suggests that phosphorylation of PRAS40-Thr246 may facilitate efficient phosphorylation of PRAS40 on its mTORC1-dependent sites. In the present study, we investigated the mechanism of PRAS40-Ser183 phosphorylation in response to insulin. Insulin promoted PRAS40-Ser183 phosphorylation after a euglycaemic-hyperinsulinaemic clamp in human skeletal muscle. The insulin-induced PRAS40-Ser183 phosphorylation was further evidenced in vivo in rat skeletal and cardiac muscle, and in vitro in A14 fibroblasts, 3T3L1 adipocytes and L6 myotubes. Inhibition of mTORC1 by rapamycin or amino acid deprivation partially abrogated insulin-mediated PRAS40-Ser183 phosphorylation in cultured cell lines. However, lowering insulin-induced PRAS40-Thr246 phosphorylation using wortmannin or palmitate in cell lines, or by feeding rats a high-fat diet, completely abolished insulin-mediated PRAS40-Ser183 phosphorylation. In addition, replacement of Thr246 by Ala reduced insulin-mediated PRAS40-Ser183 phosphorylation. We conclude that PRAS40-Ser183 is a component of insulin action, and that efficient phosphorylation of PRAS40-Ser183 by mTORC1 requires the phosphorylation of PRAS40-Thr246 by PKB/Akt. Show less
OBJECTIVE: /st> To assess the impact of different subsets of symptomatic hand osteoarthritis (OA) on pain and disability. METHODS: /st> From 308 patients with hand OA a group with... Show moreOBJECTIVE: /st> To assess the impact of different subsets of symptomatic hand osteoarthritis (OA) on pain and disability. METHODS: /st> From 308 patients with hand OA a group with carpometacarpal joint (CMCJ) symptoms only (group I, n=20) was identified as well as groups with symptoms at the interphalangeal joints (IPJs) only (group II, n=138), and symptoms at both sites (group III, n=150). Hand pain and function, assessed with the AUSCAN, were compared between groups using linear mixed models. Radiological OA was assessed using the Kellgren-Lawrence grading scale. RESULTS: /st> Mean (SD) AUSCAN scores for groups I, II and III were 23.1 (11.7), 18.3 (11.9) and 26.4 (12.5), respectively. After adjustment for age, gender, body mass index, family effects and number of symptomatic hand joints, significant differences in AUSCAN scores of 7.4 (95% CI 1.8 to 13.0) between groups I and II, and 5.7 (95% CI 2.7 to 8.6) between groups II and III were found. AUSCAN scores were 5.8 (95% CI 3.1 to 8.6) higher for patients with versus patients without CMCJ symptoms. Kellgren-Lawrence scores did not differ between groups. CONCLUSION: /st> In symptomatic hand OA, CMCJ OA contributes more to pain and disability than IPJ OA. Hence, treatment of CMCJ OA should be emphasised, even if it coincides with IPJ OA. Show less
